MiR-410 is overexpressed in liver and colorectal tumors and enhances tumor cell growth by silencing FHL1 via a direct/indirect mechanism

Yu Wang; Jie Fu; Mengmeng Jiang; Xiaoai Zhang; Long Cheng; Xiaojie Xu; Zhongyi Fan; Jing Zhang; Qinong Ye; Haifeng Song

doi:10.1371/journal.pone.0108708

MiR-410 is overexpressed in liver and colorectal tumors and enhances tumor cell growth by silencing FHL1 via a direct/indirect mechanism

PLoS One. 2014 Oct 1;9(10):e108708. doi: 10.1371/journal.pone.0108708. eCollection 2014.

Authors

Yu Wang¹, Jie Fu², Mengmeng Jiang², Xiaoai Zhang³, Long Cheng⁴, Xiaojie Xu⁴, Zhongyi Fan⁴, Jing Zhang², Qinong Ye⁴, Haifeng Song²

Affiliations

¹ Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing, China; SDU School of Life Science, Jinan, China.
² Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing, China.
³ State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China.
⁴ Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing, China.

Abstract

FHL1 is an important tumor-suppressor that is downregulated in multiple tumors by unknown mechanisms. We demonstrated that miR-410 specifically targets the 3'UTR of FHL1. Furthermore, using DNA bisulfite modification and sequencing experiments, we demonstrated that the FHL1 promoter is hypermethylated in cancer cells. FHL1 methylation is increased upon miR-410 expression, suggesting that the regulation of FHL1 by miR-410 occurs by a dual mechanism. Using chromatin immunoprecipitation assays, we observed that miR-410 overexpression results in the increased binding of DNMT3A at the FHL1 promoter, which could explain how miR-410 regulates FHL1 methylation. Importantly, in vitro and in vivo results suggest that miR-410 may have oncogenic properties. Furthermore, both miR-410 and DNMT3A are upregulated in clinical human liver and colorectal tumors cancers. Our results suggest that miR-410 may function as an oncomiR and are consistent with its key function in regulating FHL1 in certain digestive system cancers.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

3' Untranslated Regions
Animals
Cell Line, Tumor
Colorectal Neoplasms / genetics*
Colorectal Neoplasms / pathology
DNA (Cytosine-5-)-Methyltransferases / metabolism
DNA Methyltransferase 3A
Disease Models, Animal
Gene Expression Regulation, Neoplastic
Gene Silencing*
Heterografts
Humans
Intracellular Signaling Peptides and Proteins / genetics*
LIM Domain Proteins / genetics*
Liver Neoplasms / genetics*
Liver Neoplasms / pathology
Male
MicroRNAs / genetics*
Muscle Proteins / genetics*
Promoter Regions, Genetic
Protein Binding

Substances

3' Untranslated Regions
DNMT3A protein, human
FHL1 protein, human
Intracellular Signaling Peptides and Proteins
LIM Domain Proteins
MIRN410 microRNA, human
MicroRNAs
Muscle Proteins
DNA (Cytosine-5-)-Methyltransferases
DNA Methyltransferase 3A

Grants and funding

This work was supported by Postdoctoral Science Foundation (201150M1523) and National Natural Science Foundation (81301941 and 81272701). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.