ACK1 promotes hepatocellular carcinoma progression via downregulating WWOX and activating AKT signaling.

Several studies have revealed that ACK1 is upregulated in various cancers and promotes tumor progression. However, the role and mechanism of ACK1 in hepatocellular carcinoma (HCC) remains unknown. In this study, the expression of ACK1 was assessed in several cell lines and 150 pairs of HCC and adjacent noncancerous liver tissues. The protein expression of p-ACK1 and WWOX were detected by immunohistochemistry to evaluate their correlation with ACK1. Flow cytometry, caspase 3/7 activity assay, BrdU cell proliferation assay, MTT assay and Transwell assay were used to detect apoptosis, proliferation, invasion and migration of HCC cells. The regulatory effect of ACK1 on WWOX, AKT, p-AKT, MMP2 and MMP9 in HCC cells was confirmed by immuno-blotting. We found that ACK1 was more highly expressed in HCC tissues than in non-HCC tissues, and over-expression of ACK1 was correlated with clinicopathological features of poor prognosis. Clinical analysis demonstrated that ACK1 is an independent prognostic marker for predicting overall survival and disease-free survival of HCC patients. Pearson's correlation coefficient analysis indicated that ACK1 was positively associated with p-ACK1 and was negatively associated with WWOX expression. In vitro studies showed that knockdown of ACK1 promoted HCC cell apoptosis and repressed HCC cells invasion, migration and proliferation. Furthermore, knockdown of ACK1 resulted in upregulation of WWOX and inactivation of AKT signaling. In this study, we also found that knockdown of ACK1 resulted in the downregulation of MMP2 and MMP9 in HCC. Our results indicate that ACK1 is an independent prognostic marker and promotes HCC progression via downregulating WWOX and activating AKT signaling.