Gα12 overexpressed in hepatocellular carcinoma reduces microRNA-122 expression via HNF4α 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 alpha(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 alpha(12) to find miRNAs regulated by the G alpha(12) pathway; among them, miR-122 was most greatly repressed. miR-122 directly inhibits c-Met expression, playing a role in HCC progression. G alpha(12) destabilized HNF4 alpha by accelerating ubiquitination, impeding constitutive expression of miR-122. miR-122 mimic transfection diminished the ability of G alpha(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 alpha(12) knockdown attenuated c-Met expression by restoring HNF4 alpha levels, and elicited tumor cell apoptosis but diminished Ki67 intensities. In human HCC samples, G alpha(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 alpha(12) and miR-122 levels discriminated recurrence-free and overall survival rates of HCC patients. Collectively, G alpha(12) overexpression in HCC inhibits MIR122 transactivation by inactivating HNF4 alpha, which causes c-Met induction, contributing to cancer aggressiveness.