ARF6 promotes hepatocellular carcinoma proliferation through activating STAT3 signaling

Abstract

Purpose Hepatocellular Carcinoma (HCC) is one of the most common causes of cancer death worldwide. However, the molecular mechanism underlying HCC proliferation remains obscure. In this study, we show that high expression of ARF6 is related to a poor clinical prognosis, which could drive the proliferation of HCC. Methods The expression level of ARF6 in HCC tissues was detected by immunohistochemistry and western blotting. Clinical significance of ARF6 was estimated in primary HCC patients. The effect of ARF6 on tumor proliferation was investigated by in vitro CCK8 and colony formation assay, and in vivo nude mouse xenograft models. ARF6 localization was investigated by immunofluorescence. Cell cycle-related proteins were evaluated by western blotting. Moreover, the correlation between ARF6 and STAT3 signaling in HCC was detected by western blotting, immunohistochemistry and xenograft assay. Results ARF6 was overexpressed in HCC tissues compared to adjacent normal liver tissues and high expression of ARF6 was significantly correlated with poor tumor differentiation, incomplete tumor encapsulation, advanced tumor TNM stage and poor prognosis. ARF6 positively regulated the cell proliferation, colony formation, and cell cycle progression of HCC cells. In vivo nude mouse xenograft models proved the oncogenic role of ARF6 in tumor growth. In addition, ARF6 promoted the activation of STAT3 signaling and ARF6 expression was positively correlated with phosphorylated STAT3 in HCC tissues. Furthermore, interference of STAT3 demonstrated STAT3 as an important signaling pathway for the oncogenic role of ARF6 in HCC. Conclusions Our findings indicate that ARF6 promotes HCC proliferation through activating STAT3 signaling, suggesting that ARF6 may serve as a novel prognostic biomarker and a therapeutic target for HCC patients.