IF studies indeed showed redistribution of β-catenin from the nucleus to the cytoplasm after CCRK knockdown compared with control in two different cell lines. The authors further

demonstrated decreased protein levels of active but not of total β-catenin in this situation. Mechanistically, they determined that CCRK knockdown decreased phosphorylation of GSK3β and the ensuing decrease in β-catenin activity. Conversely, ectopic expression of CCRK led to increased phosphorylation of GSK3β culminating in enhanced β-catenin signaling. Phosphorylation of GSK3β has been shown to mediate β-catenin activation through inhibition of β-catenin degradation complex. 9 In addition, the authors see more demonstrated that knockdown of CCRK abrogated

some known β-catenin downstream targets such as epidermal growth factor receptor (EGFR) and cyclin-D1, which was reversed by ectopic CCRK expression. These targets have independently been shown to regulate proliferation in HCC. 10, 11 Knockdown of β-catenin despite Selleck EGFR inhibitor ectopic expression of CCRK led to decreased tumor cell proliferation, and additional functional studies such as soft agar assays and tumor xenograft studies further validated these observations. The authors then asked whether the modulation of β-catenin activity by CCRK had any impact on AR expression and function because β-catenin–AR crosstalk has been previously reported. 12 Indeed, the authors determined that ectopic CCRK expression 上海皓元医药股份有限公司 led

to increased total and Ser81-phosphorylated AR, which has independently been shown to induce AR promoter activity and in turn tumor cell growth. 13 This effect was abrogated upon β-catenin silencing, suggesting that CCRK-induced β-catenin activation indeed regulates AR expression and its biological effects. Lastly, knockdown of AR affected β-catenin activity, which could be rescued by CCRK overexpression, and ectopic AR expression could increase active-β-catenin levels, which could be blocked by inhibition of CCRK. Thus, the authors established a unique AR/CCRK/β-catenin feed-forward circuitry (Fig. 1), which was also evident in a significant subset of HCC patients as concomitant up-regulation of AR/CCRK/β-catenin using both western blot analysis and immunohistochemistry. Further examination also revealed a significant correlation between overexpression of CCRK and advanced tumor stage reflected by shorter overall survival. The current study has identified a novel circuitry that consists of an AR/CCRK/β-catenin axis that may provide at least one major mechanism of hepatocarcinogenesis in this male-predominant tumor type, thus presenting unique molecular interactions that may be exploited for therapeutic intervention. This study also suggests at least one additional mechanism by which Wnt/β-catenin signaling may in fact cause tumor progression in males.