Tumor cell-specific blockade of CXCR4/SDF-1 interactions in prostate cancer cells by hTERT promoter induced CXCR4 knockdown: A possible metastasis preventing and minimizing approach.
Stromal cell-derived factor-1 (SDF-1)/CXCR4 pathway has been shown to play an important role in prostate cancer (PCa) metastasis and siRNA expression using cell-specific promoters has been demonstrated to be a potential tool for targeted gene therapy. Here, we illustrate that human telomerase reverse transcriptase (hTERT) promoter-induced CXCR4 knockdown inhibits PCa bone metastasis. We first investigated CXCR4 expressions and interactions of CXCR4/SDF-1 in PCa cells, developed a retrovirus system that could stably express CXCR4 small hairpin RNA driven by hTERT promoter and then determined the inhibitory effects of cell-specific blockade of CXCR4/SDF-1 pathway on PCa metastasis. It was shown that both PCa tissues and cell lines expressed CXCR4 and the expression in PCa tissue had a positive correlation to clinical stages while not to Gleason scores or serum PSA level. PCa metastases most presenting human tissues expressed high levels of SDF-1. Exogenous SDF-1 enhanced in vitro adhesion, migration and invasion of PCa cells and these bioeffects were repressed by hTERT promoter-induced CXCR4-shRNA expression. This CXCR4 knockdown was also found to significantly inhibit bone metastasis in vivo. We conclude that CXCR4/SDF-1 pathway plays an important role in PCa bone metastasis. hTERT promoter-induced tumor cell-specific CXCR4 gene silencing may prevent in vitro invasiveness and in vivo bone metastasis of PCa. These findings may enable new avenues of prevention and treatment for PCa metastasis.
Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. yfxing@yahoo.com
Yifei
Y
Xing
Mei
M
Liu
Yuefeng
Y
Du
Feng
F
Qu
Yangsheng
Y
Li
Qingwei
Q
Zhang
Yajun
Y
Xiao
Jun
J
Zhao
Fuqing
F
Zeng
Chuanguo
C
Xiao
D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D054377:Chemokine CXCL12 / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008957:Models, Genetic; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000628:therapy; D019718:Receptors, CXCR4 / Q000378:metabolism*; D019098:Telomerase / Q000235:genetics
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019718:Receptors, CXCR4; D019098:Telomerase