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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

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Gα12 overexpressed in hepatocellular carcinoma reduces microRNA-122 expression via HNF4α inactivation, which causes c-Met induction.

Yang Yoon Mee YM Lee Chan Gyu CG Koo Ja Hyun JH Kim Tae Hyun TH Lee Jung Min JM An Jihyun J Kim Kang Mo KM Kim Sang Geon SG

Oncotarget 20150801 22

MicroRNA-122 (miR-122) is implicated as a regulator of physiological and pathophysiological processes in the liver. Overexpression of Gα12 is associated with overall survival in patients with hepatocellular carcinoma (HCC). Array-based miRNA profiling was performed on Huh7 stably transfected with activated Gα12 to find miRNAs regulated by the Gα12 pathway; among them, miR-122 was most greatly repressed. miR-122 directly inhibits c-Met expression, playing a role in HCC progression. Gα12 destabili ...[more]

PMID: 25965999

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Project description:UnlabelledA defining feature of the mammalian liver is polyploidy, a numerical change in the entire complement of chromosomes. The first step of polyploidization involves cell division with failed cytokinesis. Although polyploidy is common, affecting ∼90% of hepatocytes in mice and 50% in humans, the specialized role played by polyploid cells in liver homeostasis and disease remains poorly understood. The goal of this study was to identify novel signals that regulate polyploidization, and we focused on microRNAs (miRNAs). First, to test whether miRNAs could regulate hepatic polyploidy, we examined livers from Dicer1 liver-specific knockout mice, which are devoid of mature miRNAs. Loss of miRNAs resulted in a 3-fold reduction in binucleate hepatocytes, indicating that miRNAs regulate polyploidization. Second, we surveyed age-dependent expression of miRNAs in wild-type mice and identified a subset of miRNAs, including miR-122, that is differentially expressed at 2-3 weeks, a period when extensive polyploidization occurs. Next, we examined Mir122 knockout mice and observed profound, lifelong depletion of polyploid hepatocytes, proving that miR-122 is required for complete hepatic polyploidization. Moreover, the polyploidy defect in Mir122 knockout mice was ameliorated by adenovirus-mediated overexpression of miR-122, underscoring the critical role miR-122 plays in polyploidization. Finally, we identified direct targets of miR-122 (Cux1, Rhoa, Iqgap1, Mapre1, Nedd4l, and Slc25a34) that regulate cytokinesis. Inhibition of each target induced cytokinesis failure and promoted hepatic binucleation.ConclusionAmong the different signals that have been associated with hepatic polyploidy, miR-122 is the first liver-specific signal identified; our data demonstrate that miR-122 is both necessary and sufficient in liver polyploidization, and these studies will serve as the foundation for future work investigating miR-122 in liver maturation, homeostasis, and disease. (Hepatology 2016;64:599-615).

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

Publications

Gα12 overexpressed in hepatocellular carcinoma reduces microRNA-122 expression via HNF4α inactivation, which causes c-Met induction.

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