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Gastroenterology. 2011 Jan;140(1):322-31. doi: 10.1053/j.gastro.2010.10.006. Epub 2010 Oct 15.

The microRNA miR-139 suppresses metastasis and progression of hepatocellular carcinoma by down-regulating Rho-kinase 2.

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  • 1State Key Laboratory for Liver Research, The University of Hong Kong, Pokfulam, Hong Kong.

Abstract

BACKGROUND & AIMS:

We investigated mechanisms of hepatocellular carcinoma (HCC) metastasis and identified an antimetastatic microRNA (miRNA), miR-139, that is down-regulated in human HCC samples.

METHODS:

Effects of stable and transient expression of miRNA-139 and its inhibitors were studied in the human HCC cell lines SMMC-7721 and BEL7402; cells were analyzed for migration and invasion. Liver samples from patients with metastatic HCC were analyzed for levels of miRNA-139; data were compared with survival data using the Kaplan-Meier method and compared between groups by the log-rank test. Tumor formation and metastasis from human HCC MHCC97L cells that did or did not express miR-139 were analyzed in mice.

RESULTS:

Down-regulation of miR-139 in HCC was associated significantly with poor prognosis of patients and features of metastatic tumors, including venous invasion, microsatellite formation, absence of tumor encapsulation, and reduced differentiation. miR-139 expression was reduced in metastatic HCC tumors compared with primary tumors. Overexpression of miR-139 in HCC cells significantly reduced cell migration and invasion in vitro and the incidence and severity of lung metastasis from orthotopic liver tumors in mice. miR-139 interacted with the 3' untranslated region of Rho-kinase 2 (ROCK2) and reduced its expression in HCC cells. Levels of miR-139 were correlated inversely with ROCK2 protein in human HCC samples. Overexpression of miR-139 did not inhibit HCC cell motility when ROCK2 was knocked down.

CONCLUSIONS:

The microRNA miR-139 interacts with ROCK2 and reduces its expression in HCC cells. Down-regulation of miR-139 increased the invasive abilities of HCC cells in vitro and HCC metastasis in vivo. Expression of miR-139 is reduced in human metastatic HCC samples and correlates with prognosis.

Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.

[PubMed - indexed for MEDLINE]
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