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Cyclin G1–mediated epithelial‐mesenchymal transition via phosphoinositide 3‐kinase/Akt signaling facilitates liver cancer progression
Author(s) -
Wen Wen,
Ding Jin,
Sun Wen,
Fu Jing,
Chen Yao,
Wu Kun,
Ning Beifang,
Han Tao,
Huang Lei,
Chen Cheng,
Xie Dong,
Li Zhong,
Feng Gensheng,
Wu Mengchao,
Xie Weifen,
Wang Hongyang
Publication year - 2012
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.25596
Subject(s) - cancer research , epithelial–mesenchymal transition , metastasis , protein kinase b , cyclin a , cyclin e , pi3k/akt/mtor pathway , cyclin d , cyclin b , cell cycle , biology , cancer , cyclin d1 , medicine , signal transduction , microbiology and biotechnology
Cyclin G1 deficiency is associated with reduced incidence of carcinogen‐induced hepatocellular carcinoma (HCC), but its function in HCC progression remains obscure. We report a critical role of cyclin G1 in HCC metastasis. Elevated expression of cyclin G1 was detected in HCCs (60.6%), and its expression levels were even higher in portal vein tumor thrombus. Clinicopathological analysis revealed a close correlation of cyclin G1 expression with distant metastasis and poor prognosis of HCC. Forced expression of cyclin G1 promoted epithelial‐mesenchymal transition (EMT) and metastasis of HCC cells in vitro and in vivo . Cyclin G1 overexpression enhanced Akt activation through interaction with p85 (regulatory subunit of phosphoinositide 3‐kinase [PI3K]), which led to subsequent phosphorylation of glycogen synthase kinase‐3β (GSK‐3β) and stabilization of Snail, a critical EMT mediator. These results suggest that elevated cyclin G1 facilitates HCC metastasis by promoting EMT via PI3K/Akt/GSK‐3β/Snail‐dependent pathway. Consistently, we have observed a significant correlation between cyclin G1 expression and p‐Akt levels in a cohort of HCC patients, and found that combination of these two parameters is a more powerful predictor of poor prognosis. Conclusions: Cyclin G1 plays a pivotal role in HCC metastasis and may serve as a novel prognostic biomarker and therapeutic target. (H EPATOLOGY 2012;55:1787–1798)