Gα12 overexpressed in hepatocellular carcinoma reduces microRNA-122 expression via HNF4α inactivation, which causes c-Met inductionopen access
- Authors
- Yang, Yoon Mee; Lee, Chan Gyu; Koo, Ja Hyun; Kim, Tae Hyun; Lee, Jung Min; An, Ji hyun; Kim, Kang Mo; Kim, Sang Geon
- Issue Date
- Aug-2015
- Publisher
- IMPACT JOURNALS LLC
- Keywords
- liver cancer; non-coding RNA; G protein; c-Met
- Citation
- ONCOTARGET, v.6, no.22, pp.19055 - 19069
- Indexed
- SCIE
SCOPUS
- Journal Title
- ONCOTARGET
- Volume
- 6
- Number
- 22
- Start Page
- 19055
- End Page
- 19069
- URI
- https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/156564
- DOI
- 10.18632/oncotarget.3957
- ISSN
- 19492553
- 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.
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