7C,D). Taken together, these results unravel a novel mechanism that cyclin G1 binds to the p85 subunit of PI3K and activates PI3K/Akt/GSK-3β/Snail signaling, which renders EMT and metastasis of HCC cells (Fig. 7E). Primary liver cancer is the fifth most common cancer and the third most common cause of cancer mortality worldwide. HCC accounts for 70%-85% of primary liver cancer according to the statistical data of the

American Cancer Society in 2007. Great efforts have been made to elucidate the molecular mechanism underlying tumorigenicity, invasion, and metastasis of HCC in order to develop novel treatments and a possible cure in the past several decades. Nevertheless, the detailed mechanism of hepatocarcinogenesis and HCC metastasis remains obscure. Cyclin G1 deregulation is associated with genomic

instability, which is frequently induced beta-catenin activation following DNA damage.4, 14, 31 It has been reported Pexidartinib solubility dmso that cyclin G1, together with MDM2, constitutes part of a negative feedback system attenuating p53 activity, and loss of cyclin G1 decreased tumor susceptibility in diethylnitrosamine-induced murine HCC.6, 15 In the current study, we found that cyclin G1 was highly expressed in HCCs and portal vein tumor thrombus, and that cyclin G1 expression was closely associated with the poor prognosis of HCC patients. Therefore, whether cyclin G1 is responsible for HCC metastasis arouses our interest. EMT is an important process during tumor metastasis. By using a variety of HCC cases and mouse HCC metastasis models, we demonstrated that cyclin G1 could promote EMT of hepatoma cells Methocarbamol and facilitate HCC metastasis. Furthermore, we clarified that cyclin G1 could interact with PI3K and activate the PI3K/Akt/GSK-3β/Snail pathway, by which E-cadherin expression was down-regulated. EMT usually occurs in the critical phases

of embryonic development. However, this important developmental program also has a sinister role in tumor metastasis. There is solid evidence indicating that EMT gives rise to the dissemination of single carcinoma cell from the site of the primary tumor.32 EMT is also reported to be involved in the progression of HCC and correlates with the prognosis of patients.24 Although numerous factors have been identified to participate in EMT, whether cyclin G1 promotes EMT and cancer metastasis remains unclear. To investigate the precise function of cyclin G1 in HCC progression, we established stable cell line overexpressing cyclin G1 by recombinant lentivirus. The morphological changes of the tumor cells led us to link the biological function of cyclin G1 with EMT induction. As anticipated, mesenchymal markers were significantly up-regulated in the cyclin G1 stable transfectants, whereas the epithelial markers were remarkably decreased.