MicroRNA-21 acts as an oncomir through multiple targets in human hepatocellular carcinoma

Changzheng Liu, Jia Yu, Shuangni Yu, Robert M. Lavker, Lei Cai, Wei Liu, Kegong Yang, Xiaodong He*, Songsen Chen

*Corresponding author for this work

Research output: Contribution to journalArticle

122 Scopus citations

Abstract

Background & Aims: MicroRNA-21 negatively regulates several targets, thereby affecting tumorigenesis. However, its mechanism of action in human hepatocellular carcinoma is poorly understood, and no direct evidence has shown a correlation between microRNA-21 function and phenotype. In this study, we investigate the function of microRNA-21 as a potent oncomir and probe the relationship between microRNA-21, its targets, and phenotypic alterations. Methods: We designed a set of rescue experiments using different combinations of anti-microRNA-21, siRNA, and a negative control to modulate the protein level of microRNA-21 targets and resulting phenotypic alterations. MicroRNA-21 was suppressed using anti-microRNA-21 to further uncover its effect on several critical signaling pathways. Results: We demonstrate that hepatocellular carcinoma is characterized by elevated levels of microRNA-21 and marked reductions of PTEN, PDCD4, and RECK expression. Silencing of PTEN and PDCD4 to prevent their induction by anti-microRNA-21 treatment led to decreased apoptosis and increased invasion, while silencing of RECK only led to increased invasion. Moreover, knockdown of microRNA-21 resulted in alterations of the Akt signaling pathway, the expression of p21 and MMP families, which are associated with apoptosis, and the cell cycle or invasiveness of cancer cells. Conclusions: MicroRNA-21 simultaneously regulates multiple programs that enhance cell proliferation, apoptosis or tumor invasiveness by targeting PTEN, PDCD4, and RECK in hepatocellular carcinomas. Targeting of microRNA-21 is sufficient to limit tumor cell proliferation and invasion in a manner that is likely to involve associated changes in multiple targets, suggesting that suppression of microRNA-21 may be a novel approach for the treatment of hepatocellular carcinoma.

Original languageEnglish (US)
Pages (from-to)98-107
Number of pages10
JournalJournal of Hepatology
Volume53
Issue number1
DOIs
StatePublished - Jul 1 2010

Keywords

  • Hepatocellular carcinoma
  • MicroRNA
  • PDCD4
  • PTEN
  • RECK

ASJC Scopus subject areas

  • Hepatology

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