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

Abstract

Abstract. 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.

Involvement of Activated Cdc42 Kinase1 in Colitis and Colorectal Neoplasms

“…We also found associations between ACK1 expression and dysplasia grade in both types of precursor lesions for CRC. This is in accordance with studies of several other tissues which showed ACK1 expression correlated with malignant progression [2–6]. By contrast, we found both UC-related CRC and sporadic CRC were negative for ACK1 protein expression.…”

“…Although Ack1 overexpression has been observed in multiple cancers, including digestive system tumors, most functional studies of ACK1 signaling pathways are focused on the respiratory and reproductive system [2–5]. Our study revealed extensively increased expression of ACK1 protein in colorectal inflammation and dysplasia, but the potentially functional role and molecular mechanism for ACK1 overexpression in these colorectal diseases are currently completely unknown.…”

“…Genomic amplification and overexpression of ACK1 have been shown in a variety of human tumors. In cell lines of epithelial origin, ACK1 integrates extracellular growth factor stimuli from multiple ligand-activated activated receptor tyrosine kinases, to initiate intracellular signaling cascades that are critical for cell survival, cell proliferation, cell differentiation, and cell migration [2–10]. …”

A new tumor suppressor lncRNA RP11-190D6.2 inhibits the proliferation, migration, and invasion of epithelial ovarian cancer cells

“…WWOX is a type of tumor suppressor gene and is linked with the FRA16D common chromosomal fragile site 15. Furthermore, researchers found that it was associated with many cancers, including EOC,16 hepatocellular carcinoma,17 and colon cancer,18 bladder cancer,19 osteosarcoma,20 and other cancers. In EOC, WWOX plays significant roles in the regulation of the cell cycle and apoptosis 16.…”

Activated Cdc42-associated kinase 1 (ACK1) binds the sterile α motif (SAM) domain of the adaptor SLP-76 and phosphorylates proximal tyrosines

“…6). ACK1 has been implicated previously in hepatocellular carcinoma metastasis (38). We observed a decrease in the random motility of T cells upon exogenous ACK1 expression compared with wild-type cells on ICAM-1-coated plates (Fig.…”