Alpha1-ACT Functions as a Tumour Suppressor in Hepatocellular Carcinoma by Inhibiting the PI3K/AKT/mTOR Signalling Pathway via Activation of PTEN

作者：Zhu, Hanzhang; Liu, Qiaoyu; Tang, Junwei; Xie, Yu; Xu, Xiaoliang; Huang, Ruyi; Zhang, Yuanguangyan; Jin, Kangpeng; Sun, Beicheng^*

来源：Cellular Physiology and Biochemistry, 2017, 41(6): 2289-2306.

DOI：10.1159/000475648

• alpha 1-ACT
• HCC
• PTEN
• PI3K
• AKT
• mTOR

Background & Aims: To investigate the expression and prognostic value of alpha 1-ACT (Alpha1-antichymotrypsin) in patients with HCC (hepatocellular carcinoma) and identify the mechanism by which alpha 1-ACT inhibits proliferation and promotes apoptosis of HCC. Methods: We first measured alpha 1-ACT expression levels and determined their relationship with the clinicopathological characteristics and prognosis of patients with HCC. We then established stable HCC cell lines with both alpha 1-ACT overexpression and knockdown and performed a functional analysis in vitro. We first examined the relationship between alpha 1-ACT and the PTEN/PI3K/AKT/mTOR pathway using Western blotting. Then, we determined whether alpha 1-ACT can directly bind to PTEN using co-immunoprecipitation. Finally, we measured alpha 1-ACT expression to evaluate its correlation with the PI3K/AKT/mTOR pathway-related apoptosis proteins in a xenograft tumour mouse model using immunohistochemistry. Results: The alpha 1-ACT expression level was significantly lower in the HCC tissues than in the paratumour tissues and was negatively positively correlated with the level of Ki67, AFP, the AJCC stage, tumour size and tumour invasion. The overexpression of alpha 1-ACT can inhibit cell proliferation and increase cell apoptosis by activating PI3K/AKT/mTOR-mediated apoptosis via binding to PTEN and activating it in vitro. Additionally, the overexpression of alpha 1-ACT can also increase the proportion of cells in the G0/G1 stage by increasing cyclin p21 expression and inhibiting the migration and invasion abilities of HCC cells by regulating MMP2 and MMP9. The xenotransplantation studies with nude mice also showed that overexpression of alpha 1-ACT inhibited tumourigenesis and knockdown of alpha 1-ACT had the opposite effect. Conclusions: Our study demonstrates that alpha 1-ACT suppresses liver cancer development and metastasis via targeting the PTEN/PI3K/AKT/mTOR signalling pathway, which may be a potential target for therapeutic intervention in HCC.

• 出版日期2017
• 单位南京医科大学