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miR-137 is a tumor suppressor in endometrial cancer and is repressed by DNA hypermethylation. Lab Invest 2018 11;98(11):1397-1407

Date

06/30/2018

Pubmed ID

29955087

Pubmed Central ID

PMC6214735

DOI

10.1038/s41374-018-0092-x

Scopus ID

2-s2.0-85049129398   5 Citations

Abstract

Endometrial cancer is the most common gynecological cancer in the United States. We wanted to identify epigenetic aberrations involving microRNAs (miRNAs), whose genes become hypermethylated in endometrial primary tumors. By integrating known miRNA sequences from the miRNA database (miRBase) with DNA methylation data from methyl-CpG-capture sequencing, we identified 111 differentially methylated regions (DMRs) associated with CpG islands (CGIs) and miRNAs. Among them, 22 DMRs related to 29 miRNAs and within 8 kb of CGIs were hypermethylated in endometrial tumors but not in normal endometrium. miR-137 was further validated in additional endometrial primary tumors. Hypermethylation of miR-137 was found in both endometrioid and serous endometrial cancer (P < 0.01), and it led to the loss of miR-137 expression. Treating hypermethylated endometrial cancer cells with epigenetic inhibitors reactivated miR-137. Moreover, genetic overexpression of miR-137 suppressed cancer cell proliferation and colony formation in vitro. When transfected cancer cells were implanted into nude mice, the cells that overexpressed miR-137 grew more slowly and formed smaller tumors (P < 0.05) than vector transfectants. Histologically, xenograft tumors from cancer cells expressing miR-137 were less proliferative (P < 0.05), partly due to inhibition of EZH2 and LSD1 expression (P < 0.01) in both the transfected cancer cells and tumors. Reporter assays indicated that miR-137 targets EZH2 and LSD1. These results suggest that miR-137 is a tumor suppressor that is repressed in endometrial cancer because the promoter of its gene becomes hypermethylated.

Author List

Zhang W, Chen JH, Shan T, Aguilera-Barrantes I, Wang LS, Huang TH, Rader JS, Sheng X, Huang YW

Authors

Yi-Wen Huang PhD Assistant Professor in the Obstetrics and Gynecology department at Medical College of Wisconsin
Janet Sue Rader MD Chair, Professor in the Obstetrics and Gynecology department at Medical College of Wisconsin
Li-Shu Wang PhD Associate Professor in the Medicine department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Adenocarcinoma
Animals
Cell Line, Tumor
DNA Methylation
Endometrial Neoplasms
Enhancer of Zeste Homolog 2 Protein
Female
Gene Silencing
Histone Demethylases
Humans
Mice, Nude
MicroRNAs
jenkins-FCD Prod-403 0f9a74600e4e79798f8fa6f545ea115f3dd948b2