miR-665 inhibits epithelial-to-mesenchymal transition in bladder cancer via the SMAD3/SNAIL axis

Weiyu Wang; Yufan Ying; Haiyun Xie; Jiangfeng Li; Xueyou Ma; Liujia He; Mingjie Xu; Shiming Chen; Haixiang Shen; Xiangyi Zheng; Ben Liu; Xiao Wang; Liping Xie

doi:10.1080/15384101.2021.1929677

miR-665 inhibits epithelial-to-mesenchymal transition in bladder cancer via the SMAD3/SNAIL axis

Cell Cycle. 2021 Jul;20(13):1242-1252. doi: 10.1080/15384101.2021.1929677. Epub 2021 Jul 1.

Authors

Weiyu Wang¹, Yufan Ying¹, Haiyun Xie¹, Jiangfeng Li¹, Xueyou Ma¹, Liujia He¹, Mingjie Xu¹, Shiming Chen¹, Haixiang Shen¹, Xiangyi Zheng¹, Ben Liu¹, Xiao Wang¹, Liping Xie¹

Affiliation

¹ Department of Urology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China.

Abstract

Emerging research indicates that miRNAs can regulate cancer progression by influencing molecular pathways. Here, we studied miR-665, part of the DLK1-DIO3 miRNA cluster, which is downregulated by upstream methylation in bladder cancer. MiR-665 overexpression significantly downregulated the expression of SMAD3, phospho-SMAD3, and SNAIL, reversed epithelial-mesenchymal transition progression, and inhibited the migration of bladder cancer cells. To predict potential targets of miR-665, we used online databases and subsequently determined that miR-665 binds directly to the 3' untranslated region of SMAD3. Moreover, silencing of SMAD3 with small interfering RNAs phenocopied the effect of miR-665 overexpression, and overexpression of SMAD3 restored miR-665-overexpression-induced metastasis. This study revealed the role of the miR-665/SMAD3/SNAIL axis in bladder cancer, as well as the potential of miR-665 as a promising therapeutic target.

Keywords: bladder cancer; epithelial-mesenchymal transition; miR-665; migration.

Publication types

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

MeSH terms

3' Untranslated Regions
Binding Sites
Cell Line, Tumor
Cell Movement
Databases, Genetic
Epithelial-Mesenchymal Transition*
Gene Expression Regulation, Neoplastic
Humans
MicroRNAs / genetics
MicroRNAs / metabolism*
Neoplasm Invasiveness
Phosphorylation
Signal Transduction
Smad3 Protein / genetics
Smad3 Protein / metabolism*
Snail Family Transcription Factors / genetics
Snail Family Transcription Factors / metabolism*
Urinary Bladder Neoplasms / genetics
Urinary Bladder Neoplasms / metabolism*
Urinary Bladder Neoplasms / pathology

Substances

3' Untranslated Regions
MIRN665 microRNA, human
MicroRNAs
SMAD3 protein, human
SNAI1 protein, human
Smad3 Protein
Snail Family Transcription Factors

Grants and funding

This work was supported by the China Postdoctoral Science Foundation [2018M632489]; National Natural Science Foundation of China [81802564]; National Natural Science Foundation of China [81874203]; National Natural Science Foundation of China [81902612]; National Natural Science Foundation of China [81772744]; National Natural Science Foundation of China [81972374]; Zhejiang Provincial Natural Science Foundation of China [LY20H160022]; Zhejiang Province Medical and Health Scientific Research Project [2019RC033]; Zhejiang Provincial Natural Science Foundation of China [LY20H160030].