Targeting the FoxJ3/FoxO6 axis suppresses hepatocellular carcinoma growth by inducing cell cycle arrest and apoptosis.

OBJECTIVE: To explore the biological function of Forkhead box J3 (FoxJ3) in hepatocellular carcinoma (HCC). METHODS: FoxJ3 expression in HCC was analyzed using next-generation sequencing, and its association with overall survival and other Fox family proteins was evaluated. The biological roles of FoxJ3 and its relationship with Fox family members were investigated in vitro through MTT, cell cycle, and apoptosis assays. A xenograft model was established to assess the effects of FoxJ3 knockdown on tumor growth. RESULTS: FoxJ3 expression was significantly upregulated in HCC tissues, which was associated with poor prognosis and survival. Among Fox proteins family, forkhead box O6 (FoxO6) showed the strongest correlation with FoxJ3 expression. Furthermore, FoxJ3 knockdown suppressed the HCC cell proliferation in vitro and inhibited tumor growth in vivo. Mechanistically, FoxJ3 knockdown induced cell-cycle arrest and apoptosis, as demonstrated by decreased expression of PCNA, Ki67, Bcl-2, CDK4, and cyclin D1, alongside increased Bax and the activation of key apoptotic executers, cleaved caspase-3 and cleaved PARP. Moreover, FoxJ3 knockdown reduced the expression of FoxO6. CONCLUSIONS: FoxJ3 may act as an oncogene in HCC via regulating FoxO6. Its knockdown inhibits HCC cell proliferation mainly via cell-cycle arrest and apoptosis induction. FoxJ3/FoxO6 axis may represent a novel therapeutic target for HCC.