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

• Published in: Experimental cell research 2016-12, Vol.349 (2), p.302-309
• Main Authors: Chen, Haiwen, Chen, Qi, Luo, Qidong
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Cell Hypoxia; Cell invasion; Cell Line, Tumor; Cell migration; Cell Movement - genetics; Cellular biology; Epithelial-Mesenchymal Transition - genetics; Gene Expression Regulation, Neoplastic; Humans; Hypoxia; Male; Medical prognosis; Neoplasm Invasiveness - genetics; Nerve Growth Factors - metabolism; Netrin-1; Phosphoproteins - metabolism; Prostate - metabolism; Prostate cancer; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Signal Transduction - genetics; Transcription Factors; Tumor Suppressor Proteins - metabolism; Tumors; YAP
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/j.yexcr.2016.10.023

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. •Hypoxia increases the expression of netrin-1 in prostate cancer cells.•Knockdown of netrin-1 inhibits hypoxia-induced invasion, migration and EMT.•Netrin-1 is involved in hypoxia-induced activation of YAP.•Hypoxia-induced YAP activation accounts for DC145 cell invasion and migration.•YAP elevation abates the inhibition of netrin-1 silence on cell metasis upon hypoxia.