Alpha1-ACT Functions As A Tumor Suppressor Inhepatocellular Carcinoma By Inhibiting PI3K/AKT Signaling Pathway Via Activating PTEN

Background:Hepatocellular carcinoma(HCC)is one of the leading causes of deaths in worldwide.Thus,finding of the potential mechanisms and prognostic markers are important for improving better treatment options.Aims:Our study aims to elucidate tumor suppressive mechanism and prognostic value of alphal-ACT in HCC development.To investigate the expression and prognostic value of al-ACT in patients with hepatocellular carcinoma(HCC)and identify the mechanism by which al-ACT inhibits proliferation and promotes apoptosis of HCC.Methods:We first detected al-ACT expression and its relationship with clinicopathological characteristics and prognosis in HCC patients.We then established stable HCC cell lines with al-ACT overexpression and knockdown and performed the functional analysis in vitro.At first,we examined the relationship between the al-ACT and PTEN/PI3K/AKT/mTOR pathway using Western blotting.Then,we examined whether al-ACT can bind to PTEN directly using Co-immunoprecipitation.Finally,al-ACT expression was detected to evaluate its correlation with PI3K/AKT/mTOR pathway related apoptosis proteins in xenograft tumor mouse model using immunohistochemistry.Results:al-ACT expression was significantly lower in HCC tissues than in paratumor tissues and negtively correlated with the level of Ki67,AFP,AJCC stage,tumor size and tumor invasion.The expression level of al-ACT was positively correlated with the survival time of patients with hepatocellular carcinoma.Cox analysis also showed that al-ACT was one of the independent prognostic factors for survival.Overexpression of al-ACT can.inhibited HCC cell proliferation and increased HCC cell apoptosis by activating PI3K/AKT/mTOR mediated apoptosis via binding to PTEN and activating it in vitro.Apart from that overexpression of al-ACT also can increase the proportion of HCC cells in G0/G1 stage by increasing cyclin p21 expression and inhibit the migration and invasion abilities of HCC cells by regulating MMP2 and MMP9.Xenotransplantation studies with nude mice also found that overexpression of al-ACT inhibited tumorigenesis and al-ACT knockdown had an opposite effect.Conclusions:Our study demonstrates that ?1-ACT may play an important role in the development and progression of hepatocellular carcinoma(HCC),and it can be used as a reliable indicator to evaluate the prognosis of hepatocellular carcinoma.?1-ACT suppresses liver cancer proliferation and promotes apoptosis via targeting the PTEN/PI3K/AKT/mTOR signaling pathway,which may be serves as the one of a potential target for therapeutic intervention in HCC.