Dataset Information

Cadherin-6 is a putative tumor suppressor and target of epigenetically dysregulated miR-429 in cholangiocarcinoma.

ABSTRACT: Cholangiocarcinoma (CC) is a rare malignancy of the extrahepatic or intrahepatic biliary tract with an outstanding poor prognosis. Non-surgical therapeutic regimens result in minimally improved survival of CC patients. Global genomic analyses identified a few recurrently mutated genes, some of them in genes involved in epigenetic patterning. In a previous study, we demonstrated global DNA methylation changes in CC, indicating major contribution of epigenetic alterations to cholangiocarcinogenesis. Here, we aimed at the identification and characterization of CC-related, differentially methylated regions (DMRs) in potential microRNA promoters and of genes targeted by identified microRNAs. Twenty-seven hypermethylated and 13 hypomethylated potential promoter regions of microRNAs, known to be associated with cancer-related pathways like Wnt, ErbB, and PI3K-Akt signaling, were identified. Selected DMRs were confirmed in 2 independent patient cohorts. Inverse correlation between promoter methylation and expression suggested miR-129-2 and members of the miR-200 family (miR-200a, miR-200b, and miR-429) as novel tumor suppressors and oncomiRs, respectively, in CC. Tumor suppressor genes deleted in liver cancer 1 (DLC1), F-box/WD-repeat-containing protein 7 (FBXW7), and cadherin-6 (CDH6) were identified as presumed targets in CC. Tissue microarrays of a representative and well-characterized cohort of biliary tract cancers (n=212) displayed stepwise downregulation of CDH6 and association with poor patient outcome. Ectopic expression of CDH6 on the other hand, delayed growth in the CC cell lines EGI-1 and TFK-1, together suggesting a tumor suppressive function of CDH6. Our work represents a valuable repository for the study of epigenetically altered miRNAs in cholangiocarcinogenesis and novel putative, CC-related tumor suppressive miRNAs and oncomiRs.

SUBMITTER: Goeppert B

PROVIDER: S-EPMC5221660 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Cadherin-6 is a putative tumor suppressor and target of epigenetically dysregulated miR-429 in cholangiocarcinoma.

Goeppert Benjamin B Ernst Christina C Baer Constance C Roessler Stephanie S Renner Marcus M Mehrabi Arianeb A Hafezi Mohammadreza M Pathil Anita A Warth Arne A Stenzinger Albrecht A Weichert Wilko W Bähr Marion M Will Rainer R Schirmacher Peter P Plass Christoph C Weichenhan Dieter D

Epigenetics 20160903 11

Cholangiocarcinoma (CC) is a rare malignancy of the extrahepatic or intrahepatic biliary tract with an outstanding poor prognosis. Non-surgical therapeutic regimens result in minimally improved survival of CC patients. Global genomic analyses identified a few recurrently mutated genes, some of them in genes involved in epigenetic patterning. In a previous study, we demonstrated global DNA methylation changes in CC, indicating major contribution of epigenetic alterations to cholangiocarcinogenesi ...[more]

PMID: 27593557

Similar Datasets

Project description:Gastric cancer is the second leading cause of cancer death and remains a major clinical challenge due to poor prognosis and limited treatment options. Therefore, the basic mechanisms underlying gastric tumorigenesis deserve investigation. Although regulation of the galactoside-binding lectin galectin-7 in cancer has been studied, its role in tumor formation and progression remains controversial. In this study, we investigated galectin-7 expression and its role in gastric cancer. Immunohistochemical staining using a tissue microarray of gastric cancer patients revealed significantly low expression levels of galectin-7 in malignant tissues compared with matched normal tissues, and decreased expression of galectin-7 in malignant tissues was associated with advanced TMN stage disease (p=0.034). Importantly, low expression of galectin-7 in normal tissues was associated with a poor survival rate (p=0.0561). Over-expression of galectin-7 in AGS gastric adenocarcinoma cells suppressed cell proliferation, migration, and invasion, whereas ablation of galectin-7 in KATO III gastric carcinoma cells reversed these properties. AGS cells that overexpressed galectin-7 could not form gastric tumors in xenografted mice. More than 70% hypermethylation was observed in 7 of 9 gastric cancer cell lines tested and 5-aza-cytidine treatment lowered galectin-7 expression by reducing methylation in 24 cancer cell lines from five different organ origins. We analyzed CpG islands in the galectin-7 genomic region and detected hypermethylation at +1566bp of exon 2, the predicted p53 binding region. DNA hypermethylation of this region was also detected in gastric cancer tissues from 20 patients. Taken together, our data indicate that galectin-7 has a tumor suppressive function, and that the gene is epigenetically modified by DNA methylation and significantly down-regulated in gastric cancer. Further study of galectin-7 regulation may lead to improved gastric cancer diagnosis and therapy.

Dataset Information

Cadherin-6 is a putative tumor suppressor and target of epigenetically dysregulated miR-429 in cholangiocarcinoma.

Publications

Cadherin-6 is a putative tumor suppressor and target of epigenetically dysregulated miR-429 in cholangiocarcinoma.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets