G?12 overexpressed in hepatocellular carcinoma reduces microRNA-122 expression via HNF4? inactivation, which causes c-Met induction.

ABSTRACT: MicroRNA-122 (miR-122) is implicated as a regulator of physiological and pathophysiological processes in the liver. Overexpression of G?12 is associated with overall survival in patients with hepatocellular carcinoma (HCC). Array-based miRNA profiling was performed on Huh7 stably transfected with activated G?12 to find miRNAs regulated by the G?12 pathway; among them, miR-122 was most greatly repressed. miR-122 directly inhibits c-Met expression, playing a role in HCC progression. G?12 destabilized HNF4? by accelerating ubiquitination, impeding constitutive expression of miR-122. miR-122 mimic transfection diminished the ability of G?12 to increase c-Met and to activate ERK, STAT3, and Akt/mTOR, suppressing cell proliferation with augmented apoptosis. Consistently, miR-122 transfection prohibited tumor cell colony formation and endothelial tube formation. In a xenograft model, G?12 knockdown attenuated c-Met expression by restoring HNF4? levels, and elicited tumor cell apoptosis but diminished Ki67 intensities. In human HCC samples, G?12 levels correlated to c-Met and were inversely associated with miR-122. Both miR-122 and c-Met expression significantly changed in tumor node metastasis (TNM) stage II/III tumors. Moreover, changes in G?12 and miR-122 levels discriminated recurrence-free and overall survival rates of HCC patients. Collectively, G?12 overexpression in HCC inhibits MIR122 transactivation by inactivating HNF4?, which causes c-Met induction, contributing to cancer aggressiveness.

SUBMITTER: Yang YM 

PROVIDER: S-EPMC4662475 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature