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Zhang, Wanghai, John Hart, Howard L. McLeod, and Hanlin L. Wang. "Differential Expression of the AP-1 Transcription Factor Family Members in Human Colorectal Epithelial and Neuroendocrine Neoplasms." American Journal of Clinical Pathology 124, no. 1 (July 2005): 11–19. http://dx.doi.org/10.1309/t1h2y2chwy7pd2bn.
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Wang, Wei, Bjorn W. Hackanson, and Heike L. Pahl. "Epigenetic Down-Regulation Of AML2 Expression By EZH2 Contributes To NF-E2 Overexpression In Myeloproliferative Neoplasms." Blood 122, no. 21 (November 15, 2013): 1605. http://dx.doi.org/10.1182/blood.v122.21.1605.1605.
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Abstract The transcription factor NF-E2 is overexpressed in the vast majority of patients with Myeloproliferative Neoplasms (MPN). In Essential Thrombocythemia (ET) and Primary Myelofibrosis (PMF) NF-E2 levels are elevated independent of the presence or absence of the JAK2V617Fmutation. We have recently shown that NF-E2 overexpression in a murine model leads to an MPN phenotype followed by spontaneous transformation to acute leukemia in a subset of mice. We have demonstrated that increased NF-E2 transcription is mediated by the transcription factor and proto-oncogene AML-1, which is overexpressed in MPN patients, again irrespective of the JAK2V617Fstatus. AML-1 binds to a conserved enhancer region located 3500 bp upstream of the NF-E2 transcriptional start site. Since AML-1 responsive genes are often also inversely regulated by the tumor suppressor AML-2 (RUNX3), we investigated whether NF-E2 expression is affected by AML-2 as well. Using chomatin immunoprecipitation assays (ChIP) we show that AML-2 binds the NF-E2 enhancer in vivo at a site distinct from but in proximity to the three AML-1 sites in the -3500bp region. AML-2 binding strongly represses transcription off the NF-E2 enhancer in reporter gene assays. This repression is abrogated by site directed mutagenesis of the AML-2 recognition sequence. Likewise, lentivirally induced AML-2 expression drastically reduces the amount of NF-E2 protein in erythroid and myeloid cells. These data clearly demonstrate that NF-E2 expression is directly regulated by AML-2. AML-2 thus serves as a repressor on the hematopoietic NF-E2 gene, a function previously noted mainly in solid tumors. In primary cells from patients with polycythemia vera (PV) AML-2 mRNA expression is significantly reduced. Moreover, ChIP assays demonstrate that in primary PV cells, significantly less AML-2 is bound to the NF-E2 enhancer than in healthy controls. Decreased repression by AML-2 thus cooperates with increased AML-1 induced transcription to elevate NF-E2 levels in PV patients. It has been demonstrated that AML-2 expression can be regulated by two distinct epigenetic mechanisms. For one, DNA methylation of the AML-2 promoter has been reported to silence AML-2 expression in gastric, colorectal and bladder cancers. On the other hand, aberrant histone methylation in the promoter region can also silence AML-2 expression. Here we show that DNA methylation of the AML-2 promoter is unaltered in PV patients. Rather, PV patients display aberrant histone methylation in the AML-2 promoter. Compared to healthy controls, H3K27me3 is significantly increased and H3K4me3 is significantly decreased in primary PV cells. This results in an inactive chromatin conformation on the AML-2 promoter in PV patients. Moreover, we show here that the histone-lysine-methyl-transferase “enhancer of zeste homologue 2” (EZH2), which confers the K3K27me3 mark, binds to the AML-2 promoter and decreases AML-2 expression. PV patients demonstrate significantly increased levels of EZH2 binding to the AML-2 promoter Treatment of primary PV cells and MPN cell lines with 2'-deoxy-5-azacytidine (DAC, Decitabine) ex vivo reverses the altered histone methylation, restoring the pattern found in healthy controls and decreases EZH2 binding to the AML-2 promoter. At the same time, Decitabine treatment induces AML-2 protein expression, decreases EZH2 expression and reduces the elevated NF-E2 levels. Moreover, a post-PV AML patient receiving Decitabine, displayed normalization of AML-2 promoter histone methylation and EZH2 binding on day 8 and day 15 of treatment. Taken together our data demonstrate that epigenetic silencing of AML-2 contributes to the elevated NF-E2 expression observed in MPN patients. Treatment with Decitabine restores physiological histone modifications to the AML-2 locus and decreases NF-E2 levels by reactivating AML-2 expression. These data provide a molecular rationale for extending the clinical investigation of epigenetic modifiers such as Decitabine or Azacitidine, currently used in MDS and AML, to patients with MPNs. A phase I study using Azacitidine in high risk PMF patients is currently being planned by the MPD-RC. Disclosures: No relevant conflicts of interest to declare.
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Masliantsev, Konstantin, Lucie Karayan-Tapon, and Pierre-Olivier Guichet. "Hippo Signaling Pathway in Gliomas." Cells 10, no. 1 (January 18, 2021): 184. http://dx.doi.org/10.3390/cells10010184.
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The Hippo signaling pathway is a highly conserved pathway involved in tissue development and regeneration that controls organ size through the regulation of cell proliferation and apoptosis. The core Hippo pathway is composed of a block of kinases, MST1/2 (Mammalian STE20-like protein kinase 1/2) and LATS1/2 (Large tumor suppressor 1/2), which inhibits nuclear translocation of YAP/TAZ (Yes-Associated Protein 1/Transcriptional co-activator with PDZ-binding motif) and its downstream association with the TEAD (TEA domain) family of transcription factors. This pathway was recently shown to be involved in tumorigenesis and metastasis in several cancers such as lung, breast, or colorectal cancers but is still poorly investigated in brain tumors. Gliomas are the most common and the most lethal primary brain tumors representing about 80% of malignant central nervous system neoplasms. Despite intensive clinical protocol, the prognosis for patients remains very poor due to systematic relapse and treatment failure. Growing evidence demonstrating the role of Hippo signaling in cancer biology and the lack of efficient treatments for malignant gliomas support the idea that this pathway could represent a potential target paving the way for alternative therapeutics. Based on recent advances in the Hippo pathway deciphering, the main goal of this review is to highlight the role of this pathway in gliomas by a state-of-the-art synthesis.
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Neri, Giuseppe, Giovanni Arpa, Camilla Guerini, Federica Grillo, Marco Vincenzo Lenti, Paolo Giuffrida, Daniela Furlan, et al. "Small Bowel Adenocarcinomas Featuring Special AT-Rich Sequence-Binding Protein 2 (SATB2) Expression and a Colorectal Cancer-Like Immunophenotype: A Potential Diagnostic Pitfall." Cancers 12, no. 11 (November 19, 2020): 3441. http://dx.doi.org/10.3390/cancers12113441.
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Special AT-rich sequence-binding protein 2 (SATB2) is a transcription factor expressed by colonic cryptic epithelium and epithelial neoplasms of the lower gastrointestinal (GI) tract, as well as by small bowel adenocarcinomas (SBAs), though at a lower rate. Nevertheless, up to now, only small SBA series, often including a very limited number of Crohn’s disease-associated SBAs (CrD-SBAs) and celiac disease-associated SBAs (CD-SBA), have been investigated for SATB2 expression. We evaluated the expression of SATB2 and other GI phenotypic markers (cytokeratin (CK) 7 and CK20, caudal type homeobox 2 (CDX2) and alpha-methylacyl-CoA racemase (AMACR)), as well as mismatch repair (MMR) proteins, in 100 SBAs, encompassing 34 CrD-SBAs, 28 CD-SBAs and 38 sporadic cases (Spo-SBAs). Any mutual association and correlation with other clinico-pathologic features, including patient prognosis, were searched. Twenty (20%) SATB2-positive SBAs (4 CrD-SBAs, 7 CD-SBAs and 9 Spo-SBAs) were identified. The prevalence of SATB2 positivity was lower in CrD-SBA (12%) in comparison with both CD-SBAs (25%) and Spo-SBAs (24%). Interestingly, six SBAs (two CD-SBAs and four Spo-SBAs) displayed a full colorectal carcinoma (CRC)-like immunoprofile (CK7−/CK20+/CDX2+/AMACR+/SATB2+); none of them was a CrD-SBA. No association between SATB2 expression and MMR status was observed. Although SATB2-positive SBA patients showed a more favorable outcome in comparison with SATB2-negative ones, the difference did not reach statistical significance. When cancers were stratified according to CK7/CK20 expression patterns, we found that CK7−/CK20- SBAs were enriched with MMR-deficient cases (71%) and patients with CK7−/CK20− or CK7−/CK20+ SBAs had a significantly better survival rate compared to those with CK7+/CK20− or CK7+/CK20+ cancers (p = 0.002). To conclude, we identified a small (6%) subset of SBAs featuring a full CRC-like immunoprofile, representing a potential diagnostic pitfall in attempts to identify the site of origin of neoplasms of unknown primary site. In contrast with data on colorectal carcinoma, SATB2 expression is not associated with MMR status in SBAs. CK patterns influence patient survival, as CK7−/CK20− cancers show better prognosis, a behavior possibly due to the high rate of MMR-deficient SBAs within this subgroup.
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Panic, Nikola, Alberto Larghi, Rosarita Amore, Roberta Pastorino, Milutin Bulajic, Guido Costamagna, and Stefania Boccia. "Single Nucleotide Polymorphisms within the 8Q24 Region are Not Associated with the Risk of Intraductal Papillary Mucinous Neoplasms of the Pancreas." Journal of Gastrointestinal and Liver Diseases 25, no. 3 (September 1, 2016): 311–15. http://dx.doi.org/10.15403/jgld.2014.1121.253.q24.
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Background & Aims: Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas have been reported to be associated with an increased risk of developing extra-pancreatic malignancies. A common genetic background has been hypothesised to be responsible for such an association. Human chromosomal region 8q24 has been associated with many types of cancer. The majority of these associations lie at approximately 128 Mb on chromosome 8. We conducted a study in order to examine the association between IPMN and single nucleotide polymorphisms (SNPs) from the 8q24 region, namely rs10505477, rs6983267, rs7014346, rs6993464, previously reported to influence general cancer susceptibility.
Methods. The study was performed on 117 IPMN cases and 231 controls. Cases were enrolled at the Digestive Endoscopy Unit, Policlinico Agostino Gemelli from January, 2010 to June, 2011, with either a prevalent or incident IPMN diagnosis. Status of SNPs was determined using a StepOne Real-time PCR system (Applied Biosystems) and TaqMan SNP Genotyping Assay™ 40X. Unconditional multiple logistic regression models were used to estimate odds ratios and 95% confidence intervals for the association of selected SNPs and IPMNs.
Results. Cases were more likely to report a 1st degree family history of cancer (p<0.001), as well as heavy smoking (p=0.001) and heavy drinking habits (p<0.001). No significant association was observed between IPMN and selected SNPs. The results were confirmed also when stratified according to any 1st-degree family history of cancer.
Conclusion. Patients with IPMN do not have a higher prevalence of SNPs in the human chromosomal region 8q24 in respect to the control population.
Abbreviations: CASC8: cancer susceptibility candidate 8; CRC: colorectal cancer; ENPP2: ectonucleotide pyrophosphatase/phosphodiesterase 2; EPM: extra-pancreatic malignancy; eQTLs: expression quantitative trait loci; IPMN: intraductal papillary mucinous neoplasm; MYC: myelocytomatosis viral oncogene homolog gene; NOV: nephroblastoma over-expressed gene; PCR: polymerase chain reaction; POU5F1P1: POU class 5 homeobox 1 pseudogene 1 gene; S-MRCP: magnetic resonance cholangiopancreatography with secretin stimulation; SNP: single nucleotide polymorphism; TCF4: transcription factor 4.
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Grady, W. M. "Epigenetic events in the colorectum and in colon cancer." Biochemical Society Transactions 33, no. 4 (August 1, 2005): 684–88. http://dx.doi.org/10.1042/bst0330684.
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Colon cancers arise from benign neoplasms and evolve into adenocarcinomas through a stepwise histological progression sequence, proceeding from either adenomas or hyperplastic polyps/serrated adenomas. Genetic alterations have been associated with specific steps in this polyp–adenocarcinoma sequence and are believed to drive the histological progression of colon cancer. Recently, epigenetic alterations, which include CGI (CpG island) DNA methylation, have been shown to occur in colon polyps and colon cancer. The aberrant methylation of genes appears to co-operate with the genetic alterations to drive the initiation and progression of colon polyps to colon cancer. CGI DNA methylation is an epigenetic mechanism that represses gene transcription in normal cellular processes, but it becomes excessive and aberrant in many neoplasms. The aberrant DNA methylation affects CpG-rich regions, called CGIs, in the 5′ region of genes and results in transcriptional silencing through effects on transcription factor binding and associated changes in chromatin structure. These hypermethylated genes are not only probable pathogenic events affecting colon-cancer formation, but also neoplasm-specific molecular events that may be useful as molecular markers for colon tumours. Furthermore, aberrant DNA methylation of tumour-suppressor genes may occur secondary to a genetic predisposition or to a field-cancerization effect in the colon and may be useful as molecular markers for the risk of developing colon cancer.
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Li, Chang-feng, Yong-chao Li, Yun Wang, and Li-bo Sun. "The Effect of LncRNA H19/miR-194-5p Axis on the Epithelial-Mesenchymal Transition of Colorectal Adenocarcinoma." Cellular Physiology and Biochemistry 50, no. 1 (2018): 196–213. http://dx.doi.org/10.1159/000493968.
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Background/Aims: Since the combined actions of lncRNAs and miRNAs have been considered to be involved in the occurrence and development of various neoplasms, the main purpose of this study was to discover whether and how lncRNA H19 and miR-194 influenced the epithelial-mesenchymal transition (EMT) process of colorectal adenocarcinoma (CRA). Methods: Totally 214 pairs of CRA and adjacent normal tissues were collected, and 5 human CRA cell lines (i.e. HCT116, HT-29, RKO SW280 and Lovo) were purchased. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was adopted to quantify the H19 and miR-194-5p expressions in cells and tissues. The expressions of FoxM1, E-cadherin, vimentin, N-cadherin were determined using western blot. On the side, si-H19, si-NC, miR-194-5p mimic, miR-194-5p inhibitor and negative control (NC) were transfected into CRA cell lines. Meanwhile, the invasive, migratory and proliferative conditions of the cells were assessed through transwell, wound healing and colony-forming experiments, with final verification of the relationship between H19 and miR-194-5p employing dual-luciferase reporter gene assay. Results: Highly-expressed H19, lowly-expressed miR-194-5p, low-grade differentiation and lymph node metastasis appeared as the independent predictors of unfavorable prognosis in CRA patients’ (all P< 0.05). It indicated that FoxM1 expression displayed positive correlations with H19 expression, yet negative associations with miR-194-5p expression within CRA tissues (P< 0.05). In addition, transfection of H19-siRNA and miR-145-5p mimic triggered a conspicuous increase in E-cadherin expression, as well as an evidently down-regulation in vimentin and N-cadherin expressions within HT29 and RKO cells (P< 0.05). On the other hand, the invasive and migratory capacities of CRA cells were significantly hindered (P< 0.05). Moreover, the luciferase reporter gene assay confirmed that H19 modified miR-194-5p expression through directly targeting at it (P< 0.05). Ultimately, FoxM1 could reverse the role of miR-194-5p in inhibiting invasion, migration and EMT of CRA cells (P< 0.05). Conclusion: LncRNA H19/miR-194/FoxM1 axis could serve as a profound target for the diagnosis and treatment of CRA.
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Heichler, Christina, Kristina Scheibe, Anabel Schmied, Carol I. Geppert, Benjamin Schmid, Stefan Wirtz, Oana-Maria Thoma, et al. "STAT3 activation through IL-6/IL-11 in cancer-associated fibroblasts promotes colorectal tumour development and correlates with poor prognosis." Gut 69, no. 7 (November 4, 2019): 1269–82. http://dx.doi.org/10.1136/gutjnl-2019-319200.
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ObjectiveCancer-associated fibroblasts (CAFs) influence the tumour microenvironment and tumour growth. However, the role of CAFs in colorectal cancer (CRC) development is incompletely understood.DesignWe quantified phosphorylation of STAT3 (pSTAT3) expression in CAFs of human colon cancer tissue using a tissue microarray (TMA) of 375 patients, immunofluorescence staining and digital pathology. To investigate the functional role of CAFs in CRC, we took advantage of two murine models of colorectal neoplasia and advanced imaging technologies. In loss-of-function and gain-of-function experiments, using genetically modified mice with collagen type VI (COLVI)-specific signal transducer and activator of transcription 3 (STAT3) targeting, we evaluated STAT3 signalling in fibroblasts during colorectal tumour development. We performed a comparative gene expression profiling by whole genome RNA-sequencing of fibroblast subpopulations (COLVI+ vs COLVI–) on STAT3 activation (IL-6 vs IL-11).ResultsThe analysis of pSTAT3 expression in CAFs of human TMAs revealed a negative correlation of increased stromal pSTAT3 expression with the survival of colon cancer patients. In the loss-of-function and gain-of-function approach, we found a critical role of STAT3 activation in fibroblasts in driving colorectal tumourigenesis in vivo. With different imaging technologies, we detected an expansion of activated fibroblasts in colorectal neoplasias. Comparative gene expression profiling of fibroblast subpopulations on STAT3 activation revealed the regulation of transcriptional patterns associated with angiogenesis. Finally, the blockade of proangiogenic signalling significantly reduced colorectal tumour growth in mice with constitutive STAT3 activation in COLVI+ fibroblasts.ConclusionAltogether our work demonstrates a critical role of STAT3 activation in CAFs in CRC development.
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Patnaik, A., E. G. Chiorean, A. Tolcher, K. Papadopoulos, M. Beeram, D. Kee, M. Waddell, E. Gilles, and A. Buchbinder. "EZN-2968, a novel hypoxia-inducible factor-1α (HIF-1α) messenger ribonucleic acid (mRNA) antagonist: Results of a phase I, pharmacokinetic (PK), dose-escalation study of daily administration in patients (pts) with advanced malignancies." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): 2564. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.2564.
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2564 Background: HIF-1 is a transcription factor that regulates expression of many key genes, notably those switching cell metabolism to anaerobic glycolysis and inducing neovascularization in response to hypoxia. Increased HIF-1α levels are associated with poor prognosis in several neoplasms. EZN-2968 is a potent locked nucleic acid antisense oligonucleotide suppressing HIF-1α mRNA translation in vitro (IC50 ∼1–5 nM). Methods: This study was designed to determine the safety, tolerability, PK, maximum tolerated dose, recommended dose, and preliminary evidence of antitumor activity of EZN-2968. Pts with advanced malignancies were treated with EZN-2968 administered as a daily 2-hr IV infusion x 5 days every 4 weeks using a 3+3 dose-escalating design. Dose escalation was based on toxicities observed during Cycle 1. Results: 19 pts (11 men; median age = 60 y [47–79 y]) were treated with EZN-2968 doses of 0.5 (3 pts), 0.8 (3 pts), 1.2 (3 pts), 1.8 (4 pts), 2.7 (3 pts), and 4.1 (3 pts) mg/kg/day. Tumor types included colorectal cancer (7 pts); renal cancer (4 pts); soft-tissue sarcoma (STS; 2 pts); angiosarcoma (1 pt); melanoma (1 pt); and breast, ovarian, pancreatic, and prostate cancers (1 pt each). No dose-limiting toxicities were observed. The most common adverse events (Aes) were vomiting (32%); fatigue (26%); and anemia, diarrhea, nausea, and tumor pain (each 21%). Most Aes were Grade 1 or 2. Plasma PK for Day 1 is tabulated below. Stable disease was observed for 1 pt with angiosarcoma (28 wks) and 1 pt with renal cancer (12 wks). Conclusions: EZN-2968 was well tolerated in previously treated pts with advanced malignancies. PK data do not show accumulation of EZN-2968. Dose escalation is ongoing; final results will be presented at the meeting. Durable stable disease has been observed. [Table: see text] [Table: see text]
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Wang, Dongyang, Jianjun Zhang, Zengjun Li, Jianjun Han, Yongsheng Gao, Ming Chen, and Yanqing Li. "Upregulation of Fibroblast Growth Factor 19 Is Associated with the Initiation of Colorectal Adenoma." Digestive Diseases 37, no. 3 (December 5, 2018): 214–25. http://dx.doi.org/10.1159/000494454.
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Fibroblast growth factor 19 (FGF19) promotes tumor growth in various types of cancer, but its function has not been investigated in the context of colorectal adenoma. Here, we report that FGF19 expression was greater in colorectal adenoma than in normal tissues, as measured by an enzyme-linked immunosorbent assay, quantitative reverse-transcription PCR and immunohistochemistry. FGF19 expression was also elevated in a subset of human colon cancer cell lines. Moreover, FGF receptor 4 (FGFR4), the cognate receptor for FGF19, was upregulated in colorectal adenoma tissues. Lipid levels and body mass index values strongly correlated with FGF19 and FGFR4 levels in patients with colon adenomas. These observations indicate that the FGF19/FGFR4 pathway may be involved in the development of neoplasia, and that FGF19 may be a valuable diagnostic marker for the identification of patients with colorectal adenomas.
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Lewandowska, Paulina, Jaroslaw Wierzbicki, Marek Zawadzki, Anil Agrawal, and Małgorzata Krzystek-Korpacka. "Biphasic Expression of Atypical Chemokine Receptor (ACKR) 2 and ACKR4 in Colorectal Neoplasms in Association with Histopathological Findings." Biomolecules 11, no. 1 (December 23, 2020): 8. http://dx.doi.org/10.3390/biom11010008.
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Facilitating resolution of inflammation using atypical chemokine receptors (ACKR) as an anticancer strategy is considered but requires a deeper understanding of receptor role in carcinogenesis. We aimed at transcriptional analysis (RTqPCR) of ACKR2 and ACKR4 expression in colorectal adenoma-adenocarcinoma sequence in paired normal-neoplastic tissues from 96 polyps and 51 cancers. On average, ACKR2 was downregulated in neoplastic as compared to non-affected tissue in polyp (by 2.7-fold) and cancer (by 3.1-fold) patients. The maximal downregulation (by 8.2-fold) was observed in adenomas with the highest potential for malignancy and was gradually lessening through cancer stages I-IV, owing to increased receptor expression in tumors. On average, ACKR4 was significantly downregulated solely in adenocarcinomas (by 1.5-fold), less so in patients with lymph node metastasis, owing to a gradual decrease in ACKR4 expression among N0-N1-N2 cancers in non-affected tissue without changes in tumors. In adenomas, ACKR4 downregulation in neoplastic tissue increased with increasing potential for malignancy and contribution of villous growth pattern. ACKR4 expression increased in non-affected tissue with a concomitant decrease in pathological mucosa. In conclusion, the changes in ACKRs expression occur already in precancerous colorectal lesions, culminating in the adenomas with the highest potential for malignancy. Therefore, chemoprevention by manipulating ACKRs’ expression is worth exploration.
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Jin, Bo-Ram, Kyung-Sook Chung, Minho Lee, and Hyo-Jin An. "High-Fat Diet Propelled AOM/DSS-Induced Colitis-Associated Colon Cancer Alleviated by Administration of Aster glehni via STAT3 Signaling Pathway." Biology 9, no. 2 (February 2, 2020): 24. http://dx.doi.org/10.3390/biology9020024.
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Many epidemiological observational studies suggest that a high-fat diet (HFD) accelerates the risk of colorectal cancer (CRC). Inflammation can play a key role in the relationship between colon cancer and HFD. Although reported by several studies, controlled experimental studies have not explored this relationship. We established an HFD-fed colitis-associated colon cancer (CAC) mice model and evaluated the anti-tumorigenic effects of AG on HFD-propelled CAC along with its mechanism of action. Previously, we found that Aster glehni (AG) exerts chemopreventive effects on azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced CAC in a mice model, and has anti-adipogenic effects in a HFD-induced obesity mice model. In the HFD-propelled CAC mice model, AG significantly reduced cancer-related death, prevented body weight loss, and alleviated splenic enlargement. Additionally, AG prevented colon shortening and reduced the number of colorectal polyps. Histological studies demonstrated the up-regulation of inflammation, hyperplasia, and neoplasia in HFD-propelled CAC mice, whereas AG suppressed colonic disease progression and tumorigenesis. Furthermore, AG significantly inhibited the signal transducer and activator of transcription 3 (STAT3) signaling pathway and attenuated the protein expression of the STAT3 target gene, which mediates transcription factor-dependent tumor cell proliferation. These results indicate that AG abrogates inflammation-induced tumor progression in HFD-propelled CAC mice by inhibiting STAT3 activation.
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Prabhu, Jyothi S., Aruna Korlimarla, Arindam Banerjee, Shivangi Wani, K. Payal, and Rashmita Sahoo. "Gene-Specific Methylation: Potential Markers for Colorectal Cancer." International Journal of Biological Markers 24, no. 1 (January 2009): 57–62. http://dx.doi.org/10.1177/172460080902400109.
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Purpose Aberrant methylation of the promoter region is associated with silencing of many genes in neoplasia. CpG island methylation is an epigenetic mechanism for transcriptional silencing that occurs at various stages of colon tumorigenesis. In this study, we tested the promoter methylation and expression of seven genes from various pathways of DNA repair, apoptosis and inflammation, i.e., sFRP1, MLH1, RASSF1A, CDA, v-fgr, LYN-B, and TNFR10d. Method The genes were analyzed by quantitative polymerase chain reaction for the level of gene expression. The promoter methylation status of the genes was studied by methylation-specific polymerase chain reaction. Result The correlation of promoter methylation status with suppressed gene expression patterns suggested a potential role for the silencing these genes in colon cancer progression. Conclusion Promoter methylations of the studied genes could be explored as promising biomarkers for new diagnostic, prognostic and therapeutic targets of colorectal cancer.
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Kanaan, Ziad, M. Robert Eichenberger, Michael Young, Daniel Colliver, Nigel Crawford, Gary A. Cobbs, David W. Hein, and Susan Galandiuk. "An Alternative Cyclin-D1 Splice Site is Not Linked to Inflammatory Bowel Disease-Associated Neoplasia." International Journal of Biological Markers 25, no. 1 (January 2010): 27–31. http://dx.doi.org/10.1177/172460081002500104.
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Background Inflammatory bowel diseases (IBD) encompass inflammatory disorders affecting the gastrointestinal tract, primarily ulcerative colitis (UC) and Crohn's disease (CD). The risk of developing colorectal cancer (CRC) is increased in patients with IBD. The CCND1 protein is the regulatory subunit of an enzyme that inactivates the retinoblastoma protein, a tumor suppressor protein, and promotes progression through the G1-S phase of the cell cycle. The CCND1 870G-A gene polymorphism influences susceptibility to colorectal cancer. The mutant allele of CCND1 in IBD-associated neoplasia leads to a greater frequency of alternate splicing during transcription, resulting in a more stable CCND1 protein. This creates a higher concentration of CCND1, facilitating easier passage through the G1/S checkpoint, abnormal cell cycle progression, and possibly carcinogenesis. Methods We conducted a case-control study involving 396 individuals with IBD. IBD subgroups included CD, UC, and indeterminate colitis (IC). We studied patients with sporadic colorectal cancer (n=75) and patients without gastrointestinal disease as a control group (n=93). We extracted DNA from blood and performed polymerase chain reaction followed by high-performance liquid chromatography to screen for mutations. We confirmed the polymorphism at nucleotide A870G in exon 4. For statistical analysis, we used exact analyses of two-way contingency tables. Power calculations were done and correction for multiple testing was performed by computing the false discovery rate (FDR). Results and discussion Our study had a power of 75% at a 0.05 significance level. A870G SNP allele frequency in the IBD group was 44.8%, compared to 51.6% in the control population. Only the IC group showed a significant association with CCND1 splice site after correction for multiple testing (FDR=0.042). There were no differences between the other IBD groups and controls. Conclusion We found an association between CCND1 A870G SNP and IC group only (p=0.014, FDR=0.042). However, our data do not show an association between CCND1 A870G SNP and CD-associated or UC-associated neoplasia.
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Schildgen, Verena, Monika Pieper, Soumaya Khalfaoui, Wolfgang Arnold, and Oliver Schildgen. "Human Bocavirus Infection of Permanent Cells Differentiated to Air-Liquid Interface Cultures Activates Transcription of Pathways Involved in Tumorigenesis." Cancers 10, no. 11 (October 30, 2018): 410. http://dx.doi.org/10.3390/cancers10110410.
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The parvoviral human bocavirus (HBoV) is a respiratory pathogen, able to persist in infected cells. The viral DNA has been identified in colorectal and lung tumors and thus it was postulated that the virus could be associated with tumorigenesis. This assumption was supported by the fact that in HBoV-infected patients and in an in vitro cell culture system, pro-cancerogenic and -fibrotic cytokines were expressed. In this work, it is shown by a whole transcriptome analysis that, also at the mRNA level, several pathways leading to neoplasia and tumorigenesis are significantly upregulated. In total, a set of 54 transcripts are specifically regulated by HBoV, of which the majority affects canonical pathways that may lead to tumor development if they become deregulated. Moreover, pathways leading to necrosis, apoptosis and cell death are downregulated, supporting the hypothesis that HBoV might contribute to the development of some kinds of cancer.
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Yu, Bo, Xuan Ye, Qiong Du, Bin Zhu, and Qing Zhai. "The Long Non-Coding RNA CRNDE Promotes Colorectal Carcinoma Progression by Competitively Binding miR-217 with TCF7L2 and Enhancing the Wnt/β-Catenin Signaling Pathway." Cellular Physiology and Biochemistry 41, no. 6 (2017): 2489–502. http://dx.doi.org/10.1159/000475941.
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Background/Aims: The long non-coding RNA colorectal neoplasia differentially expressed (CRNDE) contributes to the proliferation and migration of tumors. However, its molecular mechanism underlying gastric cancer remains unknown. In the present study, we investigated whether CRNDE was involved in the development of colorectal cancer via the binding of microRNA (miR)-217 with transcription factor 7-like 2 (TCF7L2) to enhance the Wnt signaling pathway. Methods: Quantitative polymerase chain reaction was used to detect CRNDE, miR-217 and TCF7L2 in colorectal cancer tissues and cells. The CCK-8 assay, wound healing assay, and Transwell assay were used to detect cell proliferation, migration and invasion, respectively. Western blotting and luciferase activity assays were used to identify CRNDE and TCF7L2 as one of the direct targets of miR-217. The activity of the Wnt/β-catenin signaling pathway was analyzed by the TOPflash assay, and the subcellular localization of β-catenin and TCF7L2 was analyzed by western blotting and confocal microscopy. Results: In this study, we found that high expression of CRNDE is negatively correlated with low expression of miR-217 in colorectal cancer tissue and colorectal cancer cells. The dual luciferase reporter analysis showed that miR-217 is bound to CRNDE and TCF7L2 and negatively regulate their expression. CRNDE down-regulation inhibited the cell proliferation, migration and invasion in vitro and in vivo and the inhibitions were both completely blocked after miR-217 inhibition or TCF7L2 overexpression. Finally, TOPflash analysis showed that the activity of Wnt/β-catenin signaling is inhibited by CRNDE down-regulation and rescued by TCF7L2 over-expression. Consistently immunostaining and western blotting analysis showed that the expression of b-catenin and TCF7L2 in the nucleus was significantly decreased by CRNDE down-regulation and was rescued by TCF7L2 over-expression. Conclusions: The present study suggest that CRNDE involves in the cell proliferation, migration and invasion of colorectal cancer cells via increasing the expression of TCF7L2 and activity of Wnt/β-catenin signaling through binding miR-217 competitively.
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Glimcher, Laurie H., Vanja Lazarevic, Joerg Ermann, and Wendy Garrett. "A Commitment to Lineage." Blood 116, no. 21 (November 19, 2010): SCI—22—SCI—22. http://dx.doi.org/10.1182/blood.v116.21.sci-22.sci-22.
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Abstract Abstract SCI-22 The transcription factor T-bet, isolated in our laboratory a decade ago, is a master regulator of Type 1 immunity in cells of both the adaptive and innate immune system. In adaptive immunity, T-bet instigates genetic programs in T helper 1 (Th1) cells and is required for production of the hallmark Th1 cytokine IFNg. It simultaneously represses the differentiation of T helper 2 cells and the profibrotic cytokines IL-13 and TGFb. We have recently determined that T-bet is also a repressor of the Th17 genetic program and have established the molecular mechanisms that underpin that function. T-bet also controls the optimal differentiation and function of the cytolytic CD8 cell, and is required for the development of the natural killer T cell. T-bet deficient animals are largely protected from autoimmune/inflammatory diseases such as multiple sclerosis, systemic lupus, type 1 diabetes and inflammatory arthritis, but are susceptible to type 2 driven diseases such as asthma and scleroderma. An exception to this overall rule is our recent discovery that in the absence of an adaptive immune system, the majority of mice lacking T-bet develop a spontaneous ulcerative colitis that progresses to colonic dysplasia and rectal adenocarcinoma. This colitis and inflammation associated colorectal cancer are MyD88 independent, driven by colitogenic flora and ameliorated by treatment with TNF blockade, antibiotics, and transfer of T regulatory cells. This phenotype maps to the T-bet deficient dendritic cell that drives this pro-inflammatory program; selective over-expression of T-bet in DCs was sufficient to reduce colonic inflammation and prevent the progression to neoplasia. The molecular pathogenesis of TRUC colitis and colitis-associated colorectal (caCRC) shares several key features with human caCRC. This model of colitis and colitis-associated colorectal cancer provides opportunities to further understand host-microbial relationships in inflammation and neoplasia and test preventative and therapeutic strategies pre-clinically. The function and mechanism of action of T-bet in the pathogenesis of immune system driven diseases will be discussed. Disclosures: Glimcher: Merck: Consultancy, Patents & Royalties, Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.
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Lizarraga, Erik, Erika Ruiz Garcia, Cesar Lopez-Camarillo, Abelardo Meneses, Horacio Astudillo, Edith Araceli Fernandez Figueroa, Leonardo Lino-Silva, et al. "Clinical and functional analysis of SOX9 in colorectal cancer." Journal of Clinical Oncology 37, no. 4_suppl (February 1, 2019): 519. http://dx.doi.org/10.1200/jco.2019.37.4_suppl.519.
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519 Background: Colorectal cancer (CRC) is the third leading cause of cancer-related deaths worldwide. CRC develops within the intestinal epithelium, which is constantly self-renewing, developmental genes could promote the initiation and progression of cancer. SOX9 transcription factor is expressed especially in intestinal stem cells and in Paneth cells, thus alterations in expression could greatly promote neoplasia. However, the clinical significance and functional role of SOX9 in CRC remains unclear. The aim of this study is to investigate the association of SOX9 expression with relapse in CRC patients and initiate functional studies by evaluating the effects of silencing SOX9 in stem cells properties such as colonospheres formation in HCT116 CRC cells. Methods: 97 FFPE biopsies from CRC patients in stage I (N = 34) and stage II (N = 63) were analyzed. Immunoreactivity of SOX9 was classified as low and high expression groups based on the percentage of positive nucleus and tissue staining intensity. SOX9 silencing was achieved using a specific siRNA and Lipofectamine-RNAiMax and confirmed by qPCR 24 h postransfection. 40,000 HCT116 and HCT116-siSOX9 cells were seeded under adherent and ultra-low attachment conditions for tumorigenesis assays. After 72 h colonospheres were seeded and quantified. ROC analysis was used to assess the clinical correlation of SOX9 with relapse. Experimental data were expressed as means and differences tested by t-Student. Results: Data showed that 12.3% of patients relapsed. Interestingly, all of them showed lower SOX9 expression (p ≤ 0.05), regardless of their relapse free survival. In functional analysis, SOX9-deficient HCT116 cells formed smaller and less-compacted spheroid when compared to non-transfected HCT116 (p ≤ 0.05). Nonetheless, cell proliferation and migration under adherent condition were similar between the groups. Conclusions: This study did not find association between SOX9 expression and relapse. So far, in vitro assays results suggest that silencing of SOX9 inhibits colonospheres formation in HCT116 cells. Further investigation will be performed in order to evaluate the functional importance of SOX9 in chemotherapy response.
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Malkin, David, Kim E. Nichols, Kristin Zelley, and Joshua D. Schiffman. "Predisposition to Pediatric and Hematologic Cancers: A Moving Target." American Society of Clinical Oncology Educational Book, no. 34 (May 2014): e44-e55. http://dx.doi.org/10.14694/edbook_am.2014.34.e44.
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Our understanding of hereditary cancer syndromes in children, adolescents, and young adults continues to grow. In addition, we now recognize the wide variation in tumor spectrum found within each specific cancer predisposition syndrome including the risk for hematologic malignancies. An increased understanding of the genetic mutations, biologic consequences, tumor risk, and clinical management of these syndromes will improve patient outcome. In this article, we illustrate the diversity of molecular mechanisms by which these disorders develop in both children and adults with a focus on Li-Fraumeni syndrome, hereditary paraganglioma syndrome, DICER1 syndrome, and multiple endocrine neoplasia syndrome. This is followed by a detailed discussion of adult-onset tumors that can occur in the pediatric population including basal cell carcinoma, colorectal cancer, medullary thyroid cancer, and adrenal cortical carcinoma, and the underlying hereditary cancer syndromes that these tumors could indicate. Finally, the topic of leukemia predisposition syndromes is explored with a specific focus on the different categories of syndromes associated with leukemia risk (genetic instability/DNA repair syndromes, cell cycle/differentiation, bone marrow failure syndromes, telomere maintenance, immunodeficiency syndromes, and transcription factors/pure familial leukemia syndromes). Throughout this article, special attention is made to clinical recognition of these syndromes, genetic testing, and management with early tumor surveillance and screening.
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Martelli, Alberto M., Francesca Paganelli, Francesca Chiarini, Camilla Evangelisti, and James A. McCubrey. "The Unfolded Protein Response: A Novel Therapeutic Target in Acute Leukemias." Cancers 12, no. 2 (February 1, 2020): 333. http://dx.doi.org/10.3390/cancers12020333.
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The unfolded protein response (UPR) is an evolutionarily conserved adaptive response triggered by the stress of the endoplasmic reticulum (ER) due, among other causes, to altered cell protein homeostasis (proteostasis). UPR is mediated by three main sensors, protein kinase RNA-like endoplasmic reticulum kinase (PERK), activating transcription factor 6α (ATF6α), and inositol-requiring enzyme-1α (IRE1α). Given that proteostasis is frequently disregulated in cancer, UPR is emerging as a critical signaling network in controlling the survival, selection, and adaptation of a variety of neoplasias, including breast cancer, prostate cancer, colorectal cancer, and glioblastoma. Indeed, cancer cells can escape from the apoptotic pathways elicited by ER stress by switching UPR into a prosurvival mechanism instead of cell death. Although most of the studies on UPR focused on solid tumors, this intricate network plays a critical role in hematological malignancies, and especially in multiple myeloma (MM), where treatment with proteasome inhibitors induce the accumulation of unfolded proteins that severely perturb proteostasis, thereby leading to ER stress, and, eventually, to apoptosis. However, UPR is emerging as a key player also in acute leukemias, where recent evidence points to the likelihood that targeting UPR-driven prosurvival pathways could represent a novel therapeutic strategy. In this review, we focus on the oncogene-specific regulation of individual UPR signaling arms, and we provide an updated outline of the genetic, biochemical, and preclinical therapeutic findings that support UPR as a relevant, novel target in acute leukemias.
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Mendoza-Rodríguez, Mónica G., C. Ángel Sánchez-Barrera, Blanca E. Callejas, Verónica García-Castillo, Diana L. Beristain-Terrazas, Norma L. Delgado-Buenrostro, Yolanda I. Chirino, et al. "Use of STAT6 Phosphorylation Inhibitor and Trimethylglycine as New Adjuvant Therapies for 5-Fluorouracil in Colitis-Associated Tumorigenesis." International Journal of Molecular Sciences 21, no. 6 (March 20, 2020): 2130. http://dx.doi.org/10.3390/ijms21062130.
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Colorectal cancer (CRC) is one of the most widespread and deadly types of neoplasia around the world, where the inflammatory microenvironment has critical importance in the process of tumor growth, metastasis, and drug resistance. Despite its limited effectiveness, 5-fluorouracil (5-FU) is the main drug utilized for CRC treatment. The combination of 5-FU with other agents modestly increases its effectiveness in patients. Here, we evaluated the anti-inflammatory Trimethylglycine and the Signal transducer and activator of transcription (STAT6) inhibitor AS1517499, as possible adjuvants to 5-FU in already established cancers, using a model of colitis-associated colon cancer (CAC). We found that these adjuvant therapies induced a remarkable reduction of tumor growth when administrated together with 5-FU, correlating with a reduction in STAT6-phosphorylation. This reduction upgraded the effect of 5-FU by increasing both levels of apoptosis and markers of cell adhesion such as E-cadherin, whereas decreased epithelial–mesenchymal transition markers were associated with aggressive phenotypes and drug resistance, such as β-catenin nuclear translocation and Zinc finger protein SNAI1 (SNAI1). Additionally, Il-10, Tgf-β, and Il-17a, critical pro-tumorigenic cytokines, were downmodulated in the colon by these adjuvant therapies. In vitro assays on human colon cancer cells showed that Trimethylglycine also reduced STAT6-phosphorylation. Our study is relatively unique in focusing on the effects of the combined administration of AS1517499 and Trimethylglycine together with 5-FU on already established CAC which synergizes to markedly reduce the colon tumor load. Together, these data point to STAT6 as a valuable target for adjuvant therapy in colon cancer.
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Singh, Jasvinder, Anup Sharma, and Nita Ahuja. "Genomics of peritoneal surface malignancies." Journal of Peritoneum (and other serosal surfaces), July 12, 2017. http://dx.doi.org/10.4081/joper.2017.62.
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Peritoneal malignancies and metastasis are traditionally approached as a terminal disease, however with multiple lines of clinical therapy; long-term survival can be achieved in selected patients using aggressive cytoreduction and hyperthermic intraperitoneal chemotherapy. This is especially true for Pseudomyxoma peritonei from appendiceal neoplasms, peritoneal mesothelioma and peritoneal metastasis from colorectal cancer. In this article, we discuss the nature of genomic alterations in these three peritoneal malignancies and their potential as prognostic and therapeutic markers in clinical decisions. Genomic characterization of malignancies using technological advances including what is now widely used and accepted next-generation genomic sequencing methods has identified genomic anomalies (i.e. mutations, epigenetic modifications, transcription and expression changes in RNA) which is used for targeted therapy, prognostication, surveillance and prediction of response to therapy.
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Vax, V. V., M. Gueorguiev, I. I. Dedov, A. B. Grossman, and M. Korbonits. "The Kr√ºppel-like transcription factor 6 gene in sporadic pituitary tumours." Endocrine-related cancer, September 2003, 397–402. http://dx.doi.org/10.1677/erc.0.0100397.
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The oncogenes and/or tumour suppressor genes which may be involved in the transformation process for the vast majority of pituitary tumours remain unknown. There is substantial evidence for derangement of cell cycle control in such tumours, but cell cycle protein mutations identified in other human malignancies are restricted to only a very small subset of sporadic pituitary neoplasms. Krüppel-like factors are DNA-binding transcriptional regulators with diverse effects including the upregulation of the cell cycle protein p21(WAF1/CIP1). It has been reported that the Krüppel-like transcription factor 6 (KLF6) gene is mutated in a proportion (15-55%) of human prostate cancers, and more recent data are emerging regarding mutated KLF6 in nasopharyngeal carcinomas, astrocytoid gliomas and colorectal cancer. We therefore speculated that other tumours such as pituitary adenomas might also harbour such mutations that may be involved in the control of cell proliferation in the pituitary. The aim of the current study was thus to analyse the KLF6 gene for mutations in sporadic pituitary tumours. We analysed 60 pituitary adenomas (15 GH-, four ACTH-, two PRL-secreting and 39 non-functioning) with direct sequence analysis of exons 2 and 3 of the KLF6 gene, the region where most of the previously described mutations are located. Three non-functioning pituitary adenomas of the 60 pituitary tumours (5%) had two identical sequence changes in exon 2 (missense mutation Val165Met, 523G-->A and a silent substitution in Ser77Ser codon 261C-->T). Analysis of genomic DNA extracted from peripheral lymphocytes in one patient confirmed these changes to be present in the germline and they therefore probably represent polymorphisms, although we cannot exclude the possibility that these are predisposing germline mutations. We conclude that mutations of the KLF6 gene are unlikely to play an important role in sporadic pituitary tumorigenesis.
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Wojnarowicz, Paulina M., Marta Garcia Escolano, Yun-Han Huang, Bina Desai, Yvette Chin, Riddhi Shah, Sijia Xu, et al. "Anti-tumor effects of an ID antagonist with no observed acquired resistance." npj Breast Cancer 7, no. 1 (May 24, 2021). http://dx.doi.org/10.1038/s41523-021-00266-0.
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AbstractID proteins are helix-loop-helix (HLH) transcriptional regulators frequently overexpressed in cancer. ID proteins inhibit basic-HLH transcription factors often blocking differentiation and sustaining proliferation. A small-molecule, AGX51, targets ID proteins for degradation and impairs ocular neovascularization in mouse models. Here we show that AGX51 treatment of cancer cell lines impairs cell growth and viability that results from an increase in reactive oxygen species (ROS) production upon ID degradation. In mouse models, AGX51 treatment suppresses breast cancer colonization in the lung, regresses the growth of paclitaxel-resistant breast tumors when combined with paclitaxel and reduces tumor burden in sporadic colorectal neoplasia. Furthermore, in cells and mice, we fail to observe acquired resistance to AGX51 likely the result of the inability to mutate the binding pocket without loss of ID function and efficient degradation of the ID proteins. Thus, AGX51 is a first-in-class compound that antagonizes ID proteins, shows strong anti-tumor effects and may be further developed for the management of multiple cancers.
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Rohr, Michael, Jordan Beardsley, Sai Preethi Nakkina, Xiang Zhu, Jihad Aljabban, Dexter Hadley, and Deborah Altomare. "A merged microarray meta-dataset for transcriptionally profiling colorectal neoplasm formation and progression." Scientific Data 8, no. 1 (August 11, 2021). http://dx.doi.org/10.1038/s41597-021-00998-5.
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AbstractTranscriptional profiling of pre- and post-malignant colorectal cancer (CRC) lesions enable temporal monitoring of molecular events underlying neoplastic progression. However, the most widely used transcriptomic dataset for CRC, TCGA-COAD, is devoid of adenoma samples, which increases reliance on an assortment of disparate microarray studies and hinders consensus building. To address this, we developed a microarray meta-dataset comprising 231 healthy, 132 adenoma, and 342 CRC tissue samples from twelve independent studies. Utilizing a stringent analytic framework, select datasets were downloaded from the Gene Expression Omnibus, normalized by frozen robust multiarray averaging and subsequently merged. Batch effects were then identified and removed by empirical Bayes estimation (ComBat). Finally, the meta-dataset was filtered for low variant probes, enabling downstream differential expression as well as quantitative and functional validation through cross-platform correlation and enrichment analyses, respectively. Overall, our meta-dataset provides a robust tool for investigating colorectal adenoma formation and malignant transformation at the transcriptional level with a pipeline that is modular and readily adaptable for similar analyses in other cancer types.
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Li, Na, Yun Li, Hongbo Gao, Jing Li, Xiaoping Ma, Xiaomei Liu, Ping Gong, Xiaobin Cui, and Yong Li. "Forkhead-box A3 (FOXA3) represses cancer stemness and partially potentiates chemosensitivity by targeting metastasis-associated in colon cancer 1 (MACC1) signaling pathway in colorectal cancer cells." Current Cancer Drug Targets 20 (December 7, 2020). http://dx.doi.org/10.2174/1568009620666201207150632.
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Background: The major challenge to the treatment of advanced colorectal cancer (CRC) is persistent occurrence of chemoresistance. One of the established etiologies is the existence of cancerstem-like cells (CSCs) using which tumors resist to external therapeutic challenges. Objective: The forkhead-box A3 (FOXA3) is a potent transcription factor that potentiates the acquisition and maintenance of stemness fate in many physiological systems. However, its effect on cancer stemness, particularly treatment, has not been explored in CRC, forming the basis of the current study. Methods: FOXA3 expression in oxaliplatin-resistant CRC tissues and cells was evaluated using RT-qPCR. Effects of FOXA3 manipulation on sensitivity to oxaliplatin were assessed using WST-1, apoptotic ELISA, colony formation and xenograft model. Effects of FOXA3 alteration on CSCs were determined using tumor sphere assay and CD44 staining. Transcriptional regulation of MACC1 by FOXA3 was studied using ChIP, Co-IP and luciferase reporter assay. Results: FOXA3 expression was significantly reduced in tumor samples from oxaliplatin-non-responsive patients compared with that in tumor samples from oxaliplatin-sensitive patients. This downregulation of FOXA3 expression predicted a poor post-chemotherapy overall- or disease-free survival in our 117-patient cohort. FOXA3 down-regulation significantly enhanced cell survival and stem-like properties, thus rendering the CRC cells unresponsiveness to oxaliplatin-induced cell death. Mechanistically, the anti-neoplasic effect of FOXA3 was mediated mainly through transcriptional repression of metastasis-associated in colon cancer 1 (MACC1) in oxaliplatin-resistant CRC cells. Conclusion: Our findings establish FOXA3 as a potent tumor suppressor in CRC, which may disrupt the maintenance of stemness and modulate sensitivity to oxaliplatin by inhibiting the transcription of MACC1 within CRC cells.
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"Iron in the Promotion and Initiation of Cancer How Free Iron Accelerates Predisposing Insulin Resistance." Advances in Hematology and Oncology Research 1, no. 1 (November 15, 2018). http://dx.doi.org/10.33140/ahor.01.01.01.
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Iron is physiologically essential to life, but biochemically it is harmful because of its evident -but unappreciated- oxidative and inflammatory tissue power when it accumulates, is dosed in excess, or is free; and that because, after entering the body, unlike any other metal, its elimination is almost non-existent in man; thus, metal is a powerful promoter of chronic degenerative diseases, from diabetes, neurodegeneration to cancer, through extensive coronary and cardio-cerebrovascular disease; modifying its clinical expressivity and accelerating its severity. Iron is a powerful oxidizing and inflammatory agent, and its accumulation causes and promotes the proliferation of cancer cells in particular, both in animals and in humans. Free and accumulated iron triggers a powerful uncontrolled Cell Proliferation, permanently feeding the survival of the neoplastic cell. After more than 50 years of experimental and preclinical studies, it is clearly demonstrating the carcinogenicity of iron; and this is also proven in humans, from breast cancer and endometrium, in women, to cancer of the colon-rectum, prostate, and pancreas in men. In Western men and women, the reductions in iron deposits have an important anti-tumor and preventive effect for the development of cancer or diabetes, two entities biologically interrelated by the states of Resistance to Insulin, an inflammatory state that favors the development of malignant neoplasms, and can accelerate its aggressiveness. It is the chronic excess of insulin or its Tissue Resistance, the biological event and the clinical syndrome that increases the cancerous power of excess iron, both silent epidemics in modern man. Moderate increases in body iron levels increase the risk of acquiring cancer, and raise the level of their mortality. And its deficiency or chelation in vivo decreases the Tumor growth (Wang F, Elliott RL, Head JF: Inhibitory effect of deferoxamine mesylate and low iron diet on the 13762NF rat mammary adenocarcinoma Anticancer Res. 1999 Jan-Feb; 19 (1A): 445-50). If excess iron mediates and increases the risk of cancer associated with Insulin resistance, any subject with this syndrome can minimize any associated health risks (and their increased risk of cancer), avoiding iron-rich diets and donating blood with regularity; Iron is the metal that causes “exponential” and punctual mutations and fusion of genes through chromosomal translocations, constituting the greatest risk factor for human carcinogenesis. Iron is physiologically essential for life but biochemically dangerous. Chronic accumulation of iron causes pantropic organ damage and excess body iron play an important role in carcinogenesis, coronary artery disease, neurodegenerative disease, stroke and inflammatory disorders. Iron is very slowly excreted from humans once it is absorbed into the body. The significance of iron excess has been markedly underestimated, despite the fact that iron overloading disorders are as common place in the US white population. Iron-overload and catalytic iron promotes activation of oxidative responsive transcription factors and pro-inflammatory cytokines that increase cancer extension and aggravate them. There is accumulative evidence for iron as a carcinogenic metal in epidemiological, clinical, animal, and cell culture studies. The role of iron in various cancers, such as colorectal and liver cancer was demonstrated. Recent advancements on the molecular mechanisms of iron carcinogenesis evolved the Insulin-resistance generation and promotion, fisiopatologic condition that is not only permissive, but may be generated cancer and promoting it. Unlike other nutritional metals, iron is highly conserved: toxicity due to excess iron can occur either acutely after a single dose or chronically due to excessive accumulation in the body from diet. In vivo studies have demonstrated that an iron deficiency induced by either feeding a low iron diet injecting the iron chelator deferoxamine mesylate decreases tumor growth (Wang F, Elliott RL, Head JF: Inhibitory effect of deferoxamine mesylate and low iron diet on the 13762NF rat mammary adenocarcinoma Anticancer Res. 1999 Jan-Feb;19(1A):445-50). Iron supplementation has at times proven ineffective and even detrimental to health. Thus, iron excess may mediate the increased cancer risk associated with insulin resistance and heme-rich diets, and subjects who are insulin resistant can minimize any health risk associated with iron overload by avoiding heme-rich flesh foods and donating blood regularly. The energy that sustains cancer cells derived preferentially from glycolysis depends on the gene p53 deficiency-iron induced. This nutrient is postulated to contribute to the initiation of cancer in vivo, but iron overload initiates and sustain cancer development if chronic infection or insulin resistance conditions are present. Cancer cells require considerably more iron than normal cells. Since iron catalytic can induce driver point mutation and create fusion genes through chromosomal translocations, iron overload is one of the most important risk factors in human carcinogenesis. Because free iron may play a catalytic role in “spontaneous” mutagenesis, moderately elevated iron stores increased overall risk for cáncer.
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Allen, Jawara, Stephanie Hao, Cynthia L. Sears, and Winston Timp. "Epigenetic Changes Induced by Bacteroides fragilis Toxin." Infection and Immunity 87, no. 6 (March 18, 2019). http://dx.doi.org/10.1128/iai.00447-18.
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ABSTRACT Enterotoxigenic Bacteroides fragilis (ETBF) is a Gram-negative, obligate anaerobe member of the gut microbial community in up to 40% of healthy individuals. This bacterium is found more frequently in people with colorectal cancer (CRC) and causes tumor formation in the distal colon of multiple intestinal neoplasia (Apcmin/+) mice; tumor formation is dependent on ETBF-secreted Bacteroides fragilis toxin (BFT). Because of the extensive data connecting alterations in the epigenome with tumor formation, initial experiments attempting to connect BFT-induced tumor formation with methylation in colon epithelial cells (CECs) have been performed, but the effect of BFT on other epigenetic processes, such as chromatin structure, remains unexplored. Here, the changes in gene expression (transcriptome sequencing [RNA-seq]) and chromatin accessibility (assay for transposase-accessible chromatin using sequencing) induced by treatment of HT29/C1 cells with BFT for 24 and 48 h were examined. Our data show that several genes are differentially expressed after BFT treatment and that these changes relate to the interaction between bacteria and CECs. Further, sites of increased chromatin accessibility are associated with the location of enhancers in CECs and the binding sites of transcription factors in the AP-1/ATF family; they are also enriched for common differentially methylated regions (DMRs) in CRC. These data provide insight into the mechanisms by which BFT induces tumor formation and lay the groundwork for future in vivo studies to explore the impact of BFT on nuclear structure and function.
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Proutière, Alexis, Laurence du Merle, Bruno Périchon, Hugo Varet, Myriam Gominet, Patrick Trieu-Cuot, and Shaynoor Dramsi. "Characterization of a Four-Component Regulatory System Controlling Bacteriocin Production in Streptococcus gallolyticus." mBio 12, no. 1 (January 5, 2021). http://dx.doi.org/10.1128/mbio.03187-20.
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ABSTRACT Bacteriocins are natural antimicrobial peptides produced by bacteria to kill closely related competitors. The opportunistic pathogen Streptococcus gallolyticus subsp. gallolyticus was recently shown to outcompete commensal enterococci of the murine microbiota under tumoral conditions thanks to the production of a two-peptide bacteriocin named gallocin. Here, we identified four genes involved in the regulatory control of gallocin in S. gallolyticus subsp. gallolyticus UCN34 that encode a histidine kinase/response regulator two-component system (BlpH/BlpR), a secreted peptide (GSP [gallocin-stimulating peptide]), and a putative regulator of unknown function (BlpS). While BlpR is a typical 243-amino-acid (aa) response regulator possessing a phospho-receiver domain and a LytTR DNA-binding domain, BlpS is a 108-aa protein containing only a LytTR domain. Our results showed that the secreted peptide GSP activates the dedicated two-component system BlpH/BlpR to induce gallocin transcription. A genome-wide transcriptome analysis indicates that this regulatory system (GSP-BlpH/BlpR) is specific for bacteriocin production. Importantly, as opposed to BlpR, BlpS was shown to repress gallocin gene transcription. A conserved operator DNA sequence of 30 bp was found in all promoter regions regulated by BlpR and BlpS. Electrophoretic mobility shift assays (EMSA) and footprint assays showed direct and specific binding of BlpS and BlpR to various regulated promoter regions in a dose-dependent manner on this conserved sequence. Gallocin expression appears to be tightly controlled in S. gallolyticus subsp. gallolyticus by quorum sensing and antagonistic activity of 2 LytTR-containing proteins. Competition experiments in gut microbiota medium and 5% CO2 to mimic intestinal conditions demonstrate that gallocin is functional under these in vivo-like conditions. IMPORTANCE Streptococcus gallolyticus subsp. gallolyticus, formerly known as Streptococcus bovis biotype I, is an opportunistic pathogen causing septicemia and endocarditis in the elderly often associated with asymptomatic colonic neoplasia. Recent studies indicate that S. gallolyticus subsp. gallolyticus is both a driver and a passenger of colorectal cancer. We previously showed that S. gallolyticus subsp. gallolyticus produces a bacteriocin, termed gallocin, enabling colonization of the colon under tumoral conditions by outcompeting commensal members of the murine microbiota such as Enterococcus faecalis. Here, we identified and extensively characterized a four-component system that regulates gallocin production. Gallocin gene transcription is activated by a secreted peptide pheromone (GSP) and a two-component signal transduction system composed of a transmembrane histidine kinase receptor (BlpH) and a cytosolic response regulator (BlpR). Finally, a DNA-binding protein (BlpS) was found to repress gallocin genes transcription, likely by antagonizing BlpR. Understanding gallocin regulation is crucial to prevent S. gallolyticus subsp. gallolyticus colon colonization under tumoral conditions.