Journal
JOURNAL OF HEPATOLOGY
Volume 53, Issue 1, Pages 98-107Publisher
ELSEVIER
DOI: 10.1016/j.jhep.2010.02.021
Keywords
MicroRNA; PTEN; PDCD4; RECK; Hepatocellular carcinoma
Categories
Funding
- National Laboratory Special [2060204]
- PUMCH IBMS [2009PY13, 2009RC03]
- CAMS
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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. (C) 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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