Prio DLC Par

nloaded Rho GTPase-activating protein DLC1 is a tumor suppressor that is often deleted in liver cancer and egulated in other cancers. DLC1 regulates the actin cytoskeleton, cell shape, adhesion, migration, and ration through its Rho GTPase-activating protein activity and focal adhesion localization. In this study, nced DLC1 in nonmalignant prostate epithelial cells to explore its tumor suppression functions. Small n RNA-mediated silencing of DLC1 was insufficient to promote more aggressive phenotypes associated umor cell growth. In contrast, DLC1 silencing promoted pro-angiogenic responses through vascular enial growth factor (VEGF) upregulation, accompanied by the accumulation of hypoxia-inducible factor 1α s nuclear localization. Notably, modulation of VEGF expression by DLC1 was dependent on epidermal factor receptor–MAP/ERK kinase–hypoxia-inducible factor 1 signaling but on RhoA pathways. CliniVEGF upregulation is a highly significant event in prostate cancers in which DLC1 is downregulated. cally, Thus, our results strongly suggest that loss of DLC1 may serve as a “second hit” in promoting angiogenesis in a paracrine fashion during tumorigenesis. Cancer Res; 70(21); 8270–5. ©2010 AACR.