Cyclin G1-mediated epithelial-mesenchymal transition via phosphoinositide 3-kinase/Akt signaling facilitates liver cancer progression |
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Authors: | 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 |
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Affiliation: | International Cooperation Laboratory on Signal Transduction of Eastern Hepatobiliary Surgery Institute, Shanghai, China. |
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Abstract: | 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. |
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