G12 overexpression in hepatocellular carcinoma promotes epithelial-mesenchymal transition through microRNAs deregulation

Abstract

Hepatocellular carcinoma (HCC) has a poor prognosis due to its aggressive nature. Ligand activation of G-protein coupled receptor with enhanced G-protein activity may contribute to tumorigenesis and tumor progression in microenvironments. Here, we report the overexpression of Gα12 in HCC and its effect on deregulation of microRNAs in association with epithelial-mesenchymal transition. Gα12 expression levels were higher in human HCC than surrounding normal tissue. Array analyses using Huh7 cells stably transfected with an active mutant of Gα12 (Gα12QL) enabled us to extract down-regulated microRNAs. Of them, decreases of miR-200b/a, -192 and -215 contributed to ZEB induction through the up-regulation of MDM2. Transfection with miR-200b, -192 or miR-215 mimic antagonized HCC cell migration and invasion facilitated by Gα12QL. In tumor xenograft studies, sustained knockdown of Gα12 decreased the overall growth rate and average volume of tumors derived from SK-Hep1, a mesenchymal liver tumor cell line. In human HCC samples, levels of the identified microRNAs were all decreased, and correlated with the induction of mesenchymal markers. Moreover, decreases of the miRNAs discriminated microvascular invasion versus non-microvascular invasion of HCC. Conclusion: Increase of Gα12 in HCC deregulates a set of miRNAs promoting epithelial-mesenchymal transition of HCC and may be responsible for tumor microvascular invasion, implying that Gα12 signaling and the downstream mediators may be utilized as therapeutic targets and/or prognostic markers.