FSTL1 Contributes to Tumor Progression Via Attenuating Apoptosis in a AKT/GSK-3β - Dependent Manner in Hepatocellular Carcinoma

Background: Several investigations have demonstrated that follistatin-like 1 (FSTL1) is implicated in the initiation and progression of diverse cancers. It remains unclear whether FSTL1 acted as a cancer-promoting gene through its overexpression in HCC.

Patients And Methods: We detected FSTL1 protein expression in 210 consecutive HCC cases curatively resected in our hospital between 2004 and 2007. The correlation between FSTL1 expression in HCC tissues and post-surgical prognosis of HCCs was analyzed. The in vitro experiments including apoptosis assessment, MTT, BrdU incorporation ELISA assay, Western immunoblotting, and qRT-PCR were performed to determine the impact of FSTL1 on apoptosis and proliferation abilities of HCC cells and the relevant mechanisms.

Results: FSTL1 protein was found aberrantly increased in 172 of 210 HCC tissues (81.9%) compared to adjacent liver tissues. FSTL1 overexpression was apparently associated with larger tumor size, advanced TNM staging, portal vein invasion, intra-hepatic metastases. Patients with higher FSTL1 expression in tumors suffered from the worse overall survival rate as assessed by comparison of Kaplan-Meier survival curves. Higher FSTL1 expression in HCC tissues was identified as a independent poor post-surgical prognostic predictor for HCC. Silencing FSTL1 by siRNA promoted cell apoptosis and leaded to suppression of cell viability and proliferation in MHCC97h cells. Furthermore, enforced expression of FSTL1 obtained the opposite results in Huh7 cells. Mechanistic investigation showed that FSTL1 repressed HCC cell apoptosis through AKT/GSK-3β/Bcl2/BAX/Bim signaling.

Conclusion: These data proved that FSTL1 contributed to unfavorable post-surgical outcome of HCC patients via inhibiting cell apoptosis.