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.
Department of Urology, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, PR China.
Haiwen
H
Chen
Department of Urology, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, PR China. Electronic address: qichenqcf@sina.com.
Qi
Q
Chen
Department of Urology, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, PR China.
Qidong
Q
Luo
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D009361:Neoplasm Invasiveness / Q000235:genetics; D009414:Nerve Growth Factors / Q000378:metabolism*; D000075388:Netrin-1; D010750:Phosphoproteins / Q000378:metabolism*; D011467:Prostate / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D000091102:YAP-Signaling Proteins
D048868:Adaptor Proteins, Signal Transducing; C000617351:NTN1 protein, human; D009414:Nerve Growth Factors; D010750:Phosphoproteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D000075388:Netrin-1
Cell invasion; Cell migration; Hypoxia; Netrin-1; Prostate cancer; YAP