Expression of RhoC correlates with metastatic disease and survival of prostate cancer patients

Proc Amer Assoc Cancer Res, Volume 47, 2006 3526 RhoC is a member of the RAS superfamily of small GTP-binding proteins. Rho GTPases have previously been shown to be involved in controlling cytoskeletal reorganization through MAP kinase pathway during cell migration and invasion, and they are considered to play key roles in tumor progression. The expression of RhoC appears to be highly up-regulated in various types of cancers including, breast, melanoma, pancreatic and lung. Moreover, inhibition of the expression of this gene was shown to significantly reduce the invasiveness of tumor cells in vitro, suggesting the role of RhoC in tumor metastases, although the molecular mechanism of RhoC action is yet to be examined. In order to understand the functional roles of RhoC in tumor metastases in prostate cancer, we performed immunohistochemical analysis on tumor specimens from 63 prostate cancer patients. RhoC was generally undetectable or only weakly expressed in normal epithelia and stroma cells, however, it was found to be significantly over-expressed in the cytoplasm of high grade tumors. The patients with high Gleason score (>7) had a tendency of higher expression of RhoC, although it was statistically not significant. However, the status of both lymphnode and distant metastatis have significant positive correlation with the RhoC expression (P<0.03). Interestingly, the RhoC expression also showed significant inverse correlation to that of Drg-1 which is a recently identified metastases suppressor gene. Further analysis of five year survival data revealed that the RhoC expression was significantly correlated to patient survival (P<0.02), and that Cox regression analysis indicated RhoC as an independent marker for the prediction of patient outcome. We also examined the effect of RhoC over-expression in prostate tumor cell lines and found that RhoC significantly enhanced both invasion and motility in vitro. Furthermore, results of western blot analysis of these RhoC over-expressed cells indicated that RhoC significantly altered the status of the phosphorylation of the Akt protein. Taken together, our results indicate that RhoC is involved in the process of tumor metastases in prostate cancer by augmenting cell invasiveness through a modulation of the Akt pathway, and that RhoC may serve as a useful prognostic marker.