Downregulation of microRNA-532-5p promotes the proliferation and invasion of bladder cancer cells through promotion of HMGB3/Wnt/β-catenin signaling

Chem Biol Interact. 2019 Feb 25;300:73-81. doi: 10.1016/j.cbi.2019.01.015. Epub 2019 Jan 11.

Abstract

Accumulating evidence has shown that altered expression of microRNA-532-5p (miR-532-5p) is involved in the development and progression of various cancers. However, little is known about the role of miR-532-5p in bladder cancer. In this study, we aimed to investigate the expression, biological function, and regulatory mechanism of miR-532-5p in bladder cancer. Herein, we found that miR-532-5p expression was frequently downregulated in bladder cancer tissues and cell lines compared with normal controls. Functional experiments showed that overexpression of miR-532-5p inhibited the proliferation and invasion of bladder cancer cells, whereas inhibition of miR-532-5p showed opposite effects. Interestingly, bioinformatics analysis predicted high-mobility group protein B3 (HMGB3) as a potential target gene of miR-532-5p. Further experiments showed that miR-532-5p directly targeted the 3'-UTR of HMGB3 and negatively regulated its expression in bladder cancer cells. Moreover, HMGB3 expression was upregulated in bladder cancer tissues and showed inverse correlation with miR-532-5p expression. Notably, miR-532-5p regulated the nuclear expression of β-catenin and activation of Wnt/β-catenin signaling in bladder cancer cells. However, restoration of HMGB3 expression partially reversed the antitumor effect of miR-532-5p overexpression, while knockdown of HMGB3 partially abrogated the oncogenic effect of miR-532-5p inhibition. Taken together, our results demonstrated that miR-532-5p inhibited the proliferation and invasion of bladder cancer cells by targeting HMGB3 and downregulating Wnt/β-catenin signaling, suggesting a tumor suppressive role of miR-532-5p in bladder cancer. Our study highlights an importance of the miR-532-5p/HMGB3 axis in bladder cancer and suggests that targeting miR-532-5p/HMGB3 may have potential applications for development of bladder cancer therapy.

Keywords: Bladder cancer; HMGB3; Wnt; miR-532-5p.

MeSH terms

  • 3' Untranslated Regions
  • Antagomirs / metabolism
  • Base Sequence
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation*
  • Down-Regulation
  • HMGB3 Protein / antagonists & inhibitors
  • HMGB3 Protein / genetics
  • HMGB3 Protein / metabolism*
  • Humans
  • MicroRNAs / antagonists & inhibitors
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Sequence Alignment
  • Urinary Bladder Neoplasms / metabolism
  • Urinary Bladder Neoplasms / pathology
  • Wnt Signaling Pathway*

Substances

  • 3' Untranslated Regions
  • Antagomirs
  • HMGB3 Protein
  • MIRN532 microRNA, human
  • MicroRNAs
  • RNA, Small Interfering