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Su, Tong, Bobby Kong, Calvin Huang, Jonathan Zhu, and Colleen McHugh. "Abstract 1533: Long non-coding RNA control of cancer cell growth." Cancer Research 82, no. 12_Supplement (2022): 1533. http://dx.doi.org/10.1158/1538-7445.am2022-1533.
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Abstract Long non-coding RNAs (lncRNAs) are involved in controlling regulatory networks critical for gene expression, cellular growth, and development. Altered expression of lncRNAs are associated with tumor progression in multiple types of human cancers, but the mechanisms by which lncRNAs may control growth and proliferation in cancer cells remain unknown in most cases. Development of interventions targeting non-coding RNA regulation of cell growth would open new avenues for cancer treatment. To identify growth regulatory pathways controlled by non-coding RNAs, we used proteomics and genomics tools to study the effect of changes in lncRNA expression levels in human cancer cell lines. First, we identified five growth regulator lncRNAs based on data mining of CRISPR/Cas9 screens and high throughput sequencing studies from patient tumor and normal cells. These lncRNAs have been associated with progression and metastasis in breast, lung and colon cancers. We hypothesized that growth regulator lncRNAs play a role in cancer development by recruiting effector proteins to regulate gene expression. Next, we evaluated the cellular growth phenotype for each lncRNA in overexpression and knockdown strains using multiple established cancer cell lines. We analyzed cellular transcriptome changes after lncRNA perturbation using high-throughput RNA sequencing. Finally, RNA-protein interactions for each growth regulator lncRNA were identified using an RNA hybridization capture method paired with mass spectrometry that enables purification of direct and specific endogenous RNA-binding proteins. Using this combination of transcriptomics and proteomics data, we discovered that perturbation of growth regulator lncRNAs results in dysregulation of growth signaling pathways and increased expression of p53. We are currently identifying the sequence and structure determinants of RNA-protein complex formation to uncover the mechanisms of action of lncRNAs in controlling cancer cell growth. Citation Format: Tong Su, Bobby Kong, Calvin Huang, Jonathan Zhu, Colleen McHugh. Long non-coding RNA control of cancer cell growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1533.
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Cao, Yu, Deliang Cao, and Hongyan Ling. "The novel long non-coding RNA PANCR: A p53 activator and potential breast cancer biomarkers." Journal of Clinical Oncology 35, no. 15_suppl (2017): e23016-e23016. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e23016.
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e23016 Background: Long non-coding RNAs (LncRNAs) may serve as a biomarker and potential therapeutic target of cancers. Chromosome 16q22.1 is frequently deleted in breast cancer and may contribute to breast carcinogenesis by inactivation of tumor suppressor genes. This study characterized a new LncRNA tumor suppressor in this region, named p53 activating non-coding RNA (PANCR). This LncRNA consists of 1.5kb in length. Methods: Quantitative real-time PCR was used for examine the PANCR expression in breast cancer tissues. RNA-pull down and RNA-Immunopreicitation were used to analyze PANCR targeted protein. Results: Our data showed that PANCR was downregulated in breast cancer cell lines and tissues. In the breast cancer cell lines, PANCR expression appeared reversely correlated with cell malignancy, and in breast cancer tissues, PANCR was downregulated over 2 times in 31(62.0%) of 50 cases compared to adjacent normal breast tissues. In breast cancer cells MCF7 and immortalized human mammary epithelial cells MCF10A, ectopic expression of PANCR induced marked apoptosis, suppressing cell proliferation in culture and tumor growth in xenografts, but in contrast, shRNA–mediated silencing of PANCR promoted cell growth and proliferation. Mechanistic approaches revealed that in both MCF7 and MCF10A cell, PANCR activated p53 and upregulated pro-apoptotic proteins bid and bim and cell cycle inhibitors p21waf/cip1 and p27Kip1. We further found that the PANCR binds to and activates p53 by dissociating the p53-MDM2 complex. We further characterized the functional domain of PANCR that interacts with p53. Conclusions: The LncRNA PANCR located in the deleted Chromosome 16q22.1 region is a novel intracellular p53 activator and tumor suppressor, which may be used as a target for cancer therapy through mimicking its binding domain and activation of p53.
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Zhao, Dongyan, Xizhen Sun, Sidan Long, and Shukun Yao. "An autophagy-related long non-coding RNA signature for patients with colorectal cancer." Physiology International 108, no. 2 (2021): 202–20. http://dx.doi.org/10.1556/2060.2021.00125.
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AbstractAimLong non-coding RNAs (lncRNAs) have been identified to regulate cancers by controlling the process of autophagy and by mediating the post-transcriptional and transcriptional regulation of autophagy-related genes. This study aimed to investigate the potential prognostic role of autophagy-associated lncRNAs in colorectal cancer (CRC) patients.MethodsLncRNA expression profiles and the corresponding clinical information of CRC patients were collected from The Cancer Genome Atlas (TCGA) database. Based on the TCGA dataset, autophagy-related lncRNAs were identified by Pearson correlation test. Univariate Cox regression analysis and the least absolute shrinkage and selection operator analysis (LASSO) Cox regression model were performed to construct the prognostic gene signature. Gene set enrichment analysis (GSEA) was used to further clarify the underlying molecular mechanisms.ResultsWe obtained 210 autophagy-related genes from the whole dataset and found 1187 lncRNAs that were correlated with the autophagy-related genes. Using Univariate and LASSO Cox regression analyses, eight lncRNAs were screened to establish an eight-lncRNA signature, based on which patients were divided into the low-risk and high-risk group. Patients’ overall survival was found to be significantly worse in the high-risk group compared to that in the low-risk group (log-rank p = 2.731E-06). ROC analysis showed that this signature had better prognostic accuracy than TNM stage, as indicated by the area under the curve. Furthermore, GSEA demonstrated that this signature was involved in many cancer-related pathways, including TGF-β, p53, mTOR and WNT signaling pathway.ConclusionsOur study constructed a novel signature from eight autophagy-related lncRNAs to predict the overall survival of CRC, which could assistant clinicians in making individualized treatment.
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Bareja, Chanchal, Apoorva Uboveja, and Daman Saluja. "Abstract 1560: Elucidating the differential regulation of novel long non coding RNAs and their mechanism of action in p73 dependent manner." Cancer Research 82, no. 12_Supplement (2022): 1560. http://dx.doi.org/10.1158/1538-7445.am2022-1560.
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Abstract INTRODUCTION: The p53 tumor suppressor family is classically activated after DNA damage and plays a central role in cell fate decisions. Although, the p53 family activates many of the same genes in response to DNA damage, p73 plays distinct biological functions in development and metastasis. It is likely that p73 activates a unique transcriptional network which is critical for its anti-metastatic and anti-invasive action. Long non-coding RNAs (lncRNAs) are a class of mRNA-like transcripts longer than 200 nucleotides. They lack protein-coding ability and are believed to be involved in various kinds of biological processes. Increasing evidence suggests that lncRNA are frequently aberrantly expressed in cancers. Therefore, the roles of dysregulated functional lncRNA in human malignant tumors have attracted considerable scientific interest. The objective of our study is to find out novel long non-coding RNAs that can act as transcriptional targets of p73 and to delineate their role in p73-mediated anti-metastatic response. METHODS: For this purpose, we performed transcriptome sequencing in HCT116p73wt and HCT116p73KD cells and screened the data for modulation of expression of lncRNAs in differential manner. Quantitative Real Time PCR was further carried out to validate the data obtained after screening RNA seq Data. Promoter analysis was carried out for the identification of p73 binding sites in the selected upregulated or downregulated lncRNAs which was further confirmed by Luciferase reporter, ChIP and site directed mutagenesis assays. RESULTS: About six lncRNAs were observed to be significantly upregulated while four were down-regulated upon knockdown of p73. The promoters of selected lncRNAs were analysed in silico using TF Bind and JASPAR software for p73 binding sites and luciferase reporter assays suggested regulation of lncRNAs by p73. Chromatin immunoprecipitation showed promoter enrichment of the selected lncRNAs. Site directed mutagenesis further confirmed the exact binding sites of p73 onto the promoters of these novel long non coding RNAs. CONCLUSION: Together, our study provides insights into the differential regulation of long non-coding RNAs in p73 dependent manner which further will provide the mechanism of their action at the genome level. Citation Format: Chanchal Bareja, Apoorva Uboveja, Daman Saluja. Elucidating the differential regulation of novel long non coding RNAs and their mechanism of action in p73 dependent manner [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1560.
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Wang, Li, Zhenhong Chen, Li An, et al. "Analysis of Long Non-Coding RNA Expression Profiles in Non-Small Cell Lung Cancer." Cellular Physiology and Biochemistry 38, no. 6 (2016): 2389–400. http://dx.doi.org/10.1159/000445591.
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Background/Aims: Long non-coding RNAs (lncRNAs) play an important role in tumorigenesis. However, the role of lncRNA expression in human Non-small cell lung cancer (NSCLC) biology, prognosis and molecular classification remains unknown. Methods: We established the IncRNA profile in NSCLC by re-annotation of microarrays from the Gene expression omnibus database. Quantitative real-time PCR was used to determine expression of LINC00342. Results: 6066 differentially expressed IncRNAs were identified and we found a novel IncRNA, LINC00342 was significantly up-regulated in NSCLC tissues compared with normal tissues. We confirmed the over-expression of LINC00342 in a cohort of NSCLC patients and found LINC00342 expression level was positively correlated with lymph node metastasis and TNM stages. Furthermore, in a large online database of 1942 NSCLC patients, high expression of LINC00342 indicated poor Overall survival (HR = 1.28, 95% CI: 1.13-1.45) and post progression survival (HR = 1.43, 95% CI: 1.09-1.88). Bioinformatics analyses showed that LINC00342 was co-expressed with different protein-coding genes in NSCLC and normal tissues. Additionally, gene set enrichment analyses found that PTEN and P53 pathways genes were enriched in the groups with higher LINC00342 expression level. By small interfering RNAs mediated silence of LINC00342, proliferation ability was significantly inhibited in lung cancer cell line. Conclusion: To summary, our findings indicate that a set of IncRNAs are differentially expressed in NSCLC and we characterized a novel IncRNA, LINC00342 which is significantly up-regulated in NSCLC and could be a prognostic biomarker.
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Zhou, Yaodong, and Qing Xia. "LncRNA H19 Promotes Lung Adenocarcinoma Progression via Binding to Mutant p53 R175H." Cancers 14, no. 18 (2022): 4486. http://dx.doi.org/10.3390/cancers14184486.
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Background: Accumulating data suggest that long non-coding RNA (lncRNA) H19 and p53are closely related to the prognosis of lung cancer. This study aims to analyze the association and interaction betweenH19 and mutant p53 R175H in lung adenocarcinoma (LAC). Methods: Mutant-type (Mt) p53 R175H was assessed by using RT-PCR in LAC cells and 100 cases of LAC tissue samples for association with H19 expression. Western blot, RNA-pull down, immunoprecipitation-Western blot and animal experiments were used to evaluate the interaction between H19 and mtp53. Results: Mtp53 R175H and H19 were over-expressed in LAC tissues and cells, while H19 over-expression extended the p53 half-life and enhanced transcriptional activity. Combined with anti-p53, ShH19 can significantly inhibit tumor growth in vivo. Conclusions: H19 over-expression may induce the elevated expression of mtp53 and interact with mtp53, leading to LAC progression. In addition, the high expression of mtp53 R175H is associated with poor overall survival inpatients. The simultaneous inhibition of H19 and mtp53 may provide a novel strategy for the effective control of LAC clinically.
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Toraih, Eman A., Aya El-Wazir, Mohammad H. Hussein, et al. "Expression of long intergenic non-coding RNA, regulator of reprogramming, and its prognostic value in patients with glioblastoma." International Journal of Biological Markers 34, no. 1 (2019): 69–79. http://dx.doi.org/10.1177/1724600818814459.
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Background: Long intergenic non-coding RNA, regulator of reprogramming ( LINC-ROR) is a newly identified cytoplasmic long non-coding RNA (lncRNA), which has been found to be dysregulated in different cancers. The present work aimed to quantify LINC-ROR expression profile and assess the tumor proteins p53 and caspase 3 expressions in glioblastoma tissue specimens compared to non-cancer tissues, and to correlate these expression levels with the available clinicopathological and survival data. Methods: LINC-ROR relative expression in 57 glioblastoma cancer tissues and 10 non-cancer tissues was quantified by real-time polymerase chain reaction (qPCR). In addition, methylation-specific PCR of O-6-methylguanine-DNA methyltransferase ( MGMT) promoter and immunohistochemical expression of apoptosis related proteins: p53 and caspase 3 were performed. Results: The up-regulation of LINC-ROR was encountered in 89.5% of patients. The higher expression of LINC-ROR was associated with poor disease progression-free and overall survival as well as a younger age of patients ( P=0.036). p53 protein was expressed only in glioblastoma but not in non-cancer tissues while caspase 3 was weakly expressed in most non-cancer tissues and in varying degrees in glioblastoma (24% weak, 30% moderate, and 16% strong expression). The Kaplan–Meier survival plot illustrated poor survival in glioblastoma patients with over-expressed LINC-ROR ( P=0.010) and down-regulated p53 ( P=0.002). Multivariate analysis showed that glioblastoma patients were clustered into two distinct groups based on LINC-ROR expression profile, p53 staining levels and patients’ overall survival. Conclusions: LINC-ROR up-regulation may have a role in glioblastoma tumorigenesis and could be a potential prognostic marker for this fatal disease.
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Chen, Qiongyun, Xiaoqing Huang, Xuan Dong, Jingtong Wu, Fei Teng, and Hongzhi Xu. "Long non-coding RNA ERICH3-AS1 is an unfavorable prognostic factor for gastric cancer." PeerJ 8 (January 28, 2020): e8050. http://dx.doi.org/10.7717/peerj.8050.
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Long non-coding RNAs (lncRNAs) play important roles in gastric cancer (GC), but the mechanism is not fully clear. ERICH3-AS1 (ERICH3 antisense RNA1) is affiliated with the non-coding RNA class which has proven to be involved in the prognostic of GC, but the function of ERICH3-AS1 is still unclear. In this study, we aim to explore the potential function of ERICH3-AS1 in the development of GC and analyze the prognostic role of ERICH3-AS1 in GC. We found that the lncRNA ERICH3-AS1 was significantly up-regulated in GC tissues in the analysis of The Cancer Genome Atlas (TCGA) data; the Kaplan-Meier analysis showed that the higher the expression of ERICH3-AS1 was, the earlier the recurrence and the poorer the prognosis would be in patients. Cox univariate and multivariate analyses revealed that ERICH3-AS1 was a risk factor of disease-free survival (DFS) (p < 0.05) and overall survival (OS) (p < 0.05) of patients. Through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, it demonstrated that the ERBB pathways, the mitogen-activated protein kinase (MAPK) pathways, the MTOR pathways, p53 pathways and Wnt pathways were differentially enriched in ERICH3-AS1 high expression phenotype. Furthermore, the correlation analysis showed that ERICH3-AS1 had significant correlations with apoptosis-related proteins such as BCL2L10 and CASP14; cell cycle-associated proteins CDK14 and invasion and migration-associated proteins such as MMP20, MMP26 and MMP27. In summary, we identified that increased ERICH3-AS1 might be a potential biomarker for diagnosis and independent prognostic factor of GC. Moreover, ERICH3-AS1 might participate in the oncogenesis and development of tumors via cell cycle and apoptosis pathway mediated by ERBB, MAPK, MTOR, p53 and Wnt pathways.
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Lai, Xiaojia Zuo, Xintong Yang, et al. "PATH-03. FERROPTOSIS-RELATED LONG NON-CODING RNA SIGNATURES PREDICT PROGNOSIS IN PATIENTS WITH GLIOMA." Neuro-Oncology 23, Supplement_6 (2021): vi115. http://dx.doi.org/10.1093/neuonc/noab196.456.
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Abstract Ferroptosis, with iron-dependent and ROS-dependent, is a novel type of cell death in a variety of diseases and some studies confirmed that ferroptosis-related lncRNAs are involved in the occurrence and development of several cancers. However, the ferroptosis-related lncRNA in the role of gliomas is unclear. Here, we constructed a prognostic scoring model of ferroptosis-related lncRNAs in gliomas. Data were downloaded from the Chinese glioma genome atlas (CGGA), the cancer genome atlas, and FerrDb database. In this study, we found 1051 lncRNAs associated with ferroptosis by Spearman's rank correlation analysis in CGGA653, and 547 lncRNAs were related to prognosis in gliomas. Subsequently, we identified 9 ferroptosis-related signatures (AC010729.2, AC062021.1, FAM225B, FAM66C, HOXA-AS2, LINC00662, LINC00665, MIR497HG, and TMEM72-AS1) by least absolute shrinkage and selection operator and Cox proportional hazards model. Next, all glioma patients were divided into high- and low-risk groups based on the median risk score based on these signatures, and the low-risk group had better prognosis significantly than the high-risk group by Kaplan-Meier curve. Moreover, the risk score can predict survival status with high sensitivity and specificity by receiver operating characteristic curve (area under the curve at 1, 3, 5 years: 0.791, 0.84, 0.856, respectively). In addition, some pathways (cell cycle, p53 signaling pathway, apoptosis, and oxidative phosphorylation) significantly enriched in KEGG enrichment pathway, and a nomogram was constructed by integrating some independent prognostic clinicopathological features to predict the overall survival in gliomas (C-index: 0.786). In summary, these 9 ferroptosis-related signatures have potential prognostic value and could be crucial factors for treating malignant gliomas.
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Pal, Sonali, Manoj Garg, and Amit Kumar Pandey. "Deciphering the Mounting Complexity of the p53 Regulatory Network in Correlation to Long Non-Coding RNAs (lncRNAs) in Ovarian Cancer." Cells 9, no. 3 (2020): 527. http://dx.doi.org/10.3390/cells9030527.
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Amongst the various gynecological malignancies affecting female health globally, ovarian cancer is one of the predominant and lethal among all. The identification and functional characterization of long non-coding RNAs (lncRNAs) are made possible with the advent of RNA-seq and the advancement of computational logarithm in understanding human disease biology. LncRNAs can interact with deoxyribonucleic acid (DNA), ribonucleic acid (RNA), proteins and their combinations. Moreover, lncRNAs regulate orchestra of diverse functions including chromatin organization and transcriptional and post-transcriptional regulation. LncRNAs have conferred their critical role in key biological processes in human cancer including tumor initiation, proliferation, cell cycle, apoptosis, necroptosis, autophagy, and metastasis. The interwoven function of tumor-suppressor protein p53-linked lncRNAs in the ovarian cancer paradigm is of paramount importance. Several lncRNAs operate as p53 regulators or effectors and modulates a diverse array of functions either by participating in various signaling cascades or via interaction with different proteins. This review highlights the recent progress made in the identification of p53 associated lncRNAs while elucidating their molecular mechanisms behind the altered expression in ovarian cancer tumorigenesis. Moreover, the development of novel clinical and therapeutic strategies for targeting lncRNAs in human cancers harbors great promise.
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Di Agostino, Silvia. "The Impact of Mutant p53 in the Non-Coding RNA World." Biomolecules 10, no. 3 (2020): 472. http://dx.doi.org/10.3390/biom10030472.
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Long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), micro RNAs (miRNAs), and extracellular RNAs (exRNAs) are new groups of RNAs with regulation activities that have low or no protein-coding ability. Emerging evidence suggests that deregulated expression of these non-coding RNAs is associated with the induction and progression of diverse tumors throughout epigenetic, transcriptional, and post-transcriptional modifications. A consistent number of non-coding RNAs (ncRNAs) has been shown to be regulated by p53, the most important tumor suppressor of the cells frequently mutated in human cancer. It has been shown that some mutant p53 proteins are associated with the loss of tumor suppressor activity and the acquisition of new oncogenic functions named gain-of-function activities. In this review, we highlight recent lines of evidence suggesting that mutant p53 is involved in the expression of specific ncRNAs to gain oncogenic functions through the creation of a complex network of pathways that influence each other.
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Chen, Zihao, Hongping Ju, Shan Yu, et al. "Prader–Willi region non-protein coding RNA 1 suppressed gastric cancer growth as a competing endogenous RNA of miR-425-5p." Clinical Science 132, no. 9 (2018): 1003–19. http://dx.doi.org/10.1042/cs20171588.
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Gastric cancer (GC) is one of the major global health problems, especially in Asia. Nowadays, long non-coding RNA (lncRNA) has gained significant attention in the current research climate such as carcinogenesis. This research desires to explore the mechanism of Prader–Willi region non-protein coding RNA 1 (PWRN1) on regulating GC process. Differentially expressed lncRNAs in GC tissues were screened out through microarray analysis. The RNA and protein expression level were detected by quantitative real-time PCR (qRT-PCR) and Western blot. Cell proliferation, apoptosis rate, metastasis abilities were respectively determined by cell counting kit 8 (CCK8), flow cytometry, wound healing, and transwell assay. The luciferase reporter system was used to verify the targetting relationships between PWRN1, miR-425-5p, and phosphatase and tensin homolog (PTEN). RNA-binding protein immunoprecipitation (RIP) assay was performed to prove whether PWRN1 acted as a competitive endogenous RNA (ceRNA) of miR-425-5p. Tumor xenograft model and immunohistochemistry (IHC) were developed to study the influence of PWRN1 on tumor growth in vivo. Microarray analysis determined that PWRN1 was differently expressed between GC tissues and adjacent tissues. qRT-PCR revealed PWRN1 low expression in GC tissues and cells. Up-regulated PWRN1 could reduce proliferation and metastasis and increase apoptosis in GC cells, while miR-425-5p had reverse effects. The RIP assay indicated that PWRN1 may target an oncogene, miR-425-5p. The tumor xenograft assay found that up-regulated PWRN1 suppressed the tumor growth. The bioinformatics analysis, luciferase assay, and Western blot indicated that PWRN1 affected PTEN/Akt/MDM2/p53 axis via suppressing miR-425-5p. Our findings suggested that PWRN1 functioned as a ceRNA targetting miR-425-5p and suppressed GC development via p53 signaling pathway.
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Zhang, Ying, Feng Yuan, Cassandra Grello, et al. "CSIG-07. GAIN-OF-FUNCTION MUTANT P53 REGULATES LONG-NONCODING RNAS IN GLIOBLASTOMA." Neuro-Oncology 24, Supplement_7 (2022): vii39—vii40. http://dx.doi.org/10.1093/neuonc/noac209.156.
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Abstract P53 is frequently mutated in most human cancers, including glioblastoma (GBM). Many p53 mutants acquire gain-of-function oncogenic effects through only partially understood mechanisms. To investigate the role of gain-of-function mutant p53 (MUT-p53) in GBM, we performed ChIP-seq of wildtype p53 (WT-p53) and MUT-p53 GBM cell lines. Among 2834 unique peaks reads in MUT-p53 cells, we found 242 long non-coding RNAs (lncRNAs) with up to 145 fold enrichment relative to WT-p53. LncRNAs regulate many molecular and cellular functions, including gene expression, cell proliferation, death, cancer stem cell renewal and differentiation. We selected lncRNAs SOX21-AS1 and LINC00643 with highly enriched binding by MUT-p53 and investigated their expressions and functions in the p53 pathway. We performed ChIP confirmation of MUT-p53 binding to the promoters of these lncRNAs. We found that these lncRNAs are deregulated in GBM and correlated with GBM patient survival in the TCGA database. To investigate the functions of these LncRNAs, we knocked down their expressions by siRNA, and found significant cell death induced by si-SOX21-AS1, but not by si-LINC00643. Overexpression of LINC00643 in GBM cells led to inhibition of GBM cell proliferation, migration, invasion and in vivo xenograft growth. LINC00643 mediated the effects of MUT-p53. Co-expression of human LINC00643 and its mouse homologous in a RCAS transgenic mouse model of GBM reduced tumor growth and improved animal survival. To elucidate the mechanisms of action of the lncRNA, we performed Chromatin Isolation by RNA purification high-throughput sequencing (CHIRP-seq) to identify its binding targets. We found that LINC00643 binds to HIF1a 5’ promoter/enhancer region. Overexpression of LINC00643 in GBM cells at hypoxia growth condition reduced HIF1a mRNA and protein expression. Our study shows for the first time that gain-of-function mutant p53 regulates a subset of lncRNAs and that the lncRNAs mediate the oncogenic effects of the MUT-p53 in GBM.
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Lee, Yoonsung, and Young-Seuk Bae. "Long Non-Coding RNA KCNQ1OT1 Regulates Protein Kinase CK2 Via miR-760 in Senescence and Calorie Restriction." International Journal of Molecular Sciences 23, no. 3 (2022): 1888. http://dx.doi.org/10.3390/ijms23031888.
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Long non-coding RNAs (lncRNAs) play important biological roles. Here, the roles of the lncRNA KCNQ1OT1 in cellular senescence and calorie restriction were determined. KCNQ1OT1 knockdown mediated various senescence markers (increased senescence-associated β-galactosidase staining, the p53-p21Cip1/WAF1 pathway, H3K9 trimethylation, and expression of the senescence-associated secretory phenotype) and reactive oxygen species generation via CK2α downregulation in human cancer HCT116 and MCF-7 cells. Additionally, KCNQ1OT1 was downregulated during replicative senescence, and its silencing induced senescence in human lung fibroblast IMR-90 cells. Additionally, an miR-760 mimic suppressed KCNQ1OT1-mediated CK2α upregulation, indicating that KCNQ1OT1 upregulated CK2α by sponging miR-760. Finally, the KCNQ1OT1–miR-760 axis was involved in both lipopolysaccharide-mediated CK2α reduction and calorie restriction (CR)-mediated CK2α induction in these cells. Therefore, for the first time, this study demonstrates that the KCNQ1OT1–miR-760–CK2α pathway plays essential roles in senescence and CR, thereby suggesting that KCNQ1OT1 is a novel therapeutic target for an alternative treatment that mimics the effects of anti-aging and CR.
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Saluja, Daman, Apoorva Uboveja, Yatendra kumar Satija, and Fouzia Siraj. "Abstract 1552: Deciphering the mechanism of action of Long non-coding RNA fer1l4 in the suppression of invasion, migration and metastasis of colon cell carcinoma." Cancer Research 82, no. 12_Supplement (2022): 1552. http://dx.doi.org/10.1158/1538-7445.am2022-1552.
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Abstract Introduction: p73 transcription factor belongs to the p53 tumor suppressor family. Recent studies revealed that p73 wields its tumor suppressor properties by inhibiting metastasis. Although the literature on the p73 transcriptional circuit has chiefly concentrated on protein-coding genes, it has been progressively pointed out that p73 is also able to transcriptionally modulate non-coding RNA (ncRNA) members. These involve microRNAs (miRNAs) and many p53-regulated long non-coding RNAs (lncRNAs). Methods: Identification of p73 binding sites in the FER1L4 promoter region was made by JASPER and TF BIND which was further confirmed by chromatin immunoprecipitation (ChIP) and site-directed mutagenesis experiments. Effect of FER1L4 in p73 mediated cell cycle arrest and apoptosis was checked by cell cycle analysis, Annexin-V/PI, and TUNEL apoptosis assays. Depletion of FER1L4 enhanced cell proliferation, migration, and invasion in a p73-dependent manner. Furthermore, RNA-In situ hybridization (RNA-ISH) analysis of non-metastatic and metastatic human colon cancer tissue samples was carried out to compare the levels of FER1L4 and p73 in metastatic and non-metastatic tumor tissue samples. We also checked the expression of different miRNA including miR1273g-3p and its effect on PTEN expression. Results: We have identified lncRNA FER1L4 as a novel p73 transcriptional target that gets induced as a result of genotoxic stress. The binding of p73 to FER1L4 promoter was established by bioinformatics analysis, luciferase reporter, and ChIP assays. Both FER1L4 and p73 knockdown enhanced the migration and invasion rate of colorectal cancer cells. FER1L4 knockdown reduced E-cadherin expression and enhanced the expression of N-cadherin, Vimentin, Snail, and Fibronectin. Cell cycle assays revealed that FER1L4 induces a G2/M cell cycle arrest in a p73-dependent manner. Annexin V/PI and TUNEL assays revealed FER1L4 induced apoptosis in HCT116p53-/-p73+/+ colon cancer cells under genotoxic stress and FER1L4 knockdown inhibited apoptosis even in the presence of p73. The expression of pro-apoptotic markers such as Bad, Bax, Bik, Bim, Bid, Bak and PUMA decreased upon FER1L4 and p73 knockdown. FER1L4 sponges the expression of miR-1273g-3p, which in turn increases PTEN expression leading to cell cycle arrest. RNA In-situ hybridization revealed the down-regulation of both p73 and FER1L4 expression in metastatic colon cancer tissue as compared to non-metastatic tissue. Conclusion: We provide conclusive proof that p73 exerts its anti-metastatic properties by inducing lncRNA FER1L4 in response to genotoxic stress which in turn sponges the expression of miR1273g-3p, a regulator of PTEN. Citation Format: Daman Saluja, Apoorva Uboveja, Yatendra kumar Satija, Fouzia Siraj. Deciphering the mechanism of action of Long non-coding RNA fer1l4 in the suppression of invasion, migration and metastasis of colon cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1552.
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Su, Pengxiao, Fengqin Wang, Bin Qi, Ting Wang, and Shaobo Zhang. "P53 Regulation-Association Long Non-Coding RNA (LncRNA PRAL) Inhibits Cell Proliferation by Regulation of P53 in Human Lung Cancer." Medical Science Monitor 23 (April 11, 2017): 1751–58. http://dx.doi.org/10.12659/msm.900205.
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Wang, Yanqiang, Huiling He, Wei Li, et al. "MYH9 binds to lncRNA genePTCSC2and regulatesFOXE1in the 9q22 thyroid cancer risk locus." Proceedings of the National Academy of Sciences 114, no. 3 (2017): 474–79. http://dx.doi.org/10.1073/pnas.1619917114.
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A locus on chromosome 9q22 harbors a SNP (rs965513) firmly associated with risk of papillary thyroid carcinoma (PTC). The locus also comprises the forkhead box E1 (FOXE1) gene, which is implicated in thyroid development, and a long noncoding RNA (lncRNA) gene, papillary thyroid cancer susceptibility candidate 2 (PTCSC2). How these might interact is not known. Here we report thatPTCSC2binds myosin-9 (MYH9). In a bidirectional promoter shared byFOXE1andPTCSC2, MYH9 inhibits the promoter activity in both directions. This inhibition can be reversed byPTCSC2, which acts as a suppressor. RNA knockdown ofFOXE1in primary thyroid cells profoundly interferes with the p53 pathway. We propose that the interaction between the lncRNA, its binding protein MYH9, and the coding geneFOXE1underlies the predisposition to PTC triggered by rs965513.
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Zhu, Kangle, Qingqing Wang, and Lian Wang. "Analysis of Competitive Endogenous RNA Regulatory Network of Exosomal Breast Cancer Based on exoRBase." Evolutionary Bioinformatics 18 (January 2022): 117693432211132. http://dx.doi.org/10.1177/11769343221113286.
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Objective: To construct a competitive endogenous RNA (ceRNA) regulatory network derived from exosomes of human breast cancer (BC) by using the exoRbase database, to explore the possible pathogenesis of BC, and to develop new targets for future diagnosis and treatment. Methods: The exosomal gene sequencing data of BC patients and normal controls were downloaded from the exoRbase database, and the expression profiles of exosomal mRNA, long non-coding RNA (lncRNA), and circular RNA (circRNA) were analyzed by using R language. Use Targetscan and miRanda database to jointly predict and differentially express miRNA (microRNA), miRNA combined with mRNA. The miRcode database was used to predict the miRNA combined with differentially expressed lncRNA, and the starBase database was used to predict the miRNA combined with circRNA in the difference table. The related mRNA, circRNA, lncRNA, and their corresponding miRNA prediction data were imported into Cytoscape software to visualize the ceRNA network. Enrichment analysis and visualization of KEGG were carried out using KOBAS. Hub gene was determined by Cytohubba plug-in. Results: Forty-two differentially expressed mRNA, 43 differentially expressed circRNA, and 26 differentially expressed lncRNA were screened out. The ceRNA network was constructed by using Cytoscape software, including 19 mRNA nodes, 2 lncRNA nodes, 8 circRNA nodes, and 41 miRNA nodes. KEGG enrichment analysis showed that differentially expressed mRNA in the regulatory network mainly enriched the p53 signaling pathway. Find the key Hub gene PTEN. Conclusion: The ceRNA regulatory network in blood exosomes of BC patients has been successfully constructed in this study, which provides an exact target for the diagnosis and treatment of BC.
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Watanabe, Saki, Tsukasa Oda, Yuko Kuroda, et al. "Long Non-Coding RNA NEAT1 Is Upregulated By Heat Shock Factor 1 (HSF1) and Associated with Multiple Myeloma Progression." Blood 132, Supplement 1 (2018): 1904. http://dx.doi.org/10.1182/blood-2018-99-113720.
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Abstract Background and Aims: Recent transcriptome-wide analyses have revealed an overwhelming amount of transcribed but not translated non-coding RNAs capable of influencing diverse cellular processes, such as proliferation, apoptosis, and cellular damage response. Long non-coding RNA (lnc RNA), which are commonly defined as transcripts >200 nt in length, have emerged as a class of key regulatory RNA. LncRNA are deregulated in diverse human cancers and associated with disease progression, however little is available in multiple myeloma (MM). We have previously shown that lnc RNA MALAT1 was a stress response gene associated with MM progression. We found that lnc RNA NEAT1 is also highly expressed in MM cells by transcriptome analysis with next generation sequencer (NGS). NEAT1 is recently revealed to play an important role on DNA damage response (DDR) as downstream of p53, and thereby involves in carcinogenesis. However its exact role in cancers is still in controversy. In this study, we tried to elucidate role and regulation mechanism of NEAT1 during MM progression. Materials and Methods: Total 119 MM, 47 MGUS patients and 15 controls and 9 MM cell lines are subjected to the study after informed consent. The study was approved by IRB following Declaration of Helsinki. NEAT1 and its longer isoform NEAT1_2 RNA expressions were determined by RQ-PCR. RNA was extracted from purified CD138+ plasma cells from bone marrow (BM) mononuclear cells. The expression levels were normalized with ACTB and calculated with delta Ct value. Whole transcriptome analysis was performed in part of the samples by using Illumina Next Seq 500. MM cell lines transfected with tet-on p53 overexpression vector or tet-on sh-RNA HSF1 were used. RNase H-activating LNA™ GapmeR antisense oligonucleotides were used to knockdown lnc RNA in vitro. Results: The expression level of NEAT1 was significantly higher in MM (median 0.97) than MGUS (median 0.31) (p<0.0001). NEAT1 level did not differ in between control (median 0.38) and MGUS (p=0.97). Although the median level was not statistically different (0.046 in MM; 0.031 in MGUS; 0.127 in control), substantial number of MM cases showed very high level of NEAT1_2. In MM samples, both NEAT1 and NEAT1_2 expression did not differ according to ISS (p=0.52, p=0.29) and cytogenetic risk group (p=0.49, p=0.203). NEAT1 and MALAT1 expression was positively correlated (r=0.632, p<0.0001 in all samples, r=0.62, p<0.0001 in MM only). NEAT1_2 was also positively correlated with MALAT1 expression (r=0.49, p<0.0001 in MM), and NEAT1 (r=0.35, p<0.0001 in MM). NEAT1 expression level and RNA structure were confirmed by transcriptome analysis with NGS. Since p53 promotes NEAT1/NEAT1_2 expression, we checked correlation in between these two genes expression levels. NEAT1 expression were positively correlated with both p53 and p21 (r=0.30, p<0.0001, r=0.41, p<0.0001). Positive correlations were also found in between NEAT1 and HSP90s (r=0.29, p=0.029 with HSP90AA1, r=0.29, p=0.029 with HSP90AB1, r=0.411, p=0.0018 with HSP90B1). NEAT1 was upregulated by MDM2 inhibitor nutlin3A in p53 wild type cell lines and by tet-on p53 overexpression in p53 null KMS11. Interestingly bortezomib and doxorubicin significantly increased NEAT1 and NEAT1_2 by 5-10 folds in MM cell lines even in p53 null KMS11. HSP90 inhibitors did not affect NEAT1/NEAT1_2 expression, but inhibition of HSF1, which is upstream transcription factor of HSP90, by either HSF1 inhibitor KNK437 or tet-on sh-HSF1 attenuated NEAT1/NEAT1_2 expression induced by bortezomib. NEAT1 knockdown by GapmeR did not affect cell growth. Overall survival and progression free survival of the newly diagnosed MM patients did not differ in between high and low NEAT1/NEAT1_2 expression. Conclusion: Our results revealed that NEAT1/NEAT1_2 are regulated by heat shock pathway in addition to p53 pathway. Positive correlations of NEAT1 expression level with HSP90s level and existence of heat shock element in NEAT1 promoter region support this model. Considering the role of NEAT1/NEAT1_2 in DDR, our result suggests that this lncRNA may involve MM progression via damage response. Further studies elucidating roles of NEAT1 and other lncRNAs in MM contributes to development of novel therapy as well as to understand MM pathogenesis. Disclosures Tsukamoto: Kyowa-Kirin: Research Funding; Chugai: Research Funding; Eisai: Research Funding; Pfizer: Research Funding. Handa:Celgene: Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau.
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Song, Fang, and Fengshuang Li. "Long Non-Coding RNA F11-Antisense 1 (F11-AS1) Suppresses Ovarian Cancer Biological Activity by Regulating Phosphatase and Tensin Homolog Deleted on Chromosome Ten (PTEN)." Journal of Biomaterials and Tissue Engineering 11, no. 9 (2021): 1752–59. http://dx.doi.org/10.1166/jbt.2021.2632.
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Aim: To discuss F11-AS1’s effects and mechanisms in ovarian cancer development. Methods: Evaluating F11-AS1 expression by ISH assay and F11-AS1 mRNA level in difference cell lines by RT-qPCR assay. Using MTT, flow cytometry, transwell and wound healing assay to evaluate SKOV3 cell proliferation, cell apoptosis, invasion and migration. And using WB assay to measure PTEN, p-PI3K, AKT, P53 and MMP-9 proteins expressions. Results: F11-AS1 was significantly down-regulation with stage increasing in cancer tissues (P <0.01, respectively). With F11-AS1 transfection, the SKOV3 cell proliferation rate was significantly depressed with cell apoptosis and G1 phase rate significantly increasing (P <0.001, respectively). And then, invasion cell number and wound healing rate of lncRNA group which transfected with F11-AS1 significantly down-regulation (P <0.001). By WB assay, PTEN and P53 proteins expressions significantly up-regulation and p-PI3K, AKT and MMP-9 proteins expressions were significantly down-regulation (P <0.001). Conclusion: F11-AS1 depresses ovarian cancer biological activity by regulating PTEN by vitro study.
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Lu, Xiyi, Chenjun Huang, Xuezhi He, et al. "A Novel Long Non-Coding RNA, SOX21-AS1, Indicates a Poor Prognosis and Promotes Lung Adenocarcinoma Proliferation." Cellular Physiology and Biochemistry 42, no. 5 (2017): 1857–69. http://dx.doi.org/10.1159/000479543.
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Background: In recent years, long non-coding RNAs (lncRNAs) have been shown to be a novel class of regulators of cancer biological processes. Although lncRNAs are dysregulated in numerous cancer types, limited data are available on the expression profiles and potential functions of lncRNAs in lung adenocarcinoma (LUAD). This study evaluated the expression and biological roles of lncRNA SOX21 antisense RNA 1 (SOX21-AS1) in LUAD. Methods: Quantitative reverse transcription PCR (qRT-PCR) was performed to detect the expression levels of SOX21-AS1 in 68 pairs of LUAD tissues and corresponding non-tumor tissues. The effect of SOX21-AS1 on proliferation was evaluated by MTT, colony formation, EdU assays, flow-cytometric analysis and in vivo tumor formation assays. Real-time PCR, western-blot and immunohistochemistry were used to evaluate the mRNA and protein expression of p57. Results: Higher expression levels of SOX21-AS1 positively correlated with tumor size and advanced tumor–node–metastasis (TNM) stage. Multivariate analyses indicated that SOX21-AS1 expression could serve as an independent prognostic factor for overall survival of LUAD. Furthermore, knockdown of SOX21-AS1 significantly inhibited LUAD cell proliferation both in vitro and in vivo and induced cell cycle phase arrest and cell apoptosis. Importantly, through qRT-PCR and western blot analysis, we found that inhibition of SOX21-AS1 remarkably induced p57 expression. Conclusions: Collectively, our study demonstrates that SOX21-AS1 is involved in the development and progression of LUAD and that SOX21-AS1 may be a potential diagnostic factor as well as a target for new therapies for patients with LUAD.
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Diaz-Beya, Marina, Alfons Navarro, Anna Cordeiro, et al. "Exploring the Expression Profile of Long Non-Coding RNA (lncRNA) in Different Acute Myeloid Leukemia (AML) Subtypes: t(8;16)(p11;p13)/MYST3-Crebbp AML Harbors a Distinctive Lncrna Signature." Blood 126, no. 23 (2015): 1397. http://dx.doi.org/10.1182/blood.v126.23.1397.1397.
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Abstract Introduction: Long non-coding RNAs (lncRNAs) have recently emerged as important actors in the regulation of multiple cellular processes including cancer. Acute myeloid leukemia (AML) is a heterogeneous disease; most of the main cytogenetic AML subgroups harbor a specific gene expression profile. AML with translocation t(8;16)(p11;p13) (t(8;16) AML) is a subtype with specific clinical and biological characteristics including a distinctive gene (Camós et al, Cancer Research 2006) and microRNA (Díaz-Beyá et al, Leukemia 2013) expression profile. In this translocation, MYST3 on chromosome 8p11 fuses with CREBBP on chromosome 16p13.3. The MYST3-CREBBP fusion protein is able to interact with multiple transcription factors (TF) producing a disturbed transcriptional program. However, the lncRNA expression pattern of different cytogenetic AML subtypes, including t(8;16) AML, have not been described yet. Aims: To examine the expression profile of lncRNAs within different AML subtypes, and to characterize the expression pattern of lncRNAs in t(8;16) AML in comparison to other AML subtypes. Patients and Methods: 46 AML patients, 4 normal bone marrow (NBM) and 3 CD34+ NBM samples were included in the study. Samples included different AML subtypes: intermediate-risk cytogenetic AML (IR-AML, n=18), t(15;17) (APL, n=4), t(8;21) AML (n=4), inv(16) AML(n=2), t(6;9) AML (n=7), AML with monosomal karyotype (n=4), t(3;3) AML (n=1), t(9;11) AML (n=1) and t(8;16) AML (n=5). Within IR-AML patients with a different mutational profile: FLT3-ITD (n=7), NPM1 (n=5), CEBPA (n=7) and DNMT3A (n=6) were included. The lncRNA expression was studied using Affymetrix® Human Gene 2.1 ST platform which includes 9698 lncRNAs transcripts. The filtering and normalization of the array data was performed using oligo package from Bioconductor. Statistical analyses were performed with TiGR MultiExperiment Viewer, BRB tools and R. The Transcription factor Affinity Prediction Web Tool was used to determine the putative transcription factors binding to the differentially expressed lncRNAs promoters. Results: The hierarchical cluster analysis showed that all 4 NBM as well as all 3 CD34+ NBM clustered together according to their lncRNA expression. Interestingly, all 5 t(8;16) AML samples clustered together, as well as the 3 APL, the 7 t(6;9) AML and 5 out of 7 cases with CEBPA mutations. The specific lncRNA signature of APL was composed of 79 differentially expressed lncRNA and t(6;9) AML lncRNA signature comprised of 15 differentially expressed lncRNAs. When we focused on t(8;16) AML lncRNA profile, we identified an specific 113-lncRNA signature in the supervised analysis (Figure). Interestingly, when we analyzed which (TF) had motifs overrepresented in the promoters regions of the t(8;16) AML lncRNA signature, we identified GATA2 as the TF with significantly overrepresented motifs for GATA2 (p<0.001). Interestingly, levels of GATA2 were differentially expressed in t(8;16) AML samples in comparison with other AMLs samples (p<0.001). GATA2 has been described to interact with CREBBP, one of the partners involved in t(8;16) AML. Of note, 4 overexpressed lncRNAs of the signature (linc-HOXA11, HOXA11-AS, HOTTIP and NR_038120) were located in the HOXA genomic region, previously found upregulated in t(8:16) AML. Since several studies suggest an active crosstalk between microRNAs and lncRNAs, we also correlated the expression of these lncRNAs with the microRNA t(8;16) AML profile. We found significant correlation between linc-HOXA11 and miR-222* (R2 =0.996, p=0.003), HOXA11-AS and miR-let-7c (R2=0.994, p=0.006), HOTTIP and miR-196b*(R2=0.958, p=0.041), and NR_038120 with miR-486-3p (R2=0.999, p=0.0004) and miR-19a (R2=0.953, p=0.04). Conclusions: LncRNAs expression profile seems specific of several AML subtypes, including t(8;16) AML. Some of the lncRNAs of this distinctive signature in t(8;16) AML are located in the HOXA genomic region, and correlate with several of the characteristic microRNAs previously described in this entity. Interestingly, we have predicted in silico GATA2, which interacts with CREBBP, as the most significant TF that could potentially regulate this lncRNAs signature. Nonetheless, further investigation is warranted to determine the mechanisms leading to this lncRNA signature and to identify the specific targets of these lncRNAs. Río Hortega CM13/00205, FIS PI13/00999 Disclosures No relevant conflicts of interest to declare.
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Tao, Zijia, Yiqiao Zhao, and Xiaonan Chen. "Role of methyltransferase-like enzyme 3 and methyltransferase-like enzyme 14 in urological cancers." PeerJ 8 (July 22, 2020): e9589. http://dx.doi.org/10.7717/peerj.9589.
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N6-methyladenosine (m6A) modifications can be found in eukaryotic messenger RNA (mRNA), long non-coding RNA (lncRNA), and microRNA (miRNA). Several studies have demonstrated a close relationship between m6A modifications and cancer cells. Methyltransferase-like enzyme 3 (METTL3) and methyltransferase-like enzyme 14 (METTL14) are two major enzymes involved in m6A modifications that play vital roles in various cancers. However, the roles and regulatory mechanisms of METTL3 and METTL14 in urological cancers are largely unknown. In this review, we summarize the current research results for METTL3 and METTL14 and identify potential pathways involving these enzymes in kidney, bladder, prostate, and testicular cancer. We found that METTL3 and METTL14 have different expression patterns in four types of urological cancers. METTL3 is highly expressed in bladder and prostate cancer and plays an oncogenic role on cancer cells; however, its expression and role are opposite in kidney cancer. METTL14 is expressed at low levels in kidney and bladder cancer, where it has a tumor suppressive role. Low METTL3 or METTL14 expression in cancer cells negatively regulates cell growth-related pathways (e.g., mTOR, EMT, and P2XR6) but positively regulates cell death-related pathways (e.g., P53, PTEN, and Notch1). When METTL3 is highly expressed, it positively regulates the NF-kB and SHH-GL1pathways but negatively regulates PTEN. These results suggest that although METTL3 and METTL14 have different expression levels and regulatory mechanisms in urological cancers, they control cancer cell fate via cell growth- and cell death-related pathways. These findings suggest that m6A modification may be a potential new therapeutic target in urological cancer.
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Yi, Shen, Ying Xiao-jiang, Li Zhen-jun, Li Gang, Xue Wu-jin, and Jie Wei-xia. "UCA1, a long noncoding RNA, promotes the proliferation of CRC cells via p53/p21 signaling." Open Life Sciences 11, no. 1 (2016): 206–10. http://dx.doi.org/10.1515/biol-2016-0027.
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AbstractObjectiveRecently, the role of long noncoding RNAs (lncRNAs) in human colorectal cancer (CRC) has been a subject of intense focus. We set out to determine the function of one lncRNA, termed urothelial carcinoma-associated 1 (UCA1) in CRC cell proliferation and its underlying mechanisms.MethodsQuantitative real-time PCR (qRT-PCR) was applied to detect the expression level of UCA1 in 50 pairs of CRC samples compared with non-tumor colon tissues. Cell growth was determined using the Cell Counting Kit-8 (CCK-8). Western blotting was carried out to analyze the related protein expression. Flow cytometry was done to evaluate cell apoptosis by UCA1 inhibition.ResultsWe found an increased expression of UCA1 in CRC samples. Knockdown of UCA1 in HCT116 cells induced a decrease in cell proliferation rate compared to control samples. This oncogenic activity may be enhanced through p53/ p21 signaling.ConclusionOur results supported the hypothesis that upregulation of UCA1 contributes to the unlimited proliferation rate of CRC cells, at least partially through the negative regulation of p53/p21 signaling pathway. Finally, we found that UCA1 merely influenced CRC cell apoptosis.
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Baytak, Esra, Qiang Gong, Burcu Akman, Hongling Yuan, Wing C. Chan, and Can Küçük. "Whole transcriptome analysis reveals dysregulated oncogenic lncRNAs in natural killer/T-cell lymphoma and establishes MIR155HG as a target of PRDM1." Tumor Biology 39, no. 5 (2017): 101042831770164. http://dx.doi.org/10.1177/1010428317701648.
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Natural killer/T-cell lymphoma is a rare but aggressive neoplasm with poor prognosis. Despite previous reports that showed potential tumor suppressors, such as PRDM1 or oncogenes associated with the etiology of this malignancy, the role of long non-coding RNAs in natural killer/T-cell lymphoma pathobiology has not been addressed to date. Here, we aim to identify cancer-associated dysregulated long non-coding RNAs and signaling pathways or biological processes associated with these long non-coding RNAs in natural killer/T-cell lymphoma cases and to identify the long non-coding RNAs transcriptionally regulated by PRDM1. RNA-Seq analysis revealed 166 and 66 long non-coding RNAs to be significantly overexpressed or underexpressed, respectively, in natural killer/T-cell lymphoma cases compared with resting or activated normal natural killer cells. Novel long non-coding RNAs as well as the cancer-associated ones such as SNHG5, ZFAS1, or MIR155HG were dysregulated. Interestingly, antisense transcripts of many growth-regulating genes appeared to be transcriptionally deregulated. Expression of ZFAS1, which is upregulated in natural killer/T-cell lymphoma cases, showed association with growth-regulating pathways such as stabilization of P53, regulation of apoptosis, cell cycle, or nuclear factor-kappa B signaling in normal and neoplastic natural killer cell samples. Consistent with the tumor suppressive role of PRDM1, we identified MIR155HG and TERC to be transcriptionally downregulated by PRDM1 in two PRDM1-null NK-cell lines when it is ectopically expressed. In conclusion, this is the first study that identified long non-coding RNAs whose expression is dysregulated in natural killer/T-cell lymphoma cases. These findings suggest that ZFAS1 and other dysregulated long non-coding RNAs may be involved in natural killer/T-cell lymphoma pathobiology through regulation of cancer-related genes, and loss-of-PRDM1 expression in natural killer/T-cell lymphomas may contribute to overexpression of MIR155HG; thereby promoting tumorigenesis.
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Ma, Zhonghua, Peng Peng, Jing Zhou, et al. "Long Non-Coding RNA SH3PXD2A-AS1 Promotes Cell Progression Partly Through Epigenetic Silencing P57 and KLF2 in Colorectal Cancer." Cellular Physiology and Biochemistry 46, no. 6 (2018): 2197–214. http://dx.doi.org/10.1159/000489589.
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Background/Aims: Colorectal cancer (CRC) is one of the most commonly diagnosed malignancies worldwide. Current evidence has revealed the key roles of long non-coding RNAs (IncRNAs) in multiple cancers, including CRC. In this study we identified the lncRNA SH3PXD2A-AS1 as a novel molecule associated with CRC progression by analyzing the publicly available data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. Methods: Quantitative real-time polymerase chain reaction (qRT-PCR) assays were performed to examine the expression levels of SH3PXD2A-AS1 in CRC tissue samples and CRC cell lines. Cell viability examination, colony-formation experiments, ethynyl deoxyuridine (Edu) assays and flow cytometry were performed to investigate the roles of SH3PXD2A-AS1 in CRC proliferation, cell cycle regulation, and apoptosis. Transwell assays were used to explore the effects of SH3PXD2A-AS1 on CRC cells migration and invasion. A nude mice model was used to assess the effects of SH3PXD2A-AS1 on tumorigenesis in vivo. Subcellular fractionation, RNA immunoprecipitation (RIP), and chromatin immunoprecipitation (ChIP) assays were conducted to detect the molecular mechanisms of SH3PXD2A-ASl-mediated gene expression. Rescue assays were used to determine whether P57 and Kruppel-like factor 2 (KLF2) were involved in SH3PXD2A-ASl-dependent CRC proliferation. Results: We firstly found that SH3PXD2A-AS1 was significantly upregulated in CRC tissues and cell lines, and overexpression of SH3PXD2A-AS1 was correlated with tumor size, TNM stage, and lymph node metastasis in patients with CRC. Furthermore, SH3PXD2A-AS1 knockdown inhibited CRC cells proliferation, migration and invasion in vitro, and suppressed tumorigenesis in vivo. Mechanistic studies indicated that SH3PXD2A-AS1 could epiqenetically repress P57 and KLF2 expression through interaction with EZH2. Rescue experiments suggested that SH3PXD2A-ASl-mediated oncogenesis was impaired by overexpression of P57 or KLF2. Interestingly, the expression of SH3PXD2A-AS1 was inversely correlated with the expression of P57 and KLF2 in CRC tissue samples. Conclusion: Our research presents the first evidence that SH3PXD2A-AS1 acts as an oncogene in CRC, and may be a promising diagnostic or therapeutic target in patients with CRC.
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Ren, Yanli, Jinhua Shang, Jinliang Li, et al. "The long noncoding RNA PCAT-1 links the microRNA miR-215 to oncogene CRKL-mediated signaling in hepatocellular carcinoma." Journal of Biological Chemistry 292, no. 43 (2017): 17939–49. http://dx.doi.org/10.1074/jbc.m116.773978.
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The long non-coding RNA (lncRNA) PCAT-1 resides in the chromosome 8q24 cancer-risk locus and acts as a vital oncogene during tumorigenesis and progression. However, how PCAT-1 is post-transcriptionally regulated, for example, by small ncRNAs, such as microRNAs (miRNAs) is largely unknown. Here, we report how miRNAs regulate PCAT-1 expression and also investigate the biological significance of this regulation in hepatocellular carcinoma (HCC). We found that miR-215, a P53-inducible miRNA, is a key regulator of PCAT-1 expression in HCC and identified an interaction between miR-215 and PCAT-1 in dual luciferase reporter gene assays. We also found that post-transcriptional silencing of PCAT-1 by miR-215 or PCAT-1 siRNAs significantly inhibited proliferation of HCC cells and, conversely, that inhibition of endogenous miR-215 up-regulated PCAT-1 expression and promoted cell viability. The tumor-suppressing role of miR-215 was further confirmed in an in vivo mouse HCC xenograft model. Of note, gene profiling assays suggested that the kinase CRK-like proto-oncogene, adaptor protein (CRKL), is a potential downstream target of the miR–215–PCAT-1 axis in HCC, and we demonstrated that CRKL silencing significantly suppresses cell proliferation. Taken together and considering the essential role of CRKL in cancer cells, we propose that the TP53–miR-215–PCAT-1–CRKL axis might represent an important regulatory pathway in HCC. In summary, our results highlight the involvement of several ncRNAs in HCC and thus provide critical insights into the molecular pathways operating in this malignancy.
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Benitez, Jose Carlos, Tania Diaz, Carme Ferrer, et al. "LincRNA-p21 as predictive response marker for preoperative chemoradiotherapy in rectal cancer." Journal of Clinical Oncology 39, no. 15_suppl (2021): e15534-e15534. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e15534.
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e15534 Background: Preoperative chemoradiotherapy (CRT) is a standard treatment for locally advanced rectal cancer (RC) patients (pts). Despite the benefits of CRT, its use in non-responder pts can be associated with increased toxicities and resection delay. The identification of CRT response biomarkers, such as long non-coding RNAs (lncRNA), could improve the management of these pts. LincRNA-p21 is a lncRNA involved in the p53 pathway and angiogenesis regulation that acts as prognostic marker in several tumors. We aim to study lincRNA-p21 expression in pretreatment samples from RC pts treated with CRT to evaluate whether lincRNA-p21 can act as a predictive biomarker for CRT response. Methods: RNA from pretreatment endoscopy biopsies from 58 RC pts treated with preoperative CRT at Mutua Terrassa University Hospital were analyzed. Pathological response was classified according to the tumor regression grade (TRG) Dworak classification. LincRNA-p21 expression was determined by RTqPCR and was correlated with CRT response and, time to relapse (TTR), disease-free survival (DFS) and overall survival (OS). Results: Samples from 58 pts were analyzed. Most of them males (n = 40, 69%). Median age at diagnosis of 67 (44-82) years. Fifty (86.2%) pts reported stage III and, 42 (72.4%) pts assessed TRG 0-3 with a 70.7% of downstaging reported. LincRNA-p21 was upregulated in stage III tumors (p < 0.0001) and also in tumors with worst response to CRT regarding TRG, TGR0-3 (TRG0-3, n = 42 vs TRG4, n = 16, p = 0.019). In this line, the ROC curve analysis showed that lincRNA-p21 expression had capacity to distinguish pts with maximum response (TRG4) from others (AUC:0.7; p = 0.02). The binary logistic regression analysis validated its independence as response biomarker. LincRNA-p21 levels correlated with pts relapse after surgery. When the pts were classified in 3 groups, high, medium and low, according to lincRNA-p21 levels, RC pts with highest lincRNA-p21 expression had the shortest TTR. TTR for pts with high levels was 74.5 months (m) (95% CI:31-117), while it was 114 m (95% CI:95-133) for those with Medium levels and 123 m (95% CI:111-134) for those with low levels (p = 0.047). Conclusions: LincRNA-p21 is a marker of advanced disease and worse response to CRT. LincRNA-p21 may add valuable information for individualizing pre-operative CRT in locally advanced RC pts.
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Салеева, Д. В., В. Ф. Михайлов, Л. В. Шуленина, et al. "Activities of regulatory RNAs that affect development of tumor cells in patients with laryngeal cancer." ZHurnal «Patologicheskaia fiziologiia i eksperimental`naia terapiia», no. 4() (November 21, 2018): 67–74. http://dx.doi.org/10.25557/0031-2991.2018.04.67-74.
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Цель. Определение прогностической значимости и роли экспрессии некодирующих РНК (длинные РНК и микроРНК), и белка кодирующих генов в патогенезе рака гортани. Методика. Исследован биопсийный материал и периферическая кровь 35 пациентов с диагнозом плоскоклеточный рак гортани (ПРГ) с классификацией от T1N0M0 до T4N1M0. Контролем служили образцы близлежащей гистологически неизмененной ткани гортани тех же больных. Для оценки экспрессии генов исследовали кровь 27 здоровых доноров. Содержание мРНК генов ( р53, CCND1, ORAOV1, hPTEN ), длинных некодирующих РНК (днРНК): NEAT1, MALAT1, ROR , а также зрелых микроРНК (miR-21, miR-27a, miR-34a, miR-101, miR-124, miR-125b, miR-181а) в опухолевой ткани и крови определяли методом ПЦР в реальном времени (ПЦР-РВ). Результаты. Выявлено увеличение содержания мРНК генов CCND1, hPTEN , днРНК NEAT1, MALAT1 и miR-21, miR-27a в крови у пациентов с ПРГ. Установлено, что уровень мРНК генов CCND1, ORAOV1 был значимо выше при исследовании биоптатов у больных 3-й - 4-й стадии, чем у больных 1-й - 2-й стадии заболевания. Такая же закономерность выявлена для днРНК NEAT1, MALAT1 и для miR-101. Экспрессия miR-27a и miR-124 на более поздних стадиях болезни была ниже, чем у пациентов 1-2 стадии. Заключение. Выявлена возможность использования исследованных днРНК, микроРНК и мРНК белоккодирующих генов для индивидуального прогноза заболевания при создании панели биомаркеров. Aim. To study the role of non-coding RNA (long RNAs and microRNAs) expression and protein-coding genes in the pathogenesis of laryngeal cancer to determine their prognostic significance for oncotransformation. Methods. The expression of long non-coding RNAs, microRNAs and protein-coding genes was examined in biopsy samples (fresh frozen tissue) and peripheral blood samples from 35 patients with laryngeal squamous cell cancer (LSCC) at T1N0M0 - T4N1M0 stages. Samples of surrounding, histologically unchanged tissues collected from the same patients were used as control. Gene expression was evaluated in blood samples from 27 healthy donors. Contents of gene mRNAs ( p53, CCND1, ORAOV1, hPTEN ), long non-coding RNAs (IncRNA) ( NEAT1, MALAT1, ROR ), and mature miRNAs (miR-21, miR-27a, miR-34a, miR-101, miR-124, miR -125b, miR-181a) were measured in tissue and blood using real-time PCR. Results. Contents of CCND1 and hPTEN gene mRNAs, lncRNAs ( NEAT1, MALAT1), miR-21, and miR-27a were increased in blood of patients with LSCC. Levels of CCND1 and ORAOV1 gene mRNAs were significantly higher in biopsy samples from stage 3-4 patients compared to stage 1-2 patients. A similar expression pattern was observed for lncRNAs NEAT1 and MALAT1 and miR-101. On the other hand, expression of miR-27a and miR-124 was lower at later stages than at stages 1-2. Conclusion. The studied lncRNAs, microRNAs and protein-coding genes can be used in development of a biomarker panel for individual prognosis of the disease.
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Deng, Zhen, Jiaxing Hou, Hongbo Xu, et al. "The Prognostic Value of a lncRNA Risk Model Consists of 9 m6A Regulator-Related lncRNAs in Hepatocellular Carcinoma (HCC)." Evolutionary Bioinformatics 19 (January 2023): 117693432211420. http://dx.doi.org/10.1177/11769343221142013.
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Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver. Although the RNA modification N6-methyladenine (m6A) has been reported to be involved in HCC carcinogenesis, early diagnostic markers and promising personalized therapeutic targets are still lacking. In this study, we identified that 19 m6A regulators and 34 co-expressed lncRNAs were significantly upregulated in HCC samples; based on these factors, we established a prognostic signal of HCC associated with 9 lncRNAs and 19 m6A regulators using LASSO Cox regression analysis. Kaplan-Meier survival estimate revealed correlations between the risk scores and patients’ OS in the training and validation dataset. The ROC curve demonstrated that the risk score-based curve has satisfactory prediction efficiency for both training and validation datasets. Multivariate Cox’s proportional hazard regression analysis indicated that the risk score was an independent risk factor within the training and validation dataset. In addition, the risk score could distinguish HCC patients from normal non-cancerous samples and HCC samples of different pathological grades. Eventually, 232 mRNAs were co-expressed with these 9 lncRNAs according to GSE101685 and GSE112790; these mRNAs were enriched in cell cycle and cell metabolic activities, drug metabolism, liver disease-related pathways, and some important cancer related pathways such as p53, MAPK, Wnt, RAS and so forth. The expression of the 9 lncRNAs was significantly higher in HCC samples than that in the neighboring non-cancerous samples. Altogether, by using the Consensus Clustering, PCA, ESTIMATE algorithm, LASSO regression model, Kaplan-Meier survival assessment, ROC curve analysis, and multivariate Cox’s proportional hazard regression model analysis, we established a prognostic marker consisting of 9 m6A regulator-related lncRNAs that markers may have prognostic and diagnostic potential for HCC.
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Xiang, SongTao, PeiLiang Zou, JingJing Wu та ін. "Crosstalk of NF-κB/P65 and LncRNA HOTAIR-Mediated Repression of MUC1 Expression Contribute to Synergistic Inhibition of Castration-Resistant Prostate Cancer by Polyphyllin 1–Enzalutamide Combination Treatment". Cellular Physiology and Biochemistry 47, № 2 (2018): 759–73. http://dx.doi.org/10.1159/000490028.
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Background/Aims: Polyphyllin I (PPI), one of the steroidal saponins in Paris polyphylla, reportedly exhibits antitumor effects. However, the detailed mechanism underlying PPI, particularly in enhancing the effect of the androgen receptor inhibitor enzalutamide in controlling castration-resistant prostate cancer (CRPC) has not been explored. Methods: Cell viability and cell cycle distribution were measured using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) and flow cytometry assays, respectively. Long non-coding RNA (lncRNA) HOX transcript antisense RNA (HOTAIR) expression was measured by quantitative real time-PCR (qRT-PCR). Western blot analysis was performed to determine the protein expression levels of MUC1, p65, and p50. Silencing of HOTAIR was evaluated using the siRNA procedure. The promoter activity of the MUC1 gene was determined using Secrete-Pair Dual Luminescence Assay Kit. Exogenous expression of HOTAIR, p65, and MUC1 was conducted by transient transfection assay. A xenograft tumor model in nude mice was used to further evaluate the effect of the combination of PPI and enzalutamide in vivo. Results: We showed that PPI significantly inhibited growth and induced cell cycle arrest in CRPC cells. PPI also decreased p65 and MUC1 protein expression and reduced HOTAIR expression. Exogenously expressed p65 resisted the PPI-inhibited expression of HOTAIR, whereas silenced HOTAIR reduced MUC1 protein but exerted no effect on the expression of p65 and p50 proteins. Conversely, exogenously expressed HOTAIR resisted the PPI-inhibited MUC1 protein expression, and excessive expression of MUC1 antagonized the PPI-inhibited cell growth. Notably, PPI combined with enzalutamide exerted a synergistic effect. Consistent with this finding, PPI inhibited tumor growth, HOTAIR expression, as well as p65 and MUC1 protein expressions in vivo. Conclusions: Our results indicate that PPI inhibits the growth of CRPC cells by inhibiting p65 protein and concomitantly reducing HOTAIR expression, thereby suppressing MUC1 gene expression. The novel regulatory interaction of p65 and HOTAIR converge in the inhibition of MUC1 expression and overall PPI response. The combination of PPI and enzalutamide exhibits synergy. This study reveals a novel mechanism underlying the synergistic inhibitory effect of PPI and enzalutamide on the growth of CRPC cells.
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Hsieh, Pei-Fang, Cheng-Chia Yu, Pei-Ming Chu, and Pei-Ling Hsieh. "Long Non-Coding RNA MEG3 in Cellular Stemness." International Journal of Molecular Sciences 22, no. 10 (2021): 5348. http://dx.doi.org/10.3390/ijms22105348.
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Long non-coding RNAs (lncRNAs) regulate a diverse array of cellular processes at the transcriptional, post-transcriptional, translational, and post-translational levels. Accumulating evidence suggests that lncRNA MEG3 exerts a large repertoire of regulatory functions in cellular stemness. This review focuses on the molecular mechanisms by which lncRNA MEG3 functions as a signal, scaffold, guide, and decoy for multi-lineage differentiation and even cancer progression. The role of MEG3 in various types of stem cells and cancer stem cells is discussed. Here, we provide an overview of the functional versatility of lncRNA MEG3 in modulating pluripotency, differentiation, and cancer stemness.
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Wang, Yaqi, Mengzhen Xue, Fangqi Xia, et al. "Long Non-Coding RNA GAS5 in Age-Related Diseases." Current Medicinal Chemistry 29, no. 16 (2022): 2863–77. http://dx.doi.org/10.2174/0929867328666211027123932.
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Abstract: Aging refers to a natural process and a universal phenomenon in all cells, tissues, organs, and the whole organism. Long non-coding RNAs (lncRNAs) are non-coding RNAs with a length of 200 nucleotides. LncRNA growth arrest-specific 5 (lncRNA GAS5) is often down-regulated in cancer. The accumulation of lncRNA GAS5 has been found to be able to inhibit cancer growth, invasion, and metastasis while enhancing the sensitivity of cells to chemotherapy drugs. LncRNA GAS5 can be a signaling protein, which is specifically transcribed under different triggering conditions. Subsequently, it is involved in signal transmission in numerous pathways as a signal node. LncRNA GAS5, with a close relationship to multiple miRNAs, was suggested to be involved in the signaling pathway under three action modes (i.e., signal, bait, and guidance). LncRNA GAS5 was found to be involved in different age-related diseases (e.g., rheumatoid arthritis, type 2 diabetes, atherosclerosis, osteoarthritis, osteoporosis, multiple sclerosis, cancer, etc.). This study mainly summarized the regulatory effect exerted by lncRNA GAS5 on age-related diseases.
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Kloecker, G., C. Taylor, N. Vinayek, and D. Taylor. "Exosomal Long Non-Coding RNA (LNCRNA) in Lung Cancer." Annals of Oncology 23 (September 2012): ix76. http://dx.doi.org/10.1016/s0923-7534(20)32740-x.
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Xu, Wen, Bei Wang, Yuxuan Cai, et al. "ADAMTS9-AS2: A Functional Long Non-coding RNA in Tumorigenesis." Current Pharmaceutical Design 27, no. 23 (2021): 2722–27. http://dx.doi.org/10.2174/1381612827666210325105106.
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Background: Long non-coding RNAs (lncRNA) have been identified as novel molecular regulators in cancers. LncRNA ADAMTS9-AS2 can mediate the occurrence and development of cancer through various ways, such as regulating miRNAs, activating the classical signaling pathways in cancer, and so on, which have been studied by many scholars. In this review, we summarize the molecular mechanisms of ADAMTS9-AS2 in different human cancers. Methods: Through a systematic search of PubMed, lncRNA ADAMTS9-AS2 mediated molecular mechanisms in cancer are summarized inductively. Results: ADAMTS9-AS2 aberrantly expression in different cancers is closely related to cancer proliferation, invasion, migration, and inhibition of apoptosis. The involvement of ADAMTS9-AS2 in DNA methylation, mediating PI3K / Akt / mTOR signaling pathways, and regulating miRNAs and proteins, shows its significant potential as a therapeutic cancer target. Conclusion: LncRNA ADAMTS9-AS2 can become a promising biomolecular marker and a therapeutic target for human cancer.
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Chen, Yi-Cheng, Yu-Chi Chou, Yu-Tung Hsieh, et al. "Targeting Intra-Pulmonary P53-Dependent Long Non-Coding RNA Expression as a Therapeutic Intervention for Systemic Lupus Erythematosus-Associated Diffuse Alveolar Hemorrhage." International Journal of Molecular Sciences 22, no. 13 (2021): 6948. http://dx.doi.org/10.3390/ijms22136948.
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Diffuse alveolar hemorrhage (DAH) in systemic lupus erythematosus (SLE) is associated with significant mortality, requiring a thorough understanding of its complex mechanisms to develop novel therapeutics for disease control. Activated p53-dependent apoptosis with dysregulated long non-coding RNA (lncRNA) expression is involved in the SLE pathogenesis and correlated with clinical activity. We examined the expression of apoptosis-related p53-dependent lncRNA, including H19, HOTAIR and lincRNA-p21 in SLE-associated DAH patients. Increased lincRNA-p21 levels were detected in circulating mononuclear cells, mainly in CD4+ and CD14+ cells. Higher expression of p53, lincRNA-p21 and cell apoptosis was identified in lung tissues. Lentivirus-based short hairpin RNA (shRNA)-transduced stable transfectants were created for examining the targeting efficacy in lncRNA. Under pristane stimulation, alveolar epithelial cells had increased p53, lincRNA-p21 and downstream Bax levels with elevated apoptotic ratios. After pristane injection, C57/BL6 mice developed DAH with increased pulmonary expression of p53, lincRNA-p21 and cell apoptosis. Intra-pulmonary delivery of shRNA targeting lincRNA-p21 reduced hemorrhage frequencies and improved anemia status through decreasing Bax expression and cell apoptosis. Our findings demonstrate increased p53-dependent lncRNA expression with accelerated cell apoptosis in the lungs of SLE-associated DAH patients, and show the therapeutic potential of targeting intra-pulmonary lncRNA expression in a pristane-induced model of DAH.
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Decmann, Abel, Pál Perge, Peter Istvan Turai, Attila Patócs, and Peter Igaz. "Non-Coding RNAs in Adrenocortical Cancer: From Pathogenesis to Diagnosis." Cancers 12, no. 2 (2020): 461. http://dx.doi.org/10.3390/cancers12020461.
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Non-coding RNA molecules including microRNAs and long non-coding RNAs (lncRNA) have been implicated in the pathogenesis of several tumors and numerous data support their applicability in diagnosis as well. Despite recent advances, the pathogenesis of adrenocortical cancer still remains elusive and there are no reliable blood-borne markers of adrenocortical malignancy, either. Several findings show the potential applicability of microRNAs as biomarkers of malignancy and prognosis, and there are some data on lncRNA as well. In this review, we present a synopsis on the potential relevance of non-coding RNA molecules in adrenocortical pathogenesis and their applicability in diagnosis from tissue and blood.
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Arun, Gayatri, Disha Aggarwal, and David L. Spector. "MALAT1 Long Non-Coding RNA: Functional Implications." Non-Coding RNA 6, no. 2 (2020): 22. http://dx.doi.org/10.3390/ncrna6020022.
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The mammalian genome is pervasively transcribed and the functional significance of many long non-coding RNA (lncRNA) transcripts are gradually being elucidated. Metastasis Associated Lung Adenocarcinoma Transcript 1 (MALAT1) is one of the most well-studied lncRNAs. MALAT1 is a highly conserved nuclear retained lncRNA that is abundantly expressed in cells and tissues and has been shown to play a role in regulating genes at both the transcriptional and post-transcriptional levels in a context-dependent manner. However, Malat1 has been shown to be dispensable for normal development and viability in mice. Interestingly, accumulating evidence suggests that MALAT1 plays an important role in numerous diseases including cancer. Here, we discuss the current state-of-knowledge in regard to MALAT1 with respect to its function, role in diseases, and the potential therapeutic opportunities for targeting MALAT1 using antisense oligonucleotides and small molecules.
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Nath, Aritro, Paul Geeleher, and R. Stephanie Huang. "Long non-coding RNA transcriptome of uncharacterized samples can be accurately imputed using protein-coding genes." Briefings in Bioinformatics 21, no. 2 (2019): 637–48. http://dx.doi.org/10.1093/bib/bby129.
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Abstract Long non-coding RNAs (lncRNAs) play an important role in gene regulation and are increasingly being recognized as crucial mediators of disease pathogenesis. However, the vast majority of published transcriptome datasets lack high-quality lncRNA profiles compared to protein-coding genes (PCGs). Here we propose a framework to harnesses the correlative expression patterns between lncRNA and PCGs to impute unknown lncRNA profiles. The lncRNA expression imputation (LEXI) framework enables characterization of lncRNA transcriptome of samples lacking any lncRNA data using only their PCG profiles. We compare various machine learning and missing value imputation algorithms to implement LEXI and demonstrate the feasibility of this approach to impute lncRNA transcriptome of normal and cancer tissues. Additionally, we determine the factors that influence imputation accuracy and provide guidelines for implementing this approach.
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Zhang, Xiao-Zhen, Hao Liu, and Su-Ren Chen. "Mechanisms of Long Non-Coding RNAs in Cancers and Their Dynamic Regulations." Cancers 12, no. 5 (2020): 1245. http://dx.doi.org/10.3390/cancers12051245.
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Long non-coding RNA (lncRNA), which is a kind of noncoding RNA, is generally characterized as being more than 200 nucleotide transcripts in length. LncRNAs exhibit many biological activities, including, but not limited to, cancer development. In this review, a search of the PubMed database was performed to identify relevant studies published in English. The term “lncRNA or long non-coding RNA” was combined with a range of search terms related to the core focus of the review: mechanism, structure, regulation, and cancer. The eligibility of the retrieved studies was mainly based on the abstract. The decision as to whether or not the study was included in this review was made after a careful assessment of its content. The reference lists were also checked to identify any other study that could be relevant to this review. We first summarized the molecular mechanisms of lncRNAs in tumorigenesis, including competing endogenous RNA (ceRNA) mechanisms, epigenetic regulation, decoy and scaffold mechanisms, mRNA and protein stability regulation, transcriptional and translational regulation, miRNA processing regulation, and the architectural role of lncRNAs, which will help a broad audience better understand how lncRNAs work in cancer. Second, we introduced recent studies to elucidate the structure of lncRNAs, as there is a link between lncRNA structure and function and visualizing the architectural domains of lncRNAs is vital to understanding their function. Third, we explored emerging evidence for regulators of lncRNA expression, lncRNA turnover, and lncRNA modifications (including 5-methylcytidine, N6-methyladenosine, and adenosine to inosine editing), highlighting the dynamics of lncRNAs. Finally, we used autophagy in cancer as an example to interpret the diverse mechanisms of lncRNAs and introduced clinical trials of lncRNA-based cancer therapies.
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Xu, Cheng Lin, Ben Sang, Guang Zhi Liu, et al. "SENEBLOC, a long non-coding RNA suppresses senescence via p53-dependent and independent mechanisms." Nucleic Acids Research 48, no. 6 (2020): 3089–102. http://dx.doi.org/10.1093/nar/gkaa063.
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Abstract Long non-coding RNAs (lncRNAs) have emerged as important biological tuners. Here, we reveal the role of an uncharacterized lncRNA we call SENEBLOC that is expressed by both normal and transformed cells under homeostatic conditions. SENEBLOC was shown to block the induction of cellular senescence through dual mechanisms that converge to repress the expression of p21. SENEBLOC facilitates the association of p53 with MDM2 by acting as a scaffold to promote p53 turnover and decrease p21 transactivation. Alternatively, SENEBLOC was shown to affect epigenetic silencing of the p21 gene promoter through regulation of HDAC5. Thus SENEBLOC drives both p53-dependent and p53-independent mechanisms that contribute to p21 repression. Moreover, SENEBLOC was shown to be involved in both oncogenic and replicative senescence, and from the perspective of senolytic agents we show that the antagonistic actions of rapamycin on senescence are dependent on SENEBLOC expression.
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Yang, Si-Jia, Jia-Lu Weng, Bin Wei, and Xue-Kui Du. "Long non-coding RNA DUXAP8 regulates the cell proliferation and invasion of non-small-cell lung cancer." Open Life Sciences 14, no. 1 (2019): 201–7. http://dx.doi.org/10.1515/biol-2019-0022.
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AbstractTo investigate how long non-coding RNAs DUXAP8 (LncRNA DUXAP8) influence the cell proliferation and invasion of non-small-cell lung cancer (NSCLC), we detected the expression levels of LncRNA DUXAP8 in lung cancer (LC) tissues, 4 LC-related cell lines (A549, SPC-A1, SK-MES-1 and NCI-H1299) and normal lung tissues via quantitative real-time PCR (qRT-PCR). Compared with normal lung tissue, LncRNA DUXAP8 was significantly up-regulated in NSCLC, especially in stage III / IV and diameter ≥ 3cm of lung cancer. Among 4 lung cancer cell lines, LncRNA DUXAP8 in A549 cells was the highest (P<0.001). Construction of LncRNA DUXAP8 overexpression and LncRNA DUXAP8 knockout in A549 cell lines was further performed and subsequently injected into nude mice to build an in vivo tumor xenograft model. The results indicated that LncRNA DUXAP8 overexpression significantly promoted the A549 cells’ proliferation, enhanced invasion and induced tumor growth. Conversely, LncRNA DUXAP8 knockout significantly suppressed A549 cells’ proliferation, weakened invasion and inhibited tumor growth. Taken together, our results imply that LncRNA DUXAP8 is a potential regulatory molecular marker in non-small-cell lung cancer.
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Gumiela, Dorota. "The role of long non-coding RNA (lncRNA) in the development of ovarian cancer." Current Gynecologic Oncology 18, no. 2 (2020): e46-e56. http://dx.doi.org/10.15557/cgo.2020.0010.
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The aim of this study was to review research on the role of long non-coding RNA (lncRNA) in ovarian cancer. This article analyses studies on the effect of increased lncRNA expression on the size of ovarian cancer and the incidence of metastasis. The review covers a period from October 15, 2018 to August 22, 2020, and comprises 23 studies in which a total of 1,580 women with ovarian cancer participated, and an undetermined number of control groups where healthy tissue samples were collected. A review of the studies indicates that increased lncRNA expression is associated with elevated ovarian cancer size and metastatic risk. The most studied lncRNA include HOTAIR, CCAT2, GAS5, MALAT-1, UCA1. Studies assessing the expression levels of HOTAIR lncRNA and CCAT2 in normal and cancer tissue showed varying levels of expression in studies of different authors, which indicates that the expression of the same lncRNA may vary individually or is a result of study errors.
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Malouf, Gabriel, Jianping Zhang, Nizar M. Tannir, et al. "Charting DNA methylation of long non-coding RNA in clear-cell renal cell carcinoma." Journal of Clinical Oncology 33, no. 7_suppl (2015): 432. http://dx.doi.org/10.1200/jco.2015.33.7_suppl.432.
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432 Background: Long non-coding RNAs (lncRNA) play a key role in regulating cell physiology through different mechanisms including the recruitment of histone-modifying enzymes. Recently, lncRNA classification of clear-cell renal cell carcinomas (cc-RCC) established four subtypes with different clinico-pathological features. However, the interplay between those lncRNA and DNA methylation patterns remains unknown. Methods: We performed a genomic analysis of GENCODE lncRNAs in cc-RCC using The Cancer Genome Atlas (TCGA) molecular RNAseq profiles of 471 primary tumors. Furthermore, we reannotated data of DNA methylation combining 27K (n=173) and 450K (n=298) Infinium arrays. We described global correlations between lncRNA expression and DNA methylation and established lncRNA methylation subtypes based on distinct signatures. In addition, we identified lncRNA regulated by DNA methylation and associated with poor outcome. Results: We identified 2,138 lncRNAs which contain promoters located in CpG islands (CGI). Out of those, 59 (2.8%) lncRNAs showed DNA methylation in both normal and cancer as compared to 1,487 (69.5%) lncRNA which were unmethylated in both of them. Importantly, 592 (27.7%) lncRNAs gained DNA methylation in ccRCC and this was associated with the repression of the expression of 70 of them. Unsupervised clustering of lncRNA using the most variable DNA methylation probes revealed three robust subtypes associated with distinct outcome. Finally, by integrating cancer subtypes data with clinical information, we identified several lncRNAs which promoter methylation was associated with patient outcome. Conclusions: Our study represents the first integrative analysis of lncRNA and DNA methylation in ccRCC and provides new insights in the role of epigenetic alterations in kidney cancer. Furthermore, we identified a subset of lncRNA regulated epigenetically which may represent potential therapeutic targets.
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Liu, Xiaobing, Yaxing Hao, Wei Yu, et al. "Long Non-Coding RNA Emergence During Renal Cell Carcinoma Tumorigenesis." Cellular Physiology and Biochemistry 47, no. 2 (2018): 735–46. http://dx.doi.org/10.1159/000490026.
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Renal cell carcinoma (RCC) is the most common kidney cancer diagnosed across the globe and has steadily increased in incidence in recent decades. Techniques for diagnosing or treating RCC are limited, and confined mostly to later stages of the disease. Almost all RCC pathological types are resistant to chemotherapeutics and radiation therapy. To this effect, new markers for diagnosis and target therapy are urgently needed. Advanced genome sequencing technologies have revealed long non-coding RNAs (lncRNAs) as a novel marker, transcribed throughout the human genome. The emergence of lncRNAs is an aberrant expression and is involved in the tumorigenesis of RCC. LncRNAs drive cancer phenotypes through their interaction with other cellular macromolecules including DNA, protein, and RNA. Recent research on lncRNA molecular mechanisms has revealed new markers to functionally annotate these cancers’ associated transcripts, making them targets for effective diagnosis and therapeutic intervention in the fight against cancer. In this review, we first highlight the common mechanisms that underlie aberrant lncRNA expression in RCC. We go on to discuss the potential translational application of lncRNA research in the diagnosis, prognosis, and treatment of RCC.
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Sun, Yutong, and Li Ma. "New Insights into Long Non-Coding RNA MALAT1 in Cancer and Metastasis." Cancers 11, no. 2 (2019): 216. http://dx.doi.org/10.3390/cancers11020216.
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Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is one of the most abundant, long non-coding RNAs (lncRNAs) in normal tissues. This lncRNA is highly conserved among mammalian species, and based on in vitro results, has been reported to regulate alternative pre-mRNA splicing and gene expression. However, Malat1 knockout mice develop and grow normally, and do not show alterations in alternative splicing. While MALAT1 was originally described as a prognostic marker of lung cancer metastasis, emerging evidence has linked this lncRNA to other cancers, such as breast cancer, prostate cancer, pancreatic cancer, glioma, and leukemia. The role described for MALAT1 is dependent on the cancer types and the experimental model systems. Notably, different or opposite phenotypes resulting from different strategies for inactivating MALAT1 have been observed, which led to distinct models for MALAT1′s functions and mechanisms of action in cancer and metastasis. In this review, we reflect on different experimental strategies used to study MALAT1′s functions, and discuss the current mechanistic models of this highly abundant and conserved lncRNA.
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Ruan, Zhi, Hui Ma, Jing Li, Huiyong Liu, Haoruo Jia, and Feng Li. "The long non-coding RNA NEAT1 contributes to extracellular matrix degradation in degenerative human nucleus pulposus cells." Experimental Biology and Medicine 243, no. 7 (2018): 595–600. http://dx.doi.org/10.1177/1535370218760774.
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Intervertebral disc degeneration is a complex disease involving genetic and environmental factors and multiple cellular processes. The role and expression of the lncRNA NEAT1 were assessed in intervertebral disc degeneration. NEAT1 expression was assessed in degenerative and control nucleus pulposus using RT-PCR. Western blotting and RT-PCR were also used to investigate p53 and p21 levels in nucleus pulposus tissues. NEAT1 function in degenerative nucleus pulposus cells was assessed with gain- and loss-of-function experiments. ERK/MAPK signaling was also examined. NEAT1, p53, and p21 were dramatically upregulated in intervertebral disc degeneration. Furthermore, catabolic MMP13 and ADAMTS5 were dysregulated and collagen II and aggrecan were downregulated after NEAT1 overexpression. This effect was reversed by transfection with si-NEAT1 in degenerative nucleus pulposus cells. In addition, NEAT1 was found to affect the activation of the ERK/MAPK pathway. The NEAT1-induced ECM degradation may involve ERK1/2/MAPK signaling. LncRNA NEAT1 may represent a novel molecular target for intervertebral disc degeneration treatment by preventing nucleus pulposus ECM degradation. Impact statement For the first time, our study demonstrates that lncRNA NEAT1 plays a role in the occurrence and development of IDD by participating in extracellular matrix remodeling. This lncRNA regulates catabolic MMP13 and ADAMTS5 and anabolic collagen II and aggrecan by affecting the ERK/MAPK signaling pathway in degenerative human nucleus pulposus (NP) cells. Our research provides a scientific basis for targeting of NEAT1 for the IDD.
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Dehghani-Samani, Mina, Naiemeh Hassanzadeh, Hamidreza Kabiri, et al. "Correlations between Overexpression of SOX2OT Long Non-coding RNA and Susceptibility to Breast Cancer." Combinatorial Chemistry & High Throughput Screening 23, no. 9 (2020): 981–87. http://dx.doi.org/10.2174/1386207323666200514075042.
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Background and Objective: The SOX2OT lcnRNA has been recognized as a positive regulator in the transcription regulation of the SOX2 gene. Recent studies have approved the dysregulation of SOX2OT lncRNA expression patterns in some common cancer types, including esophageal, lung, and breast cancer. The objective of the present study was to investigate the correlation between overexpression of SOX2OT lcnRNA and susceptibility to breast cancer. Methods: SOX2OT lncRNA expression profiling in 15 breast cancer and normal tumour-adjacent breast tissue samples was performed by using qRT-PCR. To evaluate the diagnostic potential of the SOX2OT lncRNA, we performed ROC curve analyses. Results: The expression of SOX2OT lncRNA in patients suffering from breast cancer revealed a significant overexpression in comparison with the healthy group (P<0.001). Significantly, the elevated circulating SOX2OT lncRNA was found specific to breast cancer and could differentiate breast cancer from controls with 100% of both sensitivity and specificity. Based on the Kaplan- Meier analysis, there was no significant correlation between SOX2OT lcnRNA expression and overall survival. Conclusion: The results confirmed the association between breast cancer and higher SOX2OT lncRNA expression. According to the ROC curve results, SOX2OT lcnRNA could be a new measurable indicator of the breast cancer and a potential therapeutic target for breast cancer patients.
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Wang, Lihua, Pengcheng Bu, Yiwei Ai, et al. "A long non-coding RNA targets microRNA miR-34a to regulate colon cancer stem cell asymmetric division." eLife 5 (April 14, 2016). http://dx.doi.org/10.7554/elife.14620.
Full textAbstract:
The roles of long non-coding RNAs (lncRNAs) in regulating cancer and stem cells are being increasingly appreciated. Its diverse mechanisms provide the regulatory network with a bigger repertoire to increase complexity. Here we report a novel LncRNA, Lnc34a, that is enriched in colon cancer stem cells (CCSCs) and initiates asymmetric division by directly targeting the microRNA miR-34a to cause its spatial imbalance. Lnc34a recruits Dnmt3a via PHB2 and HDAC1 to methylate and deacetylate the miR-34a promoter simultaneously, hence epigenetically silencing miR-34a expression independent of its upstream regulator, p53. Lnc34a levels affect CCSC self-renewal and colorectal cancer (CRC) growth in xenograft models. Lnc34a is upregulated in late-stage CRCs, contributing to epigenetic miR-34a silencing and CRC proliferation. The fact that lncRNA targets microRNA highlights the regulatory complexity of non-coding RNAs (ncRNAs), which occupy the bulk of the genome.
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Naipauer, Julián, Martín E. García Solá, Daria Salyakina, et al. "A Non-Coding RNA Network Involved in KSHV Tumorigenesis." Frontiers in Oncology 11 (June 16, 2021). http://dx.doi.org/10.3389/fonc.2021.687629.
Full textAbstract:
Regulatory pathways involving non-coding RNAs (ncRNAs), such as microRNAs (miRNAs) and long non-coding RNAs (lncRNA), have gained great relevance due to their role in the control of gene expression modulation. Using RNA sequencing of KSHV Bac36 transfected mouse endothelial cells (mECK36) and tumors, we have analyzed the host and viral transcriptome to uncover the role lncRNA-miRNA-mRNA driven networks in KSHV tumorigenesis. The integration of the differentially expressed ncRNAs, with an exhaustive computational analysis of their experimentally supported targets, led us to dissect complex networks integrated by the cancer-related lncRNAs Malat1, Neat1, H19, Meg3, and their associated miRNA-target pairs. These networks would modulate pathways related to KSHV pathogenesis, such as viral carcinogenesis, p53 signaling, RNA surveillance, and cell cycle control. Finally, the ncRNA-mRNA analysis allowed us to develop signatures that can be used to an appropriate identification of druggable gene or networks defining relevant AIDS-KS therapeutic targets.