Increased expression of α-actinin-4 is associated with unfavorable pathological features and invasiveness of bladder cancer

In the present study, the association between clinicopathological parameters and alpha-actinin-4 (ACTN4) expression in bladder cancer specimens was evaluated, and the functional role of ACTN4 in bladder cancer cells was investigated. Immunohistochemistry using anti-ACTN4 antibody was performed in bladder cancer specimens (53 superficial and 42 muscle-invasive cases) from 95 patients who underwent radical cystectomy (n=46) or transurethral resection (TUR) only (n=49). We divided the levels of ACTN4 expression into 2 groups (low or high) by comparing the staining intensity in each specimen with that of the vascular endothelial cells in the same specimen, and we evaluated the correlations between these levels and pathological parameters, recurrence and prognosis. We also investigated the effects of ACTN4 suppression by siRNA on the invasive ability and proliferation of T24 and KU19-19 cells. High ACTN4 expression was significantly associated with higher tumor grade and higher pT stage. In patients with superficial bladder cancer treated only by TUR, the rate of intravesical recurrence did not differ significantly between patients with high ACTN4 expression and patients with low ACTN4 expression. In patients who had muscle-invasive tumors and underwent radical cystectomy, high ACTN4 expression was associated with neither recurrence nor poor prognosis. Nonetheless, high ACTN4 expression was shown by a large percentage (81%) of patients with muscle-invasive bladder cancer and by a small percentage (17%) of patients with superficial bladder cancer. Furthermore, the leading edges of the invasive bladder cancer showed increased ACTN4 expression. ACTN4 suppression significantly reduced the number of invading bladder cancer cells but unexpectedly increased the proliferation of bladder cancer cells. ACTN4 suppression increased the phosphorylation of ERKs but not AKT or STAT3, suggesting that the increased proliferation due to ACTN4 suppression was mediated in part by the ERK pathway. ACTN4 expression may suppress the proliferation of bladder cancer cells and may produce conditions which facilitate cancer cell invasion.