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1、2008 Landes Bioscience. Do not distribute.Cancer Biology November 2008; 2008 Landes BioscienceStromal 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 b
2、e 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 retro- virus system t
3、hat 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 posi- tive
4、 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 C
5、XCR4- 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
6、vivo bone metastasis of PCa. These findings may enable new avenues of prevention and treatment for PCa metastasis.IntroductionProstate cancer (PCa) is the most common cancer of men in the Western world and follows lung cancer and intestinal cancer as the third most frequent cause of cancer-related d
7、eath in men.1 Most of these deaths are not the result of the primary tumor growth, but rather the result of the spread of cancer to distant organs, predomi- nately bone.2 This leads to a growing interest in elucidating the molecular mechanisms underlying PCa metastasis to the bone and in developing
8、the therapeutic targets to prevent PCa metastasis. A number of hypotheses have been developed to explain the predilection of PCa for bone. These include the anatomic configura- tion of the venous drainage system from the prostate to the spine, the presence of “leaky” sinusoids in the bone marrow, th
9、e elaboration of “tumor attracting” chemotactic factors by bone and/or other marrow cells and the production of growth factors in the marrow that stimu- late proliferation and survival of seeded cells.3 However, the precise mechanism of PCa bone metastasis remains to be elucidated. In recent studies
10、, many chemoattractant cytokines have been reported to mediate the events of tumor cell adhesion, migration and invasion during metastasis to specific organs.4 Among them, the chemokine stromal cell-derived factor-1 (SDF-1) and its receptor, CXCR4, were found to induce transendothelial migration by
11、acute myeloblastic leukemia and B-lymphoma cells.5 More recently, serial studies on other cancers, including non-small cell lung cancer,6 breast cancer7 and neuroblastoma8 demonstrated that CXCR4 may be critical on orchestrating tumor cell metastasis to specific organs enriched in SDF-1. It was also
12、 revealed that CXCR4 were increasingly expressed in human malignant prostate tissues rather than in normal prostate tissues and that SDF-1 enhanced PCa cells adhesion to bone endothelial cells and their transendothelial migra- tion and invasion.9,10 These results have indicated that CXCR4/ SDF-1 pat
13、hway may be of vital importance in PCa bone metastasis. Hence, it is evident that CXCR4/SDF-1 pathway could become a Research Paper Tumor cell-specific blockade of CXCR4/SDF-1 interactions in prostate cancer cells by hTERT promoter induced CXCR4 knockdownA possible metastasis preventing and minimizi
14、ng approachYifei Xing,1,* Mei Liu,2, Yuefeng Du,1, Feng Qu,1, Yangsheng Li,1 Qingwei Zhang,1 Yajun Xiao,1 Jun Zhao,1 Fuqing Zeng1 and Chuanguo Xiao11Department of Urology; Union Hospital; Tongji Medical College; Huazhong University of Science and Technology; Wuhan China; 2Department of Gastroenterol
15、ogy; Tongji Hospital; Tongji Medical College; Huazhong University of Science and Technology; Wuhan ChinaCurrent address: Department of Urology; 1st Affiliated Hospital; Medical College; XiAn Jiaotong University; XiAn ChinaCurrent address: Department of Urology; Gulou Hospital; Nanjing Medical Univer
16、sity; Nanjing ChinaThese authors contributed equally to this work.Key words: CXCR4/SDF-1, prostate cancer; metastasis, telomerase reverse transcriptase promoter*Correspondence to: Yifei Xing; Department of Urology; Union Hospital; Tongji Medical College; Huazhong University of Science and Technology; Wuhan 430022 China; Email:Submitted: 06/22/08; Revised: 08/12/08; Accepted: 08/26/08Previously published online as a
