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1
Yamamoto, Y., Y. Kobayashi, Y. Yoshimoto, and K. Okuda. "104 EXPRESSION OF ACTIVIN A AS A LOCAL REGULATOR IN THE BOVINE OVIDUCT." Reproduction, Fertility and Development 27, no. 1 (2015): 145. http://dx.doi.org/10.1071/rdv27n1ab104.
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Activin (ACV) is known as a local regulator of several reproductive functions including follicular development and implantation in mammals. ACVA is a glycopeptide belonging to the transforming growth factor β superfamily, and is a homodimer of inhibin ßA (INHBA) subunits. Follistatin (FST), an ACV-specific binding protein, inhibits ligand-receptor binding. ACV receptor (ACVR) is a hetero-tetramer consisting of 2 kinds of protein, ACVR1 or ACVR1B and ACVR2A or ACVR2B. The oviduct provides an optimal environment for sperm capacitation, fertilization, and early embryonic development. Previous reports have demonstrated that ACVRs were expressed in bovine oocytes and embryos, and that early embryonic development is facilitated by ACVA in vitro. ACVA produced by the bovine oviduct may affect gametes and embryos as well as oviductal cells as a local regulator in cow. Bovine oviductal samples were classified into 6 stages of the oestrous cycle (day of ovulation; Days 2–3 after ovulation; Days 5–6; Days 8–12; Days 15–17; Days 19–21). We examined (1) protein expression of ACVA and FST in oviductal fluid collected from the ampulla and isthmus, (2) mRNA expression of INHBA and FST in the ampullary and isthmic oviductal tissues during the oestrous cycle, (3) the effects of oestradiol-17β (E2: 0.1, 1, 10 nM) and progesterone (P4: 1, 10, 100 nM) on mRNA expressions of INHBA and FST in cultured oviductal epithelial cells isolated from the ampulla and isthmus, and (4) mRNA expression of ACVRs in tissues and in cultured epithelial and stromal cells. The main findings were as follows: (1) Both ACVA and FST were detected throughout the oestrous cycle in the oviductal fluid of the ampulla and isthmus. (2) INHBA expression was higher in the isthmus than in the ampulla. FST expression in the ampulla was lowest at peri-ovulation, INHBA expression in the isthmus was highest on the day of ovulation and FST in the isthmus during Days 2–6 was highest. Because an increase of ACVA production and a decrease of FST production raise ACVA bioactivity, ACVA seems to be most active at peri-ovulation in both the ampulla and isthmus. (3) In the cultured isthmic oviductal epithelial cells, 10 nM E2 significantly stimulated INHBA expression, but tended to suppress FST expression. Therefore, the bioactivity of ACVA seems to be controlled by E2 during the oestrous cycle in the isthmus. (4) The expression of ACVR1B and ACVR2A was clearly detected in the tissues as well as in cultured epithelial and stromal cells. The overall findings suggest that ACVA secreted into oviductal fluid plays an important role in oviductal functions, including fertilization in the ampulla and sperm motility and viability in the isthmus. It is also suggested that ACVA acts on both epithelial and stromal cells as a local regulator of cellular functions, such as cellular proliferation and secretion in the cow.
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Szilágyi, Szabina Szófia, Wiktor Burdzinski, Jerome Jatzlau, Marcelo Ehrlich, Petra Knaus, and Yoav I. Henis. "The Activation of the Fibrodysplasia Ossificans Progressiva-Inducing ALK2-R206H Mutant Depends on the Distinct Homo-Oligomerization Patterns of ACVR2B and ACVR2A." Cells 13, no. 3 (2024): 221. http://dx.doi.org/10.3390/cells13030221.
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Mutations in activin-like kinase 2 (ALK2), e.g., ALK2-R206H, induce aberrant signaling to SMAD1/5/8, leading to Fibrodysplasia Ossificans Progressiva (FOP). In spite of extensive studies, the underlying mechanism is still unclear. Here, we quantified the homomeric and heteromeric interactions of ACVR2A, ACVR2B, ALK2-WT, and ALK2-R206H by combining IgG-mediated immobilization of one receptor with fluorescence recovery after photobleaching (FRAP) measurements on the lateral diffusion of a co-expressed receptor. ACVR2B formed stable homomeric complexes that were enhanced by Activin A (ActA), while ACVR2A required ActA for homodimerization. ALK2-WT, but not ALK2-R206H, exhibited homomeric complexes unaffected by ActA. ACVR2B formed ActA-enhanced heterocomplexes with ALK2-R206H or ALK2-WT, while ACVR2A interacted mainly with ALK2-WT. The extent of the homomeric complex formation of ACVR2A or ACVR2B was reflected in their ability to induce the oligomerization of ALK2-R206H and ALK2-WT. Thus, ACVR2B, which forms dimers without ligand, induced ActA-independent ALK2-R206H clustering but required ActA for enhancing the oligomerization of the largely dimeric ALK2-WT. In contrast, ACVR2A, which undergoes homodimerization in response to ActA, required ActA to induce ALK2-R206H oligomerization. To investigate whether these interactions are translated into signaling, we studied signaling by the FOP-inducing hyperactive ALK2-R206H mutant, with ALK2-WT signaling as control. The activation of SMAD1/5/8 signaling in cells expressing ALK2-R206H alone or together with ACVR2A or ACVR2B was measured by blotting for pSMAD1/5/8 and by transcriptional activation assays using BRE-Luc reporter. In line with the biophysical studies, ACVR2B activated ALK2-R206H without ligand, while activation by ACVR2A was weaker and required ActA. We propose that the homodimerization of ACVR2B or ACVR2A dictates their ability to recruit ALK2-R206H into higher complexes, enabling the homomeric interactions of ALK2-R206H receptors and, subsequently, their activation.
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Yuza, Kizuki, Masayuki Nagahashi, Hiroshi Ichikawa, et al. "Association of activin type II receptor mutation with microsatellite instability in gastric cancer." Journal of Clinical Oncology 35, no. 15_suppl (2017): e23191-e23191. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e23191.
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e23191 Background: Microsatellite instability-high status (MSI-H) and alterations in the DNA mismatch repair pathway associate with the efficacy of 5-FU and immune checkpoint inhibitors in patients with gastrointestinal cancers. The activin type II receptor (ACVR2) that binds to the transforming growth factor beta superfamily of ligands is frequently mutated in MSI-H colorectal cancer. However, the incidence of ACVR2 mutations in gastric cancer patients remains unclear. The aim of this study is to reveal the incidence and to examine the association between the MSI-H and ACVR2A mutations in gastric cancer patients. Methods: 124 archived FFPE gastric cancer tissues (stage I-IV), who were operated at Niigata University Medical and Dental Hospital or Niigata Cancer Center Hospital, were analyzed for ACVR2A mutation and MSI status with the NGS-based comprehensive genomic test platform. Clinicopathological characteristics of the patients were also examined. Results: All 124 gastric cancer patients were successfully analyzed. 13 out of 124 patients (10.4%) showed MSI-H status. Interestingly, 10 of 13 MSI-H patients (76.9%) showed ACVR2A mutation, where none (0%) was found among patients with microsatellite stable status (P < 0.001), indicating the strong association between ACVR2A mutation and MSI status in gastric cancer patients. In the ACVR2A mutated group, there was a female predominance (P < 0.05), and cancers of the lower part of the stomach were more common (P < 0.05), compared with the wild type group. Only one of 10 patients with ACVR2A mutation died, and the patients with ACVR2A mutation show a 5-year overall survival rate of 90%. No statistically significant difference in survival was achieved between patients with ACVR2A mutation and wild type; this is probably due to the small number of patients. Conclusions: 10 of 13 MSI-H patients showed ACVR2A mutation. Our results indicate a strong association between ACVR2A mutation and MSI-H in gastric cancer patients.
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Jia, Yongning, Hongling Yuan, Yaqun Xin, et al. "Abstract 5752: Loss-of-function mutations in ACVR2A are correlated with microsatellite instability in gastric and colorectal cancer." Cancer Research 82, no. 12_Supplement (2022): 5752. http://dx.doi.org/10.1158/1538-7445.am2022-5752.
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Abstract Background: The activin type II receptor (ACVR2), which is a member of the transforming growth factor beta (TGF-β) receptor family, is frequently mutated in colorectal cancer (CRC) and gastric cancer (GC). However, the incidence of ACVR2 mutations in MSI-H patients remains unclear. The aim of this study is to evaluate ACVR2A mutation characteristics and to examine its associations between the high microsatellite instability (MSI-H) and ACVR2A mutations in CRC and GC. Materials and Methods: We analyzed data from two cohorts: a Chinese cohort and the TCGA cohort. The Chinese cohort consisted of 1960 patients with CRC and GC, including 140 MSI-H samples and 1820 MSS samples. MSI status of these patients was derived from tumor-normal paired sequence data by targeted next generation sequencing (NGS). The TCGA cohort consists of 570 patients whose MSI status was determined. NGS data and clinical information were downloaded from the cBioPortal database (https://www.cbioportal.org). The abundance of tumor immune infiltrates was estimated by the Tumor Immune Estimation Resource (TIMER) 2.0 algorithm using gene expression data. Results: In the Chinese cohort, ACVR2A mutations were identified in 204 (18.6%) of 1960 patients, including 125 (61%) MSI-H patients and 79 (39%) MSS patients. Meanwhile, in all 140 MSI-H samples, 125 (90%) samples harbored AVCR2A mutation. The main variant of ACVR2A is loss of function mutation (ACVR2ALOF), including p.K437del(65%, 132/204), p.D96del(5%, 11/204), p.Asp96ins(4%, 9/204), and etc. ACVR2ALOF were detected in 161 patients (78.9%, 161/204), of which 125 (77%) were MSI-H and 36 (22%) were MSS. In the TCGA cohort, there were 102 (102/570) MSI-H samples, and 43% (44/102) of MSI-H samples carried ACVR2A mutation. Compared to the Chinese cohort, the ACVR2A mutation frequency in MSI-H samples was significantly lower in the TCGA cohort (43% vs 90%, p&lt;0.01). The ACVR2ALOF mutations were observed in 30 MSI-H samples and 6 MSS samples. In both cohorts, patients with ACVR2ALOF mutations exhibited higher TMB (p&lt;0.05) and PD-L1 expression (p&lt;0.0001) than those without ACVR2ALOF mutations. Furthermore, in the TCGA cohort, we found that the Tumor Infiltrating Lymphocytes (TILs) of CD4+ T cells and macrophage cells were significantly lower in ACVR2ALOF samples than those without ACVR2ALOF mutations (p&lt;0.05). Conclusions: The ACVR2ALOF was strongly correlated with MSI-H in patients of CRC and GC in both cohorts, especially in the Chinese population. Patients with ACVR2ALOF mutations have similar genomic characteristics to MSI-H, with high TMB, high PD-L1 expression, and therefore can serve as a potential biomarker for selecting candidates for immunotherapy. Citation Format: Yongning Jia, Hongling Yuan, Yaqun Xin, Fei Pang, Fei Shan, Shuangxi Li, Honglin Zhu, Ziyu Li. Loss-of-function mutations in ACVR2A are correlated with microsatellite instability in gastric and colorectal cancer [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 5752.
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Xu, Zhixiao, and Chengshui Chen. "Abnormal Expression and Prognostic Significance of Bone Morphogenetic Proteins and Their Receptors in Lung Adenocarcinoma." BioMed Research International 2021 (May 7, 2021): 1–23. http://dx.doi.org/10.1155/2021/6663990.
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Background. Lung adenocarcinoma (LUAD) is one of the most life-threatening malignancies. The crucial role of bone morphogenetic protein (BMP)/BMP receptors reveals the significance of exploring BMP protein-related prognostic predictors in LUAD. Methods. The mRNA expression of BMPs/BMP receptors was investigated in LUAD and normal lung tissues. Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes pathway analyses were performed, and the prognostic values were assessed by Kaplan-Meier Plotter. Univariate and multivariate Cox regression analyses were executed to ascertain the correlation between overall survival (OS) and the mRNA expression of BMPs/BMP receptors. The receiver operating characteristic (ROC) curves were implemented to evaluate the predictive power of the prognostic model. Then, the prognostic model was validated in the GEO cohort. Furthermore, a nomogram comprising the prognostic model was established. Results. The mRNA expression of BMP2/5/6/R2, ACVRL1, and TGFBR2/3 was lower in LUAD tissues than in normal lung tissues. High expression of BMP2/4/5/R1A/R2, ACVR1/2A/L1, and TGFBR1/3 was associated with better OS, while BMP7 and ACVR1C/2B were associated with poorer OS. Three genes (BMP5, BMP7, and ACVR2A) were screened by univariate and multivariate Cox regression analyses to develop the prognostic model in TCGA. Significantly better survival was observed in LUAD patients with a low-risk score than those with a high-risk score. The ROC curves confirmed the good performance of the prognostic model, then, the prognostic model was validated in the GSE31210 dataset. A nomogram was constructed (AUCs>0.7). And hub genes were further evaluated, including gene set enrichment analysis and immune cell infiltration. Conclusions. BMP5, BMP7, and ACVR2A are potential therapeutic targets in LUAD. The three-gene prognostic model and the nomogram are reliable tools for predicting the OS of LUAD patients.
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Zhuo, Changhua, Dan Hu, Xiandong Lin, Ying Chen, Xiongwei Zheng, and Chunkang Yang. "Down expression of activin A receptor type 2A in relation to metastatic potential and prognosis of patients with colon cancer." Journal of Clinical Oncology 36, no. 4_suppl (2018): 712. http://dx.doi.org/10.1200/jco.2018.36.4_suppl.712.
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712 Background: The ACVR2A (activin A receptor type 2A) is a membrane receptor in TGF-β signal pathway, which is involved in the regulation of cell proliferation, migration and apoptosis. The expression profiles and biological functions of ACVR2A in colon cancer is largely unknown so far. Methods: ACVR2A expression was investigated using GSE39582 database and two validation cohorts. The in vitro study of the cell proliferation and migration of human colon cell lines was also performed. Results: In GSE39582 database (n = 497), lower mRNA expression of ACVR2A was identified as an inferior prognostic factor by linear regression analysis. In one validation cohort of 15 stage IV patients, the mRNA expression of ACVR2A was significantly reduced in metastatic lesions and primary tumors compared with adjacent normal controls (P = 0.001). In another validation cohort of tissue microarray (TMA) cohort consisting 193 cases, reduced ACVR2A expression was correlated with advanced N stage (P = 0.001) and positive lymphovascular invasion (P = 0.005). Strong correlations between lower ACVR2A mRNA or protein expression and worse survival were also observed in GSE39582 database and TMA validation cohort (all P< 0.05). Moreover, our in vitro studies showed a remarkable increase of cell migration in cell ACVR2A knockdown cells. Conclusions: Taken together, our findings indicate that loss of ACVR2A has an important role in cancer progression and distant metastasis, and may serve as a prognostic marker in patients with colon cancer. Keywords: Activin a receptor type 2A (ACVR2A), Colon Cancer, tissue microarray, Metastasis, Cell proliferation, Cell migration
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Ongaro, Luisina, Xiang Zhou, Yiming Cui, Ulrich Boehm, and Daniel J. Bernard. "Gonadotrope-specific deletion of the BMP type 2 receptor does not affect reproductive physiology in mice†‡." Biology of Reproduction 102, no. 3 (2019): 639–46. http://dx.doi.org/10.1093/biolre/ioz206.
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Abstract Activins selectively stimulate follicle-stimulating hormone (FSH) secretion by pituitary gonadotrope cells. More recently, other members of the TGFbeta superfamily, the bone morphogenetic proteins (BMPs), were reported to regulate FSH synthesis. Activins and BMPs independently and synergistically stimulate transcription of the FSHbeta subunit (Fshb) gene in immortalized gonadotrope-like cells. Both ligands can signal via the activin receptor type IIA (ACVR2A) to regulate FSH synthesis in vitro. In vivo, global Acvr2a knockout mice exhibit a 60% reduction in circulating FSH relative to wild-type animals, suggesting that activins, BMPs, or related ligands might signal through additional type II receptors to regulate FSH in vivo. Although the leading candidates are ACVR2B and the BMP type II receptor (BMPR2), only the latter mediates activin or BMP2 induction of Fshb transcription in vitro. Here, we generated mice carrying a loss of function mutation in Bmpr2 specifically in gonadotropes. Puberty onset, estrous cyclicity, and reproductive organ weights were similar between control and conditional knockout females. Serum FSH and luteinizing hormone (LH) and pituitary expression of Fshb and the LHbeta subunit (Lhb) were similarly unaffected by the gene deletion in both sexes. These results suggest that BMPR2 might not play a necessary role in FSH synthesis or secretion in vivo or that another type II receptor, such as ACVR2A, can fully compensate for its absence. These data also further contribute to the emerging concept that BMPs may not be physiological regulators of FSH in vivo.
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Li, Cheng-Lin, Zhi-Bin Xu, Xing-Liang Fan, et al. "MicroRNA-21 Mediates the Protective Effects of Mesenchymal Stem Cells Derived from iPSCs to Human Bronchial Epithelial Cell Injury Under Hypoxia." Cell Transplantation 27, no. 3 (2018): 571–83. http://dx.doi.org/10.1177/0963689718767159.
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Airway epithelial cell injury is a key triggering event to activate allergic airway inflammation, such as asthma. We previously reported that administration of mesenchymal stem cells (MSCs) significantly alleviated allergic inflammation in a mouse model of asthma, and the mmu-miR-21/ACVR2A axis may be involved. However, whether MSCs protect against bronchial epithelial cell injury induced by hypoxia, and the underlying mechanism, remain unknown. In our study, the human bronchial epithelial cell line BEAS-2B was induced to undergo apoptosis with a hypoxia mimic of cobalt chloride (CoCl2) damage. Treatment of MSCs derived from induced pluripotent stem cells (iPSCs) significantly decreased apoptosis of BEAS-2B cells. There was high miR-21 expression in injured BEAS-2B cells after MSC treatment. Transfection of the miR-21 mimic significantly decreased apoptosis of BEAS-2B, and transfection of a miR-21 inhibitor significantly increased apoptosis. More importantly, the protective effects of MSCs on injured BEAS-2B were reversed by transfection of the miR-21 inhibitor. Binding sites of human miR-21 were identified in the 3’UTR of human ACVR2A. We further determined that CoCl2 stimulation increased ACVR2A expression at both the mRNA and protein levels. Moreover, transfection of the miR-21 mimic further up-regulated ACVR2A expression induced by CoCl2, whereas transfection of the miR-21 inhibitor down-regulated ACVR2A expression. In addition, MSCs increased ACVR2A expression in BEAS-2B cells; however, this effect was reversed after transfection of the miR-21 inhibitor. Our data suggested that MSCs protect bronchial epithelial cells from hypoxic injury via miR-21, which may represent an important target. These findings suggest the potentially wide application of MSCs for epithelial cell injury during hypoxia.
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Ashouri, Karam, Yan Yang, Joshua Millstein, et al. "Myostatin/activin pathway gene expression and single nucleotide polymorphisms (SNPs) in metastatic colorectal cancer (mCRC)." Journal of Clinical Oncology 42, no. 3_suppl (2024): 188. http://dx.doi.org/10.1200/jco.2024.42.3_suppl.188.
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188 Background: Cancer cachexia leads to reduced overall survival (OS) in mCRC. Novel therapeutics targeting the myostatin/activin pathway can reverse cachexia. Here we investigate the effect of myostatin/activin pathway gene expression and SNPs in mCRC patients (pts). Methods: Blood samples from 836 pts enrolled in 3 randomized first-line trials: TRIBE (FOLFIRI bevacizumab [bev]; FOLFOXIRI bev), FIRE-3 (FOLFIRI bev; FOLFIRI cetuximab [cet]) and MAVERICC (FOLFIRI bev; FOLFOX bev) were genotyped by Illumina OncoArray. The impact on outcome of 13 SNPs from 5 myostatin/activin genes ( ACVR1B, ACVR2A, ACVR2B, MSTN, INHBA) was tested. Gene expression analysis included 433 mCRC pts treated with either bev (n = 226) or cet (n = 207) in combination with first-line chemotherapy from the CALGB/SWOG 80405 trial (NCT00265850). RNA isolated from FFPE tumor samples were sequenced with HiSeq 2500 (Illumina). OS and progression-free survival (PFS) were compared by gene expression tertiles: low (L), medium (M), and high (H). Logrank test was used for univariate (UV) analysis, Cox proportional hazards regression for multivariate (MV). Results: Pts with the germline G/G variant of ACVR2B rs2276541 had worse PFS (FIRE-3 bev: 9.7 vs 12.2 months [mo]; UV P = .044, MV P = .027; HR 2.10, 95%CI 1.13 - 3.38 & FIRE-3 cet: 7.6 vs 13.2 mo; UV P = .047; HR 1.65, 95%CI 1.00 - 2.72) and tumor response (TRIBE FOLFIRI bev: 48 vs 61%, MV P = .035) compared to any A carriers. Rs3749387 C/C variant in the same gene showed longer OS (MAVERICC FOLFOX bev: 36.9 vs 24.3 mo; MV P = .005; HR = 0.41, 95%CI 0.21-0.80) and PFS (MAVERICC FOLFIRI bev: 14.5 vs 11.8 mo; MV P = .009; HR = 0.53, 95%CI 0.32-0.88) relative to G variants. Any C allele in ACVR2A rs10497025 demonstrated improved OS (MAVERICC FOLFOX bev: 25.5 vs 11.9 mo; HR = 2.38, UV P = .035; 95%CI 1.03- 5.50 & TRIBE FOLFIRI bev: 26.9 vs 22.4 mo; UV P = .017; HR = 1.90, 95%CI 1.11-3.26) and PFS (FIRE-3 - FOLFIRI cet : 32.1 vs 12.2 mo; UV P = .047; HR = 0.47, 95%CI 0.22-1.02 & MAVERICC FOLFOX bev 11.0 vs 6.8 mo; UV P = .006; HR = 2.52, 95%CI 1.26-5.00) relative to G/G. Tumor ACVR1B-H expression was associated with longer PFS (L/M/H, 9.5 vs 10.9 vs 13.5 mo, UV P = .034) and OS (L/M/H, 25.0 vs 28.2 vs 38.6 mo, UV P < .001) in all treated pts. ACVR1B-H also conferred improved OS in treatment subgroups (L/M/H; cet: 21.0 vs 27.4 vs 40.3 mo, UV P < .001; bev: 25.9 vs 29.0 vs 36.9 mo, UV P = .025). ACVR2B-L correlated with worse PFS (L/M/H, 10.3 vs 12.2 vs 11.2 mo, UV P = .043) and OS (L/M/H, 24.7 vs 33.8 vs 34.9 mo; P = .006) in the overall cohort. This association held true in cet treated patients (OS 21.2 vs 35.8 vs 37.1 mo; UV P < .001) but not bev. Conclusions: Our results suggest a role of cachexia SNPs and gene expression as a prognostic marker for mCRC undergoing first line treatment. These biomarkers may enable targeted treatments for cancer cachexia and support exploring this approach in combination with standard therapy in selected pts.
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Ma, Sen, Dejun Ji, Xiaolong Wang, Yuxin Yang, Yinghua Shi, and Yulin Chen. "Transcriptomic Analysis Reveals Candidate Ligand-Receptor Pairs and Signaling Networks Mediating Intercellular Communication between Hair Matrix Cells and Dermal Papilla Cells from Cashmere Goats." Cells 12, no. 12 (2023): 1645. http://dx.doi.org/10.3390/cells12121645.
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Hair fiber growth is determined by the spatiotemporally controlled proliferation, differentiation, and apoptosis of hair matrix cells (HMCs) inside the hair follicle (HF); however, dermal papilla cells (DPCs), the cell population surrounded by HMCs, manipulate the above processes via intercellular crosstalk with HMCs. Therefore, exploring how the mutual commutations between the cells are molecularly achieved is vital to understanding the mechanisms underlying hair growth. Here, based on our previous successes in cultivating HMCs and DPCs from cashmere goats, we combined a series of techniques, including in vitro cell coculture, transcriptome sequencing, and bioinformatic analysis, to uncover ligand-receptor pairs and signaling networks mediating intercellular crosstalk. Firstly, we found that direct cellular interaction significantly alters cell cycle distribution patterns and changes the gene expression profiles of both cells at the global level. Next, we constructed the networks of ligand-receptor pairs mediating intercellular autocrine or paracrine crosstalk between the cells. A few pairs, such as LEP-LEPR, IL6-EGFR, RSPO1-LRP6, and ADM-CALCRL, are found to have known or potential roles in hair growth by acting as bridges linking cells. Further, we inferred the signaling axis connecting the cells from transcriptomic data with the advantage of CCCExplorer. Certain pathways, including INHBA-ACVR2A/ACVR2B-ACVR1/ACVR1B-SMAD3, were predicted as the axis mediating the promotive effect of INHBA on hair growth via paracrine crosstalk between DPCs and HMCs. Finally, we verified that LEP-LEPR and IL1A-IL1R1 are pivotal ligand-receptor pairs involved in autocrine and paracrine communication of DPCs and HMCs to DPCs, respectively. Our study provides a comprehensive landscape of intercellular crosstalk between key cell types inside HF at the molecular level, which is helpful for an in-depth understanding of the mechanisms related to hair growth.
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Song, Hailiang, Tian Dong, Wei Wang, et al. "GWAS Enhances Genomic Prediction Accuracy of Caviar Yield, Caviar Color and Body Weight Traits in Sturgeons Using Whole-Genome Sequencing Data." International Journal of Molecular Sciences 25, no. 17 (2024): 9756. http://dx.doi.org/10.3390/ijms25179756.
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Caviar yield, caviar color, and body weight are crucial economic traits in sturgeon breeding. Understanding the molecular mechanisms behind these traits is essential for their genetic improvement. In this study, we performed whole-genome sequencing on 673 Russian sturgeons, renowned for their high-quality caviar. With an average sequencing depth of 13.69×, we obtained approximately 10.41 million high-quality single nucleotide polymorphisms (SNPs). Using a genome-wide association study (GWAS) with a single-marker regression model, we identified SNPs and genes associated with these traits. Our findings revealed several candidate genes for each trait: caviar yield: TFAP2A, RPS6KA3, CRB3, TUBB, H2AFX, morc3, BAG1, RANBP2, PLA2G1B, and NYAP1; caviar color: NFX1, OTULIN, SRFBP1, PLEK, INHBA, and NARS; body weight: ACVR1, HTR4, fmnl2, INSIG2, GPD2, ACVR1C, TANC1, KCNH7, SLC16A13, XKR4, GALR2, RPL39, ACVR2A, ADCY10, and ZEB2. Additionally, using the genomic feature BLUP (GFBLUP) method, which combines linkage disequilibrium (LD) pruning markers with GWAS prior information, we improved genomic prediction accuracy by 2%, 1.9%, and 3.1% for caviar yield, caviar color, and body weight traits, respectively, compared to the GBLUP method. In conclusion, this study enhances our understanding of the genetic mechanisms underlying caviar yield, caviar color, and body weight traits in sturgeons, providing opportunities for genetic improvement of these traits through genomic selection.
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Estienne, Anthony, Belén Lahoz, Peggy Jarrier, et al. "BMP15 regulates the inhibin/activin system independently of ovulation rate control in sheep." Reproduction 153, no. 4 (2017): 395–404. http://dx.doi.org/10.1530/rep-16-0507.
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Polymorphisms in the gene encoding bone morphogenetic protein 15 (BMP15) have been associated with multiple ovulations in sheep. As BMP15 regulates inhibin expression in rodents, we assumed that the ovarian inhibin/activin system could mediate part of the effect of BMP15 mutations in the regulation of ovulation rate in sheep. To answer this question, we have studied the effects of two natural loss-of-function mutations of BMP15 on the expression of components of this system. The FecXR and the FecXGr mutations, when present respectively in Rasa Aragonesa ewes at the heterozygous state and in Grivette ewes at the homozygous state, were associated with a twofold increase in ovulation rate. There were only small differences between mutant and wild-type ewes for mRNA expression of INHA, INHBA, ACVR1B, ACVR2A, FST or TGFBR3 in granulosa cells and inhibin A or activin A concentrations in follicular fluid. Moreover, the effects of mutations differed between breeds. In cultures of granulosa cells from wild-type ewes, BMP15, acting alone or in synergy with GDF9, stimulated INHA, INHBA and FST expression, but inhibited the expression of TGFBR3. Activin A did not affect INHBA expression, but inhibited the expression of ACVR2A also. The complexity of the inhibin/activin system, including positive and antagonistic elements, and the differential regulation of these elements by BMP15 and activin can explain that the effects of BMP15 mutations differ when present in different genetic backgrounds. In conclusion, the ovarian inhibin/activin system is unlikely to participate in the increase of ovulation rate associated with BMP15 mutations in sheep.
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Zhang, Jiaqing, Qiaoling Ren, Junfeng Chen, et al. "Downregulation of miR-192 Alleviates Oxidative Stress-Induced Porcine Granulosa Cell Injury by Directly Targeting Acvr2a." Cells 11, no. 15 (2022): 2362. http://dx.doi.org/10.3390/cells11152362.
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Follicular atresia is primarily caused by breakdown to granulosa cells (GCs) due to oxidative stress (OS). MicroRNAs (miRNAs) elicit a defense response against environmental stresses, such as OS, by acting as gene-expression regulators. However, the association between miRNA expression and OS in porcine GCs (PGCs) is unclear. Here, we examined the impact of H2O2-mediated OS in PGCs through miRNA-Seq. We identified 22 (14 upregulated and 8 downregulated) and 33 (19 upregulated and 14 downregulated) differentially expressed miRNAs (DEmiRNAs) at 100 μM and 300 μM H2O2, respectively, compared with the control group. Among the DEmiRNAs, mi-192 was most induced by H2O2-mediated OS, and the downregulation of miR-192 alleviated PGC oxidative injury. The dual-luciferase reporter assay results revealed that miR-192 directly targeted Acvr2a. The Acvr2a level was found to be remarkably decreased after OS. Furthermore, grape seed procyanidin B2 (GSPB2) treatment significantly reduced the H2O2-induced upregulation of miR-192, and decreased PGC apoptosis and oxidative damage. Meanwhile, GSPB2 prevented an H2O2-induced increase in caspase-3 activity, which was enhanced by the application of the miR-192 inhibitor. These results indicate that GSPB2 protects against PGC oxidative injury via the downregulation of miR-192, the upregulation of Acvr2a expression, and the suppression of the caspase-3 apoptotic signaling pathway.
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Zhang, Wei, Zanmei Xu, Zewu Zhang, Tianqiang Song, and Fei Pang. "Deciphering genomic characteristics of ERBB family members potentially involved in the recovery of anti-cancer immunity for intrahepatic cholangiocarcinoma patients." Journal of Clinical Oncology 40, no. 16_suppl (2022): e16003-e16003. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.e16003.
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e16003 Background: Previous studies showed that the efficacy of immune checkpoint inhibitor (ICI) is enhanced in hepatobiliary cancers harboring activating gene alterations of ERBB family members. The purpose of this study was to explore genomic characteristics of ERBB family members as well as the relationship of them with the activity of anti-cancer immunity in Chinese intrahepatic cholangiocarcinoma (ICC) patients. Methods: Fifty-four ICC patients which carried at least one gene mutation of ERBB family members were pre-selected from 508 ICC patients included in the China Pan-cancer project of OrigiMed 2020 (https://www.cbioportal.org/study/summary?id=pan_origimed_2020). Targeted sequencing was implemented with cancer-related 450-gene panel. Tumor mutation burden (TMB) and microsatellite status were evaluated. To explore the molecular mechanisms, two human cholangiocarcinoma cell lines, RBE and HuCCT1, were transfected with a lentivirus to obtain the cells with stable S310F mutation and overexpression of ERBB2. Results: The variation frequencies of EGFR, ERBB2, ERBB3 and ERBB4 were 2.8% (14/508), 3.5% (18/508), 3.3% (17/508) and 2.4% (12/508) in Chinese ICC patients, respectively. All the patients harboring ERBB family gene mutations were classified as TMB-H (cutoff = 10 Muts/Mb), when co-mutated with ACVR2A or TGFBR2. Moreover, ACVR2A and TGFBR2 were identified as driver genes in the cohort with oncodriveCLUST. TMB and the proportion of MSI-H patients were significantly elevated when ERBB family members co-mutated with ACVR2A (mutation vs wild: TMB, 38.2 ± 19.1 vs 7.0 ± 8.6 Muts/Mb, p<0.0001; MSI-H, 77.8% vs 4.9%, p<0.0001), or with TGFBR2 (TMB, 33.1 ± 8.7 vs 9.0 ± 14.4 Muts/Mb, p<0.0001; MSI-H, 83.3% vs 9.1%, p<0.001). Besides, ACVR2A and TGFBR2 were enriched in TGF-β pathway. Flow cytometry analysis revealed that ERBB2 S310F mutation and amplification were increased by approximate 3-fold and 3.5-fold in PD-L1 expression of cell line RBE ( p < 0.0001, respectively); by approximate 2-fold and 3-fold upregulation of PD-L1 expression in cell line HUCCT1 ( p < 0.0001, respectively). Western-blot results suggested that ERBB2 mutation/overexpression mediated PD-L1 upregulation through the RAS/ERK/c-JUN pathway. T cell cytotoxicity-mediated killing assay demonstrated that ERBB2 S310F mutation and overexpression induced the recovery of anti-cancer immunity by about 30% ( p < 0.05) both in RBE and HuCCT1 cells. Conclusions: The present study revealed two distinct genomic characteristics potentially involved in the recovery of anti-cancer immunity of intrahepatic cholangiocarcinoma patients: on one hand, co-mutation of ERBB family genes with ACVR2A or TGFBR2 was enriched in TGF-β pathway, contributing to MSI-H/TMB-H; on the other hand, ERBB2 might impact expression of PD-L1 by regulating the RAS/ERK/c-Jun pathways.
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Song, Wei, Wei-Jie Dai, Meng-hui Zhang, Han Wang та Xiao-Zhong Yang. "Comprehensive Analysis of the Expression of TGF-β Signaling Regulators and Prognosis in Human Esophageal Cancer". Computational and Mathematical Methods in Medicine 2021 (23 жовтня 2021): 1–22. http://dx.doi.org/10.1155/2021/1812227.
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More and more evidences show that TGF-β has a crucial role in tumor initiation and development. However, the mechanism of the TGF-β signal regulator in esophageal cancer (EC) is still unclear. Here, we use a variety of bioinformatics methods to analyze the expression and survival data of TGF-β signal regulators in patients with EC. We extracted the expression of the S-TGF-β signal regulator from The Cancer Genome Atlas (TCGA). The cBioPortal database was used to assess the frequency of genetic variation. The TGF-β signal regulator is expressed in EC and normal tissues. The objective is to use the Kaplan-Meier plotter database to investigate the prognostic value of TGF-β signal regulators in cancer patients. The DAVID and clusterProfiler software package were used for functional enrichment analysis. We found that patients with TGF-β signaling mutations have shorter overall survival, disease-free survival, disease-specific survival, platinum overall survival, and platinum-free progression survival. We found that compared with the noncancerous tissues of patients with EC, ZFYVE9, BMPR1B, TGFB3, TGFBRAP1, ACVRL1, TGFBR2, SMAD4, SMAD7, ACVR2A, BMPR1, and SMAD9 were significantly downregulated in tumor tissues, while ACVR1 and Smad1 were significantly upregulated in tumor samples. Univariate survival analysis showed that ACVR1, TGFBR3, TGFBRAP1, BMPR1A, SMAD4, and TGFBR2 were positively correlated with overall survival (OS) prolongation. In addition, TGF-β signal transduction regulators could be divided into two classes. Subclass 1 was involved in regulating cell adhesion, PI3K-Akt signaling, and Rap1 signaling. Subclass 2 was related to regulating angiogenesis and PI3K signaling. In short, all members of TGF-β signal regulators can be used as biomarkers to predict the prognosis of patients with EC.
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Javed, Ruheena, Lu Jing, Jinzeng Yang, Xinyun Li, Jianhua Cao, and Shuhong Zhao. "miRNA Transcriptome of Hypertrophic Skeletal Muscle with Overexpressed Myostatin Propeptide." BioMed Research International 2014 (2014): 1–19. http://dx.doi.org/10.1155/2014/328935.
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MicroRNAs (miRNAs) play an imperative role in cell proliferation, differentiation, and cell metabolism through regulation of gene expression. Skeletal muscle hypertrophy that results from myostatin depression by its propeptide provides an interesting model to understand how miRNA transcriptome is involved in myostatin-based fiber hypertrophy. This study employed Solexa deep sequencing followed by Q-PCR methods to analyze miRNA transcriptome of skeletal muscle of myostatin propeptide transgenic mice in comparison with their littermate controls. A total of 461 mature known and 69 novel miRNAs were reported from this study. Fifty-seven miRNAs were expressed differentially between transgenic and littermate controls, of which most abundant miRNAs, miR-133a and 378a, were significantly differentially expressed. Expression profiling was validated on 8 known and 2 novel miRNAs. The miRNA targets prediction and pathway analysis showed that FST, SMAD3, TGFBR1, and AcvR1a genes play a vital role in skeletal muscle hypertrophy in the myostatin propeptide transgenic mice. It is predicted that miR-101 targeted to TGFBR1 and SMAD3, miR-425 to TGFBR2 and FST, and miR-199a to AcvR2a and TGF-βgenes. In conclusion, the study offers initial miRNA profiling and methodology of miRNA targets prediction for myostatin-based hypertrophy. These differentially expressed miRNAs are proposed as candidate miRNAs for skeletal muscle hypertrophy.
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Pagani, Alessia, Mariateresa Pettinato, Alessandro Dulja, et al. "Dissecting the Mechanisms of Hepcidin and BMP-SMAD Pathway Regulation By FKBP12." Blood 138, Supplement 1 (2021): 2008. http://dx.doi.org/10.1182/blood-2021-152172.
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Abstract The BMP-SMAD pathway is activated when a dimeric ligand (BMP) interacts with a dimeric serine threonine kinase receptor (BMPRII) and triggers the activation of a dimeric BMP type I receptor (BMPRI). Catalytically active BMPRIs phosphorylate SMAD1/5/8 that, upon SMAD4 binding, translocate to the nucleus to regulate the expression of BMP target genes, including hepcidin. Hepcidin is the main regulator of iron homeostasis that controls body iron levels by binding and blocking the sole iron exporter ferroportin. In agreement, hepcidin expression is homeostatically activated by serum and liver iron, and its deficiency is a common hallmark of Hereditary Hemochromatosis (HH) and the major cause of iron overload in beta thalassemia. The components of the BMP-SMAD pathway relevant for hepcidin regulation are ALK2 and ALK3 (BMPRI); BMPR2 and ACVR2A (BMPRII), BMP2 and BMP6 (BMP ligands). Recently, we have identified the immunophilin FKBP12 as an inhibitor of hepcidin and demonstrated that FKBP12 binds ALK2 to avoid ligand-independent activation of the BMP-SMAD pathway. To investigate the mechanism of BMP-SMAD pathway and hepcidin regulation by FKBP12, we performed in vitro, ex vivo and in vivo studies. We found that FKBP12 sequestration by the immunosuppressive drug Tacrolimus (TAC) stabilizes ALK2-ALK2 homodimers and ALK2-ALK3 heterodimers in a transfected human hepatoma cell line. In addition, it increases the interaction of ALK2 with ACVR2A and BMPR2. To investigate the role of FKBP12 on BMP-SMAD signaling, BMPRI and II were silenced in murine primary hepatocytes. Despite FKBP12 co-immunoprecipitates only with ALK2, silencing of Alk2 and Alk3 completely blunts TAC-mediated BMP-SMAD pathway activation, suggesting that FKBP12 functionally interacts also with ALK3. Acvr2a silencing impairs TAC-dependent hepcidin upregulation, whereas Bmpr2 silencing does not. As expected, Fkbp12 silencing abrogates hepcidin upregulation by TAC, confirming the main role of this immunophilin in hepcidin regulation. In vivo, TAC treatment upregulates hepcidin in wild type and HH mouse models, but surprisingly, Fkbp12 mRNA downregulation by ASOs does not. Interestingly, Fkbp 2, 4 and 8 are highly expressed in murine hepatocytes and, according to literature data, are able to bind to TAC. Of note, Fkbp12 is the least expressed immunophilin in murine primary hepatocytes. To further investigate the FKBPs involved in TAC-dependent hepcidin regulation, Fkbp2, 4 and 8 were knockdown in murine primary HCs that were then treated with TAC. The TAC effect is preserved in siFkbp2- and siFkbp4-derived HCs, but abolished when Fkbp8 was downregulated. Overall these data suggest that: 1) FKBP12 regulates BMP-SMAD signaling by favoring ALK2-ALK3 homo and heterodimerization, and interaction with BMPRII in the absence of ligands; 2) TAC-mediated hepcidin upregulation is dependent upon ALK2, ALK3, ACVR2A, FKBP12 and FKBP8. 3) In vivo, TAC treatment upregulates hepcidin whereas Fkbp12 silencing does not, suggesting the existence of redundancy between the different FKBPs. Further studies are needed to dissect the role of FKBP8 in BMP-SMAD pathway and hepcidin regulation. Disclosures Aghajan: Ionis Pharmaceuticals, Inc.: Current Employment. Muckenthaler: Silence Therapeutics: Research Funding. Guo: Ionis Pharmaceuticals, Inc.: Current Employment.
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Cho, Kyung-Ah, Da-Won Choi, Yu-Hee Kim, Jungwoo Kim, Kyung-Ha Ryu, and So-Youn Woo. "Mesenchymal Stem Cell-Derived Exosomes Protect Muscle Loss by miR-145-5p Activity Targeting Activin A Receptors." Cells 10, no. 8 (2021): 2169. http://dx.doi.org/10.3390/cells10082169.
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Skeletal muscle mass is decreased under a wide range of pathologic conditions. In particular, chemotherapy is well known for inducing muscle loss and atrophy. Previous studies using tonsil-derived mesenchymal stem cells (T-MSCs) or a T-MSC-conditioned medium showed effective recovery of total body weight in the chemotherapy-preconditioned bone marrow transplantation mouse model. This study investigated whether extracellular vesicles of T-MSCs, such as exosomes, are a key player in the recovery of body weight and skeletal muscle mass in chemotherapy-treated mice. T-MSC exosomes transplantation significantly decreased loss of total body weight and muscle mass in the busulfan-cyclophosphamide conditioning regimen in BALB/c recipient mice containing elevated serum activin A. Additionally, T-MSC exosomes rescued impaired C2C12 cell differentiation in the presence of activin A in vitro. We found that T-MSC exosomes possess abundant miR-145-5p, which targets activin A receptors, ACVR2A, and ACVR1B. Indeed, T-MSC exosomes rescue muscle atrophy both in vivo and in vitro via miR-145-5p dependent manner. These results suggest that T-MSC exosomes have therapeutic potential to maintain or improve skeletal muscle mass in various activin A elevated pathologic conditions.
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Takahashi, Mina, Fumio Otsuka, Tomoko Miyoshi, et al. "Bone morphogenetic protein 6 (BMP6) and BMP7 inhibit estrogen-induced proliferation of breast cancer cells by suppressing p38 mitogen-activated protein kinase activation." Journal of Endocrinology 199, no. 3 (2008): 445–55. http://dx.doi.org/10.1677/joe-08-0226.
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Estrogen is involved in the development and progression of breast cancer. Here, we investigated the effects of bone morphogenetic proteins (BMPs) on breast cancer cell proliferation caused by estrogen using human breast cancer MCF-7 cells. MCF-7 cells express estrogen receptors (ESR1 and ESR2), BMP receptors, and SMAD signaling molecules. Estradiol and membrane-impermeable estradiol stimulated MCF-7 cell proliferation. Estradiol also reduced mRNA levels of ESR1, aromatase, and steroid sulfatase. Treatment with BMPs and activin had no effects on MCF-7 cell proliferation. However, BMP2, BMP4, BMP6, BMP7, and activin suppressed estradiol-induced cell mitosis, with the effects of BMP6, BMP7, and activin being more prominent than those of BMP2 and BMP4. Activin decreased ESR1 mRNA expression, while BMP6 and BMP7 impaired steroid sulfatase expression in MCF-7 cells. Interestingly, SMAD1,5,8 activation elicited by BMP6 and BMP7, but not by BMP2 and BMP4, was preserved even under the exposure of a high concentration of estradiol. The difference of BMP responsiveness was likely due to the differential modulation of BMP receptor expression induced by estradiol. In this regard, estradiol decreased the expression levels of BMPR1A, BMPR1B, ACVR2A, and ACVR2B but did not affect ACVR1 and BMPRII, leading to the sustained effects of BMP6 and BMP7 in estrogen-treated MCF-7 cells. Estradiol rapidly activated MAPK phosphorylation including extracellular signal-regulated kinase 1/2, p38, and stress-activated protein kinase/c-Jun NH2-terminal kinase pathways and BMP6, BMP7, and activin preferentially inhibited estradiol-induced p38 phosphorylation. SB203580, a selective p38 MAPK inhibitor effectively suppressed estradiol-induced cell mitosis, suggesting that p38 MAPK plays a key role in estrogen-sensitive breast cancer cell proliferation. Thus, a novel interrelationship between estrogen and the breast cancer BMP system was uncovered, in which inhibitory effects of BMP6 and BMP7 on p38 signaling and steroid sulfatase expression were functionally involved in the suppression of estrogen-induced mitosis of breast cancer cells.
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Inui, Masafumi, Marco Montagner, Danny Ben-Zvi, et al. "Self-regulation of the head-inducing properties of the Spemann organizer." Proceedings of the National Academy of Sciences 109, no. 38 (2012): 15354–59. http://dx.doi.org/10.1073/pnas.1203000109.
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The Spemann organizer stands out from other signaling centers of the embryo because of its broad patterning effects. It defines development along the anteroposterior and dorsoventral axes of the vertebrate body, mainly by secreting antagonists of growth factors. Qualitative models proposed more than a decade ago explain the organizer’s region-specific inductions (i.e., head and trunk) as the result of different combinations of antagonists. For example, head induction is mediated by extracellular inhibition of Wnt, BMP, and Nodal ligands. However, little is known about how the levels of these antagonists become harmonized with those of their targets and with the factors initially responsible for germ layers and organizer formation, including Nodal itself. Here we show that key ingredients of the head-organizer development, namely Nodal ligands, Nodal antagonists, and ADMP ligands reciprocally adjust each other’s strength and range of activity by a self-regulating network of interlocked feedback and feedforward loops. A key element in this cross-talk is the limited availability of ACVR2a, for which Nodal and ADMP must compete. By trapping Nodal extracellularly, the Nodal antagonists Cerberus and Lefty are permissive for ADMP activity. The system self-regulates because ADMP/ACVR2a/Smad1 signaling in turn represses the expression of the Nodal antagonists, reestablishing the equilibrium. In sum, this work reveals an unprecedented set of interactions operating within the organizer that is critical for embryonic patterning.
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Ashouri, Karam, Yasmine Baca, Joanne Xiu, et al. "Characterization of the cachexia pathway in pancreatic ductal adenocarcinoma." Journal of Clinical Oncology 42, no. 3_suppl (2024): 699. http://dx.doi.org/10.1200/jco.2024.42.3_suppl.699.
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699 Background: Cancer cachexia is characterized by progressive weight loss and skeletal muscle degradation, contributing to 33% of pancreatic ductal adenocarcinoma (PDAC) deaths. Targeting myostatin in the myostatin-activin pathway has been shown to reverse cachexia. Here, we present comprehensive clinical and molecular characterization of the myostatin-activin pathway in PDAC. Methods: 9,607 samples of PDAC tested at Caris Life Sciences (Phoenix, AZ) with WTS (Illumina NovaSeq) and NextGen DNA sequencing (NextSeq, 592 Genes and NovaSEQ, WES) were analyzed. Cachexia gene scores (GS) were calculated by averaging the positive z scores of activators and negative z scores of repressors in the myostatin-activin pathway. Activators were ACVR1B, ACVR1C, ACVR2A, ACVR2B, SMAD2, SMAD3, SMAD4, and TGFBR1, while repressors were SMAD1, SMAD5, SMAD6, SMAD7, SMURF1, and SMURF2. The top quartile (Q4) and bottom quartile (Q1) of GS were compared using chi-squared and Fisher-Exact tests. RNA deconvolution analysis with QuantiSEQ estimated cell infiltration in the tumor microenvironment (TME). Differences in overall survival (OS) were analyzed from insurance claims data and calculated from time of tissue collection using Kaplan-Meier estimates. Statistical significance was determined as a P-value adjusted for multiple comparisons ( q<0.05). Results: GS were higher in primary tumors compared to metastases (median: -0.71 vs -0.86, q<0.05). GS was associated with increased PD-L1 IHC expression (Q1 21.2% vs Q4 10.3%, q<0.001), but not TMB-high (1.9% vs 2.1%, q=1) or MSI-H status (1.1% vs 1.3%, q=1). GS correlated with increased expression of immune related genes ( CD274, CD80, IDO1, CD86, PDCD1, LAG3, CTLA4, HAVCR2, and IFNG, q<0.05). However, TME immune cell infiltration did not vary based on cachexia GS. Mutation rates of TP53 (Q1 79.4% vs Q4 73.7%), ARID1A (Q1 11.8% vs Q4 6.9%) and KRAS (Q1 92.7% vs Q4 86.4%) were associated with Q1-GS (all q<0.01), while STK11 mutations (1.1% vs 3.0%, q=0.001) were associated with Q4-GS. Spearman correlation linked cachexia GS with the lipid metabolizing genes UCP2 (rho=0.49) and UCP3 (rho=0.30), as well as the inflammatory markers CCL2/MCP-1(rho=0.34) and IL1B (rho=0.33). Decreased OS was seen with higher tumor expression of the myostatin-activin pathway activator, SMAD3 (6.6 vs 8.5 mo, HR=1.22, CI 1.12-1.33, P<0.001), and lower expression of the repressor SMAD7 (6.9 vs 8.9 mo, HR=0.91, CI 0.79-0.90, P=0.034) in metastatic PDAC. Conclusions: This is the largest molecular and clinical characterization of the myostatin-activin cachexia pathway in PDAC. Our data show that increased activation of the myostatin-activin pathway is associated with immune mediators, lipid metabolism, and inflammatory gene activation. Activators and repressors are significant predictors of survival in PDAC, suggesting possible novel therapeutic targets.
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Zhuang, YingYing, LiYa Li, HaiNing Wu, and TaiYong Fang. "CircRNA ACVR2A Sponges miR-1290 to Modulate Cell Progression in Gastric Cancer." Journal of Oncology 2022 (February 9, 2022): 1–13. http://dx.doi.org/10.1155/2022/9461054.
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Background. In recent years, the abnormal expression of circRNAs has been identified to be strongly associated with tumor tissues. In this study, we focused on circACVR2A with a remarkably upregulated expression in gastric tissues and further explored its role in the pathogenic progression of gastric cancer (GC). Methods. The differentially expressed circACVR2A in GC tissues and four cell lines (MKN-45, SNU-1, HGC-27, and SGC-7901) was identified by qRT-PCR method. Then, the effect of circACVR2A and miR-1290 on HGC-27 cell proliferation was measured by CCK8 and the colony formation methods. The effect of circACVR2A and miR-1290 on HGC-27 cell metastasis was estimated by transwell assay. The interaction of circACVR2A and miR-1290 was further detected. Results. The relative level of circACVR2A in GC tissues and cell lines is remarkably upregulated. The downregulation of circACVR2A promotes GC cell proliferation and metastasis and suppressed the expression level of E-cadherin and Vimentin. The miR-1290 inhibitor reversed the effect of circACVR2A on cell progression in GC cell. Conclusion. circACVR2A competitively sponged miR-1290 and was exerted as a tumor suppressor gene oncogene via a circACVR2A/miR-1290 axis, suggesting it as a possible biomarker for GC therapy.
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Fitzpatrick, E., M. P. Johnson, T. D. Dyer, et al. "Genetic association of the activin A receptor gene (ACVR2A) and pre-eclampsia." Molecular Human Reproduction 15, no. 3 (2009): 195–204. http://dx.doi.org/10.1093/molehr/gap001.
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Thulluru, H. K., O. J. Michel, C. B. M. Oudejans, and M. van Dijk. "ACVR2A promoter polymorphism rs1424954 in the Activin-A signaling pathway in trophoblasts." Placenta 36, no. 4 (2015): 345–49. http://dx.doi.org/10.1016/j.placenta.2015.01.010.
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Juen Yong, Hannah Ee, Padma Murthi, Bill Kalionis, Shaun Patrick Brennecke, and Rosemary Jeanne Keogh. "Altered activin receptor ACVR2A expression in pre-eclampsia contributes to abnormal placentation." Placenta 36, no. 9 (2015): A3. http://dx.doi.org/10.1016/j.placenta.2015.07.194.
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Souquet, Benoit, Sophie Tourpin, Sébastien Messiaen, Delphine Moison, René Habert, and Gabriel Livera. "Nodal Signaling Regulates the Entry into Meiosis in Fetal Germ Cells." Endocrinology 153, no. 5 (2012): 2466–73. http://dx.doi.org/10.1210/en.2011-2056.
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The mechanisms regulating the entry into meiosis in mammalian germ cells remain incompletely understood. We investigated the involvement of the TGF-β family members in fetal germ cell meiosis initiation. Nodal, a member of the TGF-β family, and its target genes are precociously expressed in embryonic gonads and show sexual dimorphism in favor of the developing testis. Nodal receptor genes, Acvr2a and Acvr2b, Alk4, and Tdgf1/Cripto, were identified in male germ cells. Nodal itself, Tdgf1, and Lefty1 and Lefty2 are targets of Nodal signaling and were all found specifically expressed in male germ cells. To elucidate the role of this signaling pathway, activin-like kinases that mediate TGF-β/Nodal/activin signaling were inhibited in 11.5 d postconception testis in organotypic culture. Activin-like kinases inhibition disrupted normal male germ cell development and induced germ cell entry into meiosis such as that observed in female germ cells at the equivalent stage. Interestingly Stra8, the gatekeeper of the mitotic/meiotic switch, was induced independently of any change of either Cyp26b1 or Fgf9 expression, the two genes currently identified as testicular meiotic inhibitors. On the other hand, recombinant Nodal significantly dampened Stra8 expression and germ cell meiosis in cultured 11.5 d postconception ovaries. Our results allowed us to propose for the first time an autocrine role of Nodal during the development of germ cells and indicate that members of the TGB-β family may reinforce the male fate and prevent meiosis in embryonic germ cells.
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Mendelova, Andrea, Veronika Holubekova, Marian Grendar, et al. "Association between 3’UTR polymorphisms in genes ACVR2A, AGTR1 and RGS2 and preeclampsia." General physiology and biophysics 37, no. 02 (2018): 185–92. http://dx.doi.org/10.4149/gpb_2017028.
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Wodziński, Damian, Agnieszka Wosiak, Jacek Pietrzak, Rafał Świechowski, Agnieszka Jeleń, and Ewa Balcerczak. "Does the expression of the ACVR2A gene affect the development of colorectal cancer?" Genetics and Molecular Biology 42, no. 1 (2019): 32–39. http://dx.doi.org/10.1590/1678-4685-gmb-2017-0332.
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Glotov, Andrey S., Sergey V. Kazakov, Elena S. Vashukova, et al. "Targeted sequencing analysis of ACVR2A gene identifies novel risk variants associated with preeclampsia." Journal of Maternal-Fetal & Neonatal Medicine 32, no. 17 (2018): 2790–96. http://dx.doi.org/10.1080/14767058.2018.1449204.
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Liu, Qidong, Guiying Wang, Yafang Chen, Guoping Li, Dandan Yang, and Jiuhong Kang. "A miR-590/Acvr2a/Rad51b Axis Regulates DNA Damage Repair during mESC Proliferation." Stem Cell Reports 3, no. 6 (2014): 1103–17. http://dx.doi.org/10.1016/j.stemcr.2014.10.006.
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Canali, Susanna, Amanda B. Core, Kimberly B. Zumbrennen-Bullough, et al. "Activin B Induces Noncanonical SMAD1/5/8 Signaling via BMP Type I Receptors in Hepatocytes: Evidence for a Role in Hepcidin Induction by Inflammation in Male Mice." Endocrinology 157, no. 3 (2016): 1146–62. http://dx.doi.org/10.1210/en.2015-1747.
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Abstract Induction of the iron regulatory hormone hepcidin contributes to the anemia of inflammation. Bone morphogenetic protein 6 (BMP6) signaling is a central regulator of hepcidin expression in the liver. Recently, the TGF-β/BMP superfamily member activin B was implicated in hepcidin induction by inflammation via noncanonical SMAD1/5/8 signaling, but its mechanism of action and functional significance in vivo remain uncertain. Here, we show that low concentrations of activin B, but not activin A, stimulate prolonged SMAD1/5/8 signaling and hepcidin expression in liver cells to a similar degree as canonical SMAD2/3 signaling, and with similar or modestly reduced potency compared with BMP6. Activin B stimulates hepcidin via classical activin type II receptors ACVR2A and ACVR2B, noncanonical BMP type I receptors activin receptor-like kinase 2 and activin receptor-like kinase 3, and SMAD5. The coreceptor hemojuvelin binds to activin B and facilitates activin B-SMAD1/5/8 signaling. Activin B-SMAD1/5/8 signaling has some selectivity for hepatocyte-derived cells and is not enabled by hemojuvelin in other cell types. Liver activin B mRNA expression is up-regulated in multiple mouse models of inflammation associated with increased hepcidin and hypoferremia, including lipopolysaccharide, turpentine, and heat-killed Brucella abortus models. Finally, the activin inhibitor follistatin-315 blunts hepcidin induction by lipopolysaccharide or B. abortus in mice. Our data elucidate a novel mechanism for noncanonical SMAD activation and support a likely functional role for activin B in hepcidin stimulation during inflammation in vivo.
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Menyhart, Otília, Tatsuhiko Kakisaka, Lőrinc Sándor Pongor, Hiroyuki Uetake, Ajay Goel, and Balázs Győrffy. "Uncovering Potential Therapeutic Targets in Colorectal Cancer by Deciphering Mutational Status and Expression of Druggable Oncogenes." Cancers 11, no. 7 (2019): 983. http://dx.doi.org/10.3390/cancers11070983.
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Background: Numerous driver mutations have been identified in colorectal cancer (CRC), but their relevance to the development of targeted therapies remains elusive. The secondary effects of pathogenic driver mutations on downstream signaling pathways offer a potential approach for the identification of therapeutic targets. We aimed to identify differentially expressed genes as potential drug targets linked to driver mutations. Methods: Somatic mutations and the gene expression data of 582 CRC patients were utilized, incorporating the mutational status of 39,916 and the expression levels of 20,500 genes. To uncover candidate targets, the expression levels of various genes in wild-type and mutant cases for the most frequent disruptive mutations were compared with a Mann–Whitney test. A survival analysis was performed in 2100 patients with transcriptomic gene expression data. Up-regulated genes associated with worse survival were filtered for potentially actionable targets. The most significant hits were validated in an independent set of 171 CRC patients. Results: Altogether, 426 disruptive mutation-associated upregulated genes were identified. Among these, 95 were linked to worse recurrence-free survival (RFS). Based on the druggability filter, 37 potentially actionable targets were revealed. We selected seven genes and validated their expression in 171 patient specimens. The best independently validated combinations were DUSP4 (p = 2.6 × 10−12) in ACVR2A mutated (7.7%) patients; BMP4 (p = 1.6 × 10−04) in SOX9 mutated (8.1%) patients; TRIB2 (p = 1.35 × 10−14) in ACVR2A mutated patients; VSIG4 (p = 2.6 × 10−05) in ANK3 mutated (7.6%) patients, and DUSP4 (p = 7.1 × 10−04) in AMER1 mutated (8.2%) patients. Conclusions: The results uncovered potentially druggable genes in colorectal cancer. The identified mutations could enable future patient stratification for targeted therapy.
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van Dijk, Marie, and Cees B. M. Oudejans. "STOX1: Key Player in Trophoblast Dysfunction Underlying Early Onset Preeclampsia with Growth Retardation." Journal of Pregnancy 2011 (2011): 1–7. http://dx.doi.org/10.1155/2011/521826.
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Currently, only two preeclampsia susceptibility genes (ACVR2A,STOX1) have been identified within confirmed regions with significant genome-wide linkage, although many genetic screens in multiple populations have been performed. In this paper, we focus on theSTOX1gene. The epigenetic status of this gene is discussed explaining the maternal transmission of theSTOX1susceptibility allele observed in preeclamptic families. The known upstream regulation and downstream effector genes of the transcription factor STOX1 are described. Finally, we propose a model in which we combine the cell type-specific and allele-specific effects of STOX1. This includes intrinsic effects (differential CpG island methylation) and extrinsic effects (regulation of effector genes).
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Gordinier, Mary E., Geoffrey Schau, Shanna Brotzge Pollock, Lisa Shields, and Sameer S. Talwalkar. "Genomic characterization of vulvar squamous cell carcinoma to reveal differential gene expression based on clinical outcome." Journal of Clinical Oncology 41, no. 16_suppl (2023): e17633-e17633. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.e17633.
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e17633 Background: The greatest challenge in the management of vulvar squamous cell carcinoma (VSCC) is treatment of recurrent disease where options for surgery and radiation have been exhausted, or treatment of disease where distant metastasis is present. Identification of mutations differentially expressed between tumor from patients who died of aggressive disease and tumor from patients with an indolent course could reveal novel prognostic indicators and guide development of therapeutic drugs. Methods: From 202 consecutive patients with VSCC, patients who recurred and died of disease (group A) were identified and matched by age, tumor size, depth of invasion and nodal status with those whose disease did not recur (group B). Tumor and matched normal samples from 21 patients were assayed by a broad NGS panel covering 648 genes, including whole exome and transcriptome sequencing. Immunohistochemistry (IHC) for PD-L1 (22C3) and p16 was also performed. Results: Whole transcriptome data revealed 6 genes that were strongly differentially expressed between the aggressive and indolent groups: ACVR2A, TGM3, ROS1, NFEL2, CCND1 and BCL6. Biologically relevant DNA mutations were significantly greater in the aggressive cohort versus the indolent cohort: 7 vs 2.3 mutations per patient. The most common genomic alterations were mutations in TP53 and the promoter region of TERT. TP53 alterations occurred almost exclusively in group A. Other common genomic events include alterations of FAT1, CDKN2A, PIK3CA, CCND1, and LRP1B. All samples were MSI stable, and tumor mutational burden was similar in groups A and B. Most VSCC specimens (81%) were positive for PD-L1. Conclusions: We report that TGM3 and ACVR2A genes are significantly under-expressed in tumors with poor outcome. Further investigation into the silencing of these genes may advance knowledge of the pathogenesis of VSCC and potentially yield therapeutic targets. Clinical outcome of VSCC appears independent of MSI, TMB or PD-L1 status. [Table: see text]
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Takeda, Haruna, Shiho Kataoka, Mizuho Nakayama, et al. "CRISPR-Cas9–mediated gene knockout in intestinal tumor organoids provides functional validation for colorectal cancer driver genes." Proceedings of the National Academy of Sciences 116, no. 31 (2019): 15635–44. http://dx.doi.org/10.1073/pnas.1904714116.
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Colorectal cancer (CRC) is the third leading cause of cancer-related deaths worldwide. Several genome sequencing studies have provided comprehensive CRC genomic datasets. Likewise, in our previous study, we performed genome-wide Sleeping Beauty transposon-based mutagenesis screening in mice and provided comprehensive datasets of candidate CRC driver genes. However, functional validation for most candidate CRC driver genes, which were commonly identified from both human and mice, has not been performed. Here, we describe a platform for functionally validating CRC driver genes that utilizes CRISPR-Cas9 in mouse intestinal tumor organoids and human CRC-derived organoids in xenograft mouse models. We used genetically defined benign tumor-derived organoids carrying 2 frequent gene mutations (Apc and Kras mutations), which act in the early stage of CRC development, so that we could clearly evaluate the tumorigenic ability of the mutation in a single gene. These studies showed that Acvr1b, Acvr2a, and Arid2 could function as tumor suppressor genes (TSGs) in CRC and uncovered a role for Trp53 in tumor metastasis. We also showed that co-occurrent mutations in receptors for activin and transforming growth factor-β (TGF-β) synergistically promote tumorigenesis, and shed light on the role of activin receptors in CRC. This experimental system can also be applied to mouse intestinal organoids carrying other sensitizing mutations as well as organoids derived from other organs, which could further contribute to identification of novel cancer driver genes and new drug targets.
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Yong, Hannah E. J., Padma Murthi, Bill Kalionis, Rosemary J. Keogh, and Shaun P. Brennecke. "Decidual ACVR2A regulates extravillous trophoblast functions of adhesion, proliferation, migration and invasion in vitro." Pregnancy Hypertension 12 (April 2018): 189–93. http://dx.doi.org/10.1016/j.preghy.2017.11.002.
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Liu, Qidong, Guiying Wang, Yao Lyu, et al. "The miR-590/Acvr2a/Terf1 Axis Regulates Telomere Elongation and Pluripotency of Mouse iPSCs." Stem Cell Reports 11, no. 1 (2018): 88–101. http://dx.doi.org/10.1016/j.stemcr.2018.05.008.
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Ferreira, L. C., C. E. M. Gomes, A. C. P. Araújo, P. F. Bezerra, P. Duggal, and S. M. B. Jeronimo. "Association between ACVR2A and early-onset preeclampsia: Replication study in a Northeastern Brazilian population." Placenta 36, no. 2 (2015): 186–90. http://dx.doi.org/10.1016/j.placenta.2014.11.007.
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Satheesh, P., T. K. Bhattacharya, P. Kumar, et al. "Gene expression and silencing of activin receptor type 2A (ACVR2A) in myoblast cells of chicken." British Poultry Science 57, no. 6 (2016): 763–70. http://dx.doi.org/10.1080/00071668.2016.1219693.
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Aushev, Vasily N., Samuel Rivero-Hinojosa, Avinash Ramu, et al. "Abstract 1153: Large-scale genomic profiling of colorectal cancer." Cancer Research 85, no. 8_Supplement_1 (2025): 1153. https://doi.org/10.1158/1538-7445.am2025-1153.
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Abstract Background: Colorectal cancer (CRC) is a heterogeneous disease driven by a multitude of genomic alterations that influence tumor progression and clinical outcomes. Genomic profiling plays a crucial role in identifying actionable mutations and understanding the molecular drivers of CRC. In this study, we analyzed genomic data from Natera’s proprietary Real-World Database, comprising more than 100, 000 CRC patients, to characterize the mutational landscape of the disease and investigate patterns across clinical and molecular subgroups. Methods: We performed an exploratory analysis of the whole-exome sequencing (WES) of tumor tissue data generated as part of commercial circulating tumor DNA testing (SignateraTM) in patients with CRC between May 2019 and November 2024. After excluding non-USA patients, clinical trial participants, and those with no informed consent or not passing QC for WES data, 73, 591 patients were included in the analysis. Variant calling was performed using Mutect2 and VarScan2 callers. MSI status was determined using the MSIsensor algorithm. For prevalence analysis, only non-synonymous mutations were included. Results: In this analysis of 73, 591 patients, the male/female ratio was 52.6%/47.1%, with cancer stages distributed as follows: stage I (11.4%), II (19.3%), III (26.7%), IV (21.7%), and other/unavailable (20.9%). The most frequently mutated genes were APC (65.6%), TP53 (57.3%), and KRAS (35.8%). The most common individual mutations were KRAS G12D (10.8%), ACVR2A K437X (9.9%), and BRAF V600E (8.4%). Microsatellite instability (MSI) was observed to be MSI-High in 11% of cases overall, with stagewise prevalence 11.2%/18.2%/10.8%/6.6% for stage I/II/III/IV, respectively. MSI status significantly influenced genomic landscape with MSI-high tumors exhibiting a significantly higher prevalence of ACVR2A K437X (72.7% vs 1.3%), BRAF V600E (45.1% vs 4.3%), and RNF43 G659X (42.8% vs 0.5%) compared to MSS tumors. Tumor location data were available for 50.9% of cases with a colon/rectal ratio of 72.3%/25.3%. Rectal tumors had a significantly lower prevalence of MSI-high status (2.3% vs 14.9%) and the associated mutations (ACVR2A K437X: 1.9% vs 12.8%, BRAF V600E: 1.5% vs 12.0%, RNF43 G659X: 0.65% vs 7.8%), but a higher prevalence of TP53 mutations (gene-level 71.3% vs 60.6%, variant-level R175H 7.1% vs 5.6%). When stratified by stage, BRAF V600E prevalence appeared lower in stage IV compared to stage I - III, however, this difference was not statistically significant after adjusting for MSI and tumor location. Conclusions: Our study represents one of the largest real-world genomic analyses in CRC, providing critical insights into the mutational landscape across clinical and molecular subgroups. These data enhance our understanding of the genomic drivers of CRC. Future studies will explore the associations between genomic subtypes, treatment patterns, and outcomes in this real-world patient population. Citation Format: Vasily N. Aushev, Samuel Rivero-Hinojosa, Avinash Ramu, J. Bryce Ortiz, Adham Jurdi, Alyssa Antonopoulos, Alexey Aleshin, Axel Grothey. Large-scale genomic profiling of colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1153.
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Goh, Brian C., Vandana Singhal, Angelica J. Herrera, et al. "Activin receptor type 2A (ACVR2A) functions directly in osteoblasts as a negative regulator of bone mass." Journal of Biological Chemistry 292, no. 33 (2017): 13809–22. http://dx.doi.org/10.1074/jbc.m117.782128.
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Bai, Long, Hsun-Ming Chang, Jung-Chien Cheng, Guiyan Chu, Peter C. K. Leung, and Gongshe Yang. "ALK2/ALK3-BMPR2/ACVR2A Mediate BMP2-Induced Downregulation of Pentraxin 3 Expression in Human Granulosa-Lutein Cells." Endocrinology 158, no. 10 (2017): 3501–11. http://dx.doi.org/10.1210/en.2017-00436.
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Yanan, Feng, Lu Rui, Li Xiaoying, et al. "Association between ACVR2A gene polymorphisms and risk of hypertensive disorders of pregnancy in the northern Chinese population." Placenta 90 (January 2020): 1–8. http://dx.doi.org/10.1016/j.placenta.2019.11.004.
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Andersson-Rusch, Clara Leticia, Ingrid Quist-Løkken, Pål Sætrom, et al. "Genome-Wide CRISPR/Cas9 Knock-out Screen Identifies Apoptosis-Relevant Genes in Multiple Myeloma." Blood 142, Supplement 1 (2023): 4660. http://dx.doi.org/10.1182/blood-2023-174444.
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Background Bone morphogenetic proteins (BMPs) are members of the transforming growth factor (TGF)-β family and have several biological functions in different cells and tissues. In multiple myeloma, BMPs enable growth arrest and apoptosis of the cancer cells. BMPs act as ligands and signal by binding a tetrameric complex of type I and type II receptors, leading to activation of SMAD1/5/8 transcription factors which allocate into the cell nucleus. The main type I receptor in myeloma cells is ALK2, encoded by the ACVR1 gene. Several BMP ligands can signal via ALK2, but the downstream signaling and mechanisms leading to apoptosis and growth arrest remain unknown. Mapping of this cascade could result in potential novel targets for treatment and therapies. Methods A genome-wide CRISPR/Cas9 knock-out screen with the GeCKO v2 library was performed in INA-6 myeloma cells. To induce apoptosis and growth arrest two treatments were performed in parallel: BMP9 and a combination of Activin B and FK506 (tacrolimus), compared with medium control. Both BMP9 and Activin B signal via the type I receptor ALK2 combined with one or more of the type II receptors ACVR2A, ACVR2B or BMPR2. Top hits were defined as genes over- or underrepresented compared with control in both treatment conditions with a p-value lower than 0.05. Reactome pathway analysis of the top hits from the screen was performed. Validation of the top ranking hits was performed by generating single-gene specific knockouts, silencing with siRNA or with inhibitors. CellTiter Glo viability assay and annexin V/propidium iodide staining analyzed by flow cytometry were used to determine apoptosis. RT-PCR and western blots were used to determine specific mRNA and protein abundance. Results The screen identified genes already known to be necessary in the BMP signaling pathway, such as ACVR1 and SMAD1 indicating technical robustness. Although the screen was designed to pick genes necessary for apoptosis and growth arrest, we were also able to identify genes that counteract BMP-induced apoptosis. Several novel genes/hits were found in the screen. Numerous well-established signaling cascades were identified from Reactome pathway analysis to be activated downstream of BMP mediated signaling. In particular, several genes belonging to the PI3K/AKT/mTOR cascade were significantly overrepresented in the screen, indicating they positively regulate ALK2-mediated apoptosis. The PI3K/AKT/mTOR pathway is known to be upregulated in several cancers, including multiple myeloma. Transcriptional regulators of TP53 were found to be significantly underrepresented, indicating negative regulation in ALK2-mediated apoptosis. The protein encoded by the TP53 gene is well known from several malignancies, including multiple myeloma. Additionally, 9 other genes with previously unknown apoptosis function were found to be relevant for its regulation. Conclusion In conclusion, BMP-induced apoptosis in multiple myeloma cells rely on the canonical BMP signaling pathway, but also on a number of previously unknown genes. The screen confirmed the importance of the PI3K/AKT/mTOR pathway for positive apoptosis regulation and transcriptional factors affecting TP53 for negative apoptosis regulation. Hits from this screen can be promising targets for future therapies and precision medicine targeting the apoptotic machinery in multiple myeloma cells.
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Pache, Gregor, Christina Schäfer, Sebastian Wiesemann, et al. "Upregulation of Id-1 via BMP-2 receptors induces reactive oxygen species in podocytes." American Journal of Physiology-Renal Physiology 291, no. 3 (2006): F654—F662. http://dx.doi.org/10.1152/ajprenal.00214.2004.
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Bone morphogenetic proteins (BMPs) are secreted signaling molecules, which play a major role in kidney development and disease. Here, we show the existence of mRNA for BMP-2 and for the BMP receptors BMPR1A, BMPR1B, BMPRII, ACVR1A, ACVR2, and ACVR2B in differentiated mouse podocytes and the protein expression of BMPR1A in human glomerular podocytes. BMP-2 dose dependently increases the free cytosolic Ca2+ concentration in podocytes proving the existence of a functional receptor in these cells. Recent data indicate that in a myoblastic cell line and in a breast cancer cell line, BMP-2 increases the expression of Id-1, a negative regulator of basic helix-loop-helix transcription factors, but the role of BMP-2 stimulated Id-1 expression in the kidney has not been further characterized. Here, we show that BMP-2 increases the expression of Id-1 in differentiated podocytes. To investigate a role of Id-1 for podocyte function, overexpression of Id-1 was induced in differentiated mouse podocytes. Id-1-overexpressing podocytes show an increased NADPH-dependent production of reactive oxygen species (ROS). This effect can be evoked by BMP-2 and can be antagonized by anti-Id-1 antisense oligonucleotides. The data indicate that BMP-2 may, via an increased expression of Id-1 and an increased generation of ROS, contribute to important cellular functions in podocytes. ROS supposedly play a major role in cell adhesion, cell injury, ion transport, fibrogenesis, angiogenesis and are involved in the pathogenesis of membranous nephropathy.
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Krambs, Joseph R., Grazia Abou Ezzi, Juo-Chin Yao, Justin T. Li, and Daniel C. Link. "Canonical Signaling By TGF Family Members in Mesenchymal Stromal Cells Is Dispensable for Hematopoietic Niche Maintenance Under Basal and Stress Conditions." Blood 134, Supplement_1 (2019): 1209. http://dx.doi.org/10.1182/blood-2019-128693.
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The bone marrow contains a complex population of stromal and hematopoietic cells that together generate a unique microenvironment, or niche, to support hematopoiesis. Mesenchymal stromal cells are an important component of the bone marrow hematopoietic niche and include CXCL12-abundant reticular (CAR) cells, adipocytes, osteolineage cells, and arteriolar pericytes, all of which have been implicated in hematopoietic stem/progenitor cell (HSPC) maintenance. There also is evidence that adaptive changes in bone marrow stromal cells contributes to recovery from myelosuppresive therapy and the development of certain hematopoietic malignancies. However, the signals that contribute to the development, maintenance, and stress response of bone marrow mesenchymal stromal cells are poorly understood. Here, we test the hypothesis that cytokines of the transforming growth factor superfamily, which include bone morphogenetic proteins (BMPs), growth differentiation factors (GDFs), and activins/inhibins, provide signals to mesenchymal stromal cells that contribute to basal and stress hematopoiesis responses. To test this hypothesis, we abrogated canonical TGF family signaling in mesenchymal stem/progenitor cells by deleting Smad4 using a doxycycline-repressible Osterix-Cre transgene (Osx-Cre), which targets all mesenchymal stromal cells in the bone marrow. We first performed lineage-tracing studies using Osx-Cre Smad4fl/fl Ai9 mice to show that activation of Osx-Cre at birth (by removal of doxycycline) results in the efficient targeting of bone marrow mesenchymal stromal cells. Moreover, we show that Smad4 mRNA expression is essentially undetectable in sorted mesenchymal stromal cells sorted from the bone marrow of these mice. Basal hematopoiesis and bone marrow stromal cells were analyzed in 6-8 week old Osx-Cre Smad4fl/fl mice. No alterations in the number or spatial organization of CAR cells, osteoblasts, or adipocytes was observed, and expression of key niche factors, including Scf, Cxcl12, and Spp1 was normal. Basal hematopoiesis, including the number of phenotypic HSCs in bone marrow and spleen, also was normal. Recent studies have shown that inhibition of activin signaling by treating with an activin receptor 2 alpha (ACVR2a) ligand trap stimulates erythropoiesis. Although ACVR2a signaling in erythroid progenitors contributes to this effect, two groups showed that inhibition of ACVR2a signaling in bone marrow stromal cells also stimulates erythropoiesis. Thus, we next characterized basal and stress erythropoiesis in Osx-Cre Smad4fl/fl mice. The frequency of phenotypic erythroid progenitors in bone marrow and spleen was similar to control mice. The stress erythropoiesis response was assessed after induction of acute hemolytic anemia by phenylhydrazine treatment. Both the magnitude of anemia and kinetics of erythroid recovery were similar to control mice. Myelosuppressive therapy induces marked alterations in the bone marrow microenvironment that includes an expansion of osteolineage cells and adipocytes, which have been linked to hematopoietic recovery. Thus, we next characterized stress hematopoiesis in Osx-Cre Smad4fl/fl mice in response to 5-fluorouracil (5-FU) treatment. Compared to control mice, the magnitude and duration of neutropenia following 5-FU were similar. Moreover, mouse survival after repeated weekly doses of 5-FU was comparable to control mice. HSPC mobilization by G-CSF is due, in large part, by downregulation of CXCL12 expression in bone marrow mesenchymal stromal cells. A prior study suggested that SMAD signaling negatively regulates CXCL12 expression in stromal cells. Consistent with this finding, we show that treatment of cultured bone marrow derived MSCs with TGF-b1 for 48 hours results in a significant (3.3-fold, P<0.0001) decrease in CXCL12 mRNA expression. Thus, in the final experiments, we characterized G-CSF induced HSPC mobilization in Osx-Cre, Smad4fl/fl or Osx-Cre, Tgfbr2fl/fl mice. HSPC mobilization, as quantified by CFU-C and Kit+ Sca+ lineage- (KSL) cell number in blood or spleen after 5 days of G-CSF treatment was comparable to control mice. Collectively, these data suggest the TGF family member signaling in mesenchymal stromal cells is dispensable for hematopoietic niche maintenance under basal and stress conditions. Disclosures No relevant conflicts of interest to declare.
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Dulja, Alessandro, Alessia Pagani, Mariateresa Pettinato, Antonella Nai, Clara Camaschella, and Laura Silvestri. "The Immunophilin FKBP12 Inhibits Hepcidin By Modulating BMP Type I-Type II Receptors Interaction and Ligand Responsiveness." Blood 134, Supplement_1 (2019): 430. http://dx.doi.org/10.1182/blood-2019-130058.
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Introduction The liver hormone hepcidin is the master regulator of iron metabolism that modulates iron release into the circulation by binding and blocking the iron exporter ferroportin (Nemeth et al., 2004). Hepcidin expression is under the control of the BMP-SMAD pathway (Babitt et al., 2006), whose activation requires the formation of a hexameric complex composed of a dimer of BMP receptors type I (BMPR-Is), a dimer of BMPR type II (BMPR-IIs) and dimeric ligands. ALK2 and ALK3, as BMPR-Is (Steinbiecker et al., 2011), BMPR2 and ACVR2A, as BMPR-IIs (Mayeur et al., 2014), and BMP2 (Koch et al, 2017) and BMP6 (Meynard et al., 2009), as ligands, control hepcidin expression in vivo. We previously demonstrated that the immunophilin FKBP12 limits hepcidin expression in hepatocytes by binding ALK2 (Colucci et al., 2017). However, the molecular mechanism whereby FKBP12 regulates ALK2 and its relationship with BMPR-IIs and ligands in the regulation of the BMP-SMAD pathway and hepcidin expression are still unclear. Methods: BMPR-Is dimerization was evaluated by co-immunoprecipitation (CoIP) experiments performed in the HuH7 human hepatoma cell line. BMP-SMAD pathway and hepcidin promoter activation were analyzed by using a reporter vector with the luciferase under the control of BMP responsive elements or of the human hepcidin promoter, respectively. Endogenous hepcidin expression was measured by qRT-PCR. Results: Since BMPRIs act as dimers, we first tested whether FKBP12 modulates the dimerization process. MYC- and FLAG-tagged ALK2 or ALK3 were transfected in HuH7 cells in the presence of FKBP12. Cells were treated or not with tacrolimus (TAC), an immunosuppressive drug that sequesters FKBP12 from ALK2. FKBP12 promotes ALK2 homodimers, functionally inactive in the absence of ligands, with no effect on ALK3 homodimerization. TAC promotes increased ALK2 homodimerization and SMAD1/5/8 phosphorylation, demonstrating that in the absence of FKBP12, ALK2 homodimers are stabilized and functionally active. We next focused on BMP6, the physiologic ligand that binds preferentially ALK2 and plays a fundamental role in hepcidin regulation in vivo. In HuH7 cells transfected with FKBP12 and ALK2, BMP6 treatment reduced FKBP12-ALK2 binding and increased ALK2 homodimers. In agreement, SMAD1/5/8 phosphorylation was increased, indicating that FKBP12 displacement allows the formation of functional receptor complexes responsive to BMP6. BMPR-Is activate SMAD1/5/8 following BMPR-IIs phosphorylation. Since TAC induces SMAD1/5/8 phosphorylation in the absence of ligands, we hypothesized that FKBP12 displacement also affects the formation of BMPR-I/BMPR-II oligomers. HuH7 cells were transfected with ALK2, BMPR2 or ACVR2A and FKBP12, and treated or not with TAC. FKBP12 sequestration by TAC enhances the ALK2-BMPR2 and ALK2-ACVR2A interaction and accordingly activates SMAD1/5/8 signaling. Given that FKBP12 modulates BMP receptor interaction, we wondered how this functionally impacts on the response to BMP ligands, as BMP2, that guarantees basal hepcidin levels by binding ALK3, and BMP6, upregulated in iron overload that signals preferentially through ALK2. ALK3 upregulates the BMP pathway and hepcidin expression in a similar way in response to BMP2 and BMP6, in agreement with the evidence that both ligands bind ALK3. ALK2, which failed to activate the pathway in the absence ligands, leads to a greater response to BMP6, consistent with the fact that it is the BMP6 receptor. Thus FKBP12 quantitatively, rather than qualitatively, modulates the BMP-SMAD pathway activation in response to BMP ligands. Conclusions: Altogether our results clarify the molecular mechanisms of hepcidin regulation demonstrating that: 1) FKBP12 limits hepcidin expression by inducing the formation of inactive ALK2 homodimers in the absence of ligands. 2) Decreased FKBP12 binding to ALK2, by TAC or BMP6, favors the formation of active ALK2 homodimers. 3) FKBP12 sequestration increases the binding of ALK2 with the BMPR-IIs, thus favoring SMAD1/5/8 phosphorylation and pathway activation. 4) FKBP12 quantitatively modulates the response of BMPRIs to the ligands BMP2 and BMP6. Disclosures Camaschella: Vifor Iron Core: Consultancy; Celgene: Consultancy; Novartis: Consultancy.
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Brennecke, Shaun, Hannah Yong, Padma Murthi, Bill Kalionis, Judith Cartwright, and Rosemary Keogh. "52 Altered ACVR2A expression modifies the response of vascular endothelial cells to normotensive and preeclamptic activin a concentrations." Pregnancy Hypertension: An International Journal of Women's Cardiovascular Health 6, no. 3 (2016): 161. http://dx.doi.org/10.1016/j.preghy.2016.08.053.
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Funkenstein, Bruria, Ekaterina Krol, Elena Esterin, and Yong-soo Kim. "Structural and functional characterizations of activin type 2B receptor (acvr2b) ortholog from the marine fish, gilthead sea bream, Sparus aurata: evidence for gene duplication of acvr2b in fish." Journal of Molecular Endocrinology 49, no. 3 (2012): 175–92. http://dx.doi.org/10.1530/jme-12-0075.
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Myostatin (MSTN), a negative regulator of muscle growth and a member of the transforming growth factor-β superfamily, can bind the two activin type 2 receptors (ACVR2). It has been previously shown that WT mice injected with ACVR2B extracellular domain (ACVR2B-ECD) had higher muscle mass. Likewise, fish larvae immersed inPichia pastorisculture supernatant, containing goldfish Acvr2b-ECD, showed enhanced larval growth. However, it is not clear whether fish Mstn1 and Mstn2 signal through the same receptor and whether fish express more than oneacvr2bgene. In the current study, three cDNAs encodingacvr2b(saacvr2b-1, saacvr2b-2a, and saacvr2b-2b) were cloned from gilthead sea bream. All three contain the short extracellular binding domain, a short transmembrane region, and a conserved catalytic domain of serine/threonine protein kinase. Bioinformatics analysis provided evidence for the existence of twoacvr2bgenes (acvr2b-1 andacvr2b-2) in several other fish species as well, probably as a result of gene or genome duplication. The two isoforms differ in their amino acid sequences. The direct inhibitory effect of Acvr2b-ECD on Mstn activity was testedin vitro. The saAcvr2b-1-ECD was expressed in the yeastP. pastoris. Evidence is provided for N-glycosylation of Acvr2b-1-ECD. The affinity-purified Acvr2b-1-ECD inhibited recombinant mouse/rat/human mature MSTN activity when determinedin vitrousing the CAGA-luciferase assay in A204 cells. A lower inhibitory activity was obtained when unprocessed purified, furin-digested, and activated saMstn1 was used. Results of this study demonstrate for the first time the existence of twoacvr2bgenes in fish. In addition, the study shows that bioactive fish Acvr2b-ECD can be produced fromP. pastoris.
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Zhang, Manqi, Jian Chen та Gerard Conrad Blobe. "Abstract 6230: Loss of ALK4 function promotes cancer progression by regulating cell surface TGF-β receptor stability". Cancer Research 82, № 12_Supplement (2022): 6230. http://dx.doi.org/10.1158/1538-7445.am2022-6230.
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Abstract Pancreatic cancer is a lethal disease. More than 50% of pancreatic cancer patients are diagnosed with metastatic disease with a dismal 3% five-year survival rate. There is clearly an urgent need to identify novel targets to treat pancreatic cancer patients. Transforming growth factor-β (TGF-β) signaling is dysregulated during cancer progression, inhibiting tumorigenesis while promoting metastasis. Approximately half of pancreatic cancer patients have mutations of genes in the TGF-β signaling pathway, including SMAD4, SMAD3, TGFBR1, TFGBR2, ACVR1B, and ACVR2A. ALK4 (Activin receptor-like kinase 4), which is encoded by ACVR1B, is a type I receptor in the TGF-β superfamily. Mutation or copy number loss of ALK4 occurs in 34% of pancreatic cancer patients, while ALK4 expression is significantly down-regulated in many cancers, including pancreatic cancer, with low ALK4 expression associated with poor clinical outcomes. Here we demonstrate that loss of ALK4 increases cell migration and invasion, induces epithelial to mesenchymal transition (EMT), and promotes local and distal metastasis in pancreatic cancer models. Loss of ALK4 unexpectedly increases activation of the canonical TGF-β signaling pathway and significantly induces TGF-β-mediated expression of EMT mediators and effectors. Moreover, ALK4 loss increases the cell surface expression of TβRs (TGFβ receptor type I and II), without changing the receptor gene expression, by increasing N-linked glycosylation of TβRs, potentially by altering Golgi morphology and function. Proteomic analysis of newly synthesized proteins induced by ALK4 loss identified galectin-3 (Gal-3) as upregulated. Gal-3 is known to be upregulated by MGAT5 (Alpha-1,6-Mannosylglycoprotein 6-Beta-N-Acetylglucosaminyltransferase) and cross-links MGAT5-modified N-glycans on TβRs at the cell surface, suppressing TβRs endocytosis. Consistent with this observation, loss of ALK4 increased MGAT5 mRNA expression and induced Gal-3 protein expression, suggesting that ALK4 might regulate TβRs stability by promoting lattice formation with Gal-3 and preventing internalization. Taken together, our results suggest that the loss of ALK4 increases TβR receptor stability through regulating receptor glycosylation, activating TGF-β signaling, promoting the EMT transition and cancer progression. Citation Format: Manqi Zhang, Jian Chen, Gerard Conrad Blobe. Loss of ALK4 function promotes cancer progression by regulating cell surface TGF-β receptor stability [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 6230.