The Barrett‐associated variants at <i><scp>GDF</scp>7</i> and <i><scp>TBX</scp>5</i> also increase esophageal adenocarcinoma risk

Becker, Jéssica; May, Andrea; Gerges, Christian; Anders, Mario; Schmidt, Claudia; Veits, Lothar; Noder, Tania; Mayershofer, Rupert; Kreuser, Nicole; Manner, Hendrik; Venerito, Marino; Hofer, Jan-Hinnerk; Lyros, Orestis; Ahlbrand, Constantin J.; Arras, Michael; Hofer, Sebastian J.; Heinrichs, Sophie K. M.; Weise, Katharina; Hess, Timo; Böhmer, Anne C.; Kosiol, Nils; Kießlich, Ralf; Izbicki, Jakob R.; Hölscher, Arnulf H.; Bollschweiler, Elfriede; Malfertheiner, Peter; Lang, Hauke; Moehler, Markus; Lorenz, D.; Ott, Katja; Schmidt, Thomas; Nöthen, Markus M.; Hackelsberger, Andreas; Schumacher, Brigitte; Pech, Oliver; Vashist, Yogesh K.; Vieth, Michael; Weismüller, Josef; Knapp, Michael; Neuhaus, Horst; Rösch, Thomas; Ell, Christian; Gockel, Ines; Schumacher, Johannes

doi:10.1002/cam4.641

Cited by 18 publications

(8 citation statements)

References 19 publications

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“…We found that both GDF6 and GDF7 were downregulated in CRC tissues. While we could find no earlier documentation of these genes having an association with CRC risk, GDF7 is a ligand in the BMP pathway that has been shown to regulate the Hedgehog and Wnt pathways and has been associated with the pro-inflammatory phenotypes in many diseases including Barrett’s Esophagus [ 49 ] and esophageal adenocarcinoma [ 50 ]. Additionally, the role of Wnt in CRC has been established [ 51 ].…”

Section: Discussionmentioning

confidence: 99%

The TGFβ-signaling pathway and colorectal cancer: associations between dysregulated genes and miRNAs

et al. 2018

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BackgroundThe TGFβ-signaling pathway plays an important role in the pathogenesis of colorectal cancer (CRC). Loss of function of several genes within this pathway, such as bone morphogenetic proteins (BMPs) have been seen as key events in CRC progression.MethodsIn this study we comprehensively evaluate differential gene expression (RNASeq) of 81 genes in the TGFβ-signaling pathway and evaluate how dysregulated genes are associated with miRNA expression (Agilent Human miRNA Microarray V19.0). We utilize paired carcinoma and normal tissue from 217 CRC cases. We evaluate the associations between differentially expressed genes and miRNAs and sex, age, disease stage, and survival months.ResultsThirteen genes were significantly downregulated and 14 were significantly upregulated after considering fold change (FC) of > 1.50 or < 0.67 and multiple comparison adjustment. Bone morphogenetic protein genes BMP5, BMP6, and BMP2 and growth differentiation factor GDF7 were downregulated. BMP4, BMP7, INHBA (Inhibin beta A), TGFBR1, TGFB2, TGIF1, TGIF2, and TFDP1 were upregulated. In general, genes with the greatest dysregulation, such as BMP5 (FC 0.17, BMP6 (FC 0.25), BMP2 (FC 0.32), CDKN2B (FC 0.32), MYC (FC 3.70), BMP7 (FC 4.17), and INHBA (FC 9.34) showed dysregulation in the majority of the population (84.3, 77.4, 81.1, 80.2, 82.0, 51.2, and 75.1% respectively). Four genes, TGFBR2, ID4, ID1, and PITX2, were un-associated or slightly upregulated in microsatellite-stable (MSS) tumors while downregulated in microsatellite-unstable (MSI) tumors. Eight dysregulated genes were associated with miRNA differential expression. E2F5 and THBS1 were associated with one or two miRNAs; RBL1, TGFBR1, TGIF2, and INHBA were associated with seven or more miRNAs with multiple seed-region matches. Evaluation of the joint effects of mRNA:miRNA identified interactions that were stronger in more advanced disease stages and varied by survival months.ConclusionThese data support an interaction between miRNAs and genes in the TGFβ-signaling pathway in association with CRC risk. These interactions are associated with unique clinical characteristics that may provide targets for further investigations.Electronic supplementary materialThe online version of this article (10.1186/s12967-018-1566-8) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

The TGFβ-signaling pathway and colorectal cancer: associations between dysregulated genes and miRNAs

et al. 2018

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“…[37][38][39] Many of these associations have been replicated in subsequent studies. 40,41 One of the largest initiatives has pooled analyses of all GWAS studies published until February 2016, comprising 6167 cases of BE, 4112 cases of EAC, and 17,159 controls. 42 These confirmed associations for all 8 previously identified SNPs, along with 8 new risk loci; 2 of these are linked to genes that regulate body fat.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

The Epidemiology of Esophageal Adenocarcinoma

2018

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The incidence of esophageal adenocarcinoma (EAC) has increased in many Western countries and is higher in men than women. Some risk factors for EAC have been identified-mainly gastroesophageal reflux disease, Barrett's esophagus, obesity, and tobacco smoking. It is not clear whether interventions to address these factors can reduce risk of EAC, although some evidence exists for smoking cessation. Although consumption of alcohol is not associated with EAC risk, other exposures, such as physical activity, nutrition, and medication use, require further study. Genetic variants have been associated with risk for EAC, but their overall contribution is low. Studies are needed to investigate associations between risk factors and the molecular subtypes of EAC. The prognosis for patients with EAC has slightly improved, but remains poor-screening and surveillance trials of high-risk individuals are needed.

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“…Despite enormous efforts in treating the disease, including surgeries, radiation therapy, and chemotherapy, the 5‐year survival rate of oesophageal cancer has not improved significantly . Increased evidence has shown that development of oesophageal cancer is correlated with abnormal gene activity . However, the molecular mechanisms underlying the regulation of the aberrant genes in oesophageal cancer remain to be further tested for gene correction strategies.…”

Section: Introductionmentioning

confidence: 99%

STAT3 down‐regulation induces mitochondria‐dependent G2/M cell cycle arrest and apoptosis in oesophageal carcinoma cells

Shao

Zhou

et al. 2017

Clin Exp Pharma Physio

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STAT3 is persistently activated in a wide variety of human tumours, and aberrant STAT3 activity promotes tumour growth, invasion and metastasis. To explore STAT3 down-regulation in human oesophageal cancer cells, cell proliferation, apoptosis and mitochondrial mechanisms were explored in oesophageal carcinoma TE1 cell cultures. We demonstrate for the first time that STAT3 down-regulation by RNAi is sufficient to inhibit oesophageal cancer cell proliferation inducing cell apoptosis. Further, we demonstrate that mitochondrial transmembrane potential is impaired thereby leading to collapsed mitochondrial membrane potential, abnormal mitochondrial membrane depolarization, nuclear DNA fragmentation and cell cycle G2/M arrest under the conditions of STAT3 down-regulation. Thus, our results suggest that STAT3 inhibition is a valid approach to induce oesophageal carcinoma cell mitochondrial-dependent apoptosis in therapeutic strategies against oesophageal cancers.

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The Barrett‐associated variants at GDF7 and TBX5 also increase esophageal adenocarcinoma risk

Cited by 18 publications

References 19 publications

The TGFβ-signaling pathway and colorectal cancer: associations between dysregulated genes and miRNAs

The TGFβ-signaling pathway and colorectal cancer: associations between dysregulated genes and miRNAs

The Epidemiology of Esophageal Adenocarcinoma

STAT3 down‐regulation induces mitochondria‐dependent G2/M cell cycle arrest and apoptosis in oesophageal carcinoma cells

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