Expression of netrin-1 by hypoxia contributes to the invasion and migration of prostate carcinoma cells by regulating YAP activity.

Hypoxia is a hallmark of solid tumor growth microenvironment and appropriates the major contributor for the failure and poor prognosis of clinical tumor treatment, including prostate cancer (PCa). Ectopic expression of netrin-1 is reportedly associated with the progression of several carcinomas. Here, we aimed to investigate the role of netrin-1 in hypoxic metastasis potential of prostate carcinoma. Here, hypoxia induced the up-regulation of netrin-1 mRNA and protein expression in prostate cancer cell lines PC3 and DU145. Importantly, knockdown of netrin-1 dramatically suppressed cell invasion, migration and epithelial-to-mesenchymal transition (EMT) of PC3 and DU145 cells under hypoxia. Furthermore, hypoxia treatment increased the activity of Yes-associated protein (YAP) by increasing YAP expression in the nucleus and inhibiting p-YAP levels. However, YAP activation was notably restrained following netrin-1 down-regulation. Interestingly, interrupting YAP expression attenuated hypoxia-triggered cell invasion, migration and EMT of DU145 cells. More importantly, restoring YAP expression strikingly antagonized the inhibitory effects of netrin-1 decrease on the metastatic potential of prostate cancer cells. Together, these results indicate that netrin-1 may function as a positive regulator of hypoxia-triggered malignant behavior in PCa by activating the YAP signaling. Accordingly, netrin-1 could be a promising therapeutic agent against prostate carcinoma.