PSGL-1缺失促进前列腺癌神经内分泌分化及机制研究

项目名称： PSGL-1缺失促进前列腺癌神经内分泌分化及机制研究

项目编号： No.31471290

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 生物科学

项目作者： 王丽京

作者单位： 广东药科大学

项目金额： 80万元

中文摘要： 前列腺癌神经内分泌分化可导致患者雄激素阻断治疗无效而死亡。炎症因子PSGL-1特异性表达于白细胞膜上，其对前列腺癌神经内分泌分化的影响尚无报道。我们发现，在人临床前列腺癌肿瘤标本中白细胞表达的PSGL-1显著下降。PSGL-1缺失可促进自发前列腺癌基因工程小鼠(TRAMP)肿瘤出现明显的神经内分泌癌组织学特性。并且PSGL-1缺失可以减少免疫器官及肿瘤微环境中T细胞浸润及其IL-2和TNF-α分泌；促进肿瘤细胞分泌CXCL-1及抑制AR及TMPRSS2表达。那么，PSGL-1缺失是否通过抑制T细胞分泌IL-2、TNF-α，进而促进肿瘤细胞分泌CXCL-1并调节AR/TMPRSS2表达，促前列腺癌神经内分泌分化？我们将在前列腺癌临床样本、细胞及转基因动物模型中明确PSGL-1缺失促进前列腺癌神经内分泌分化的作用机制。本研究将为临床靶向治疗前列腺神经内分泌癌提供理论基础。

中文关键词： PSGL-1；前列腺癌；神经内分泌分化

英文摘要： Neuroendocrine diiferentiation (NED) in prostate cancer is not responding to androgen deprivation therapy. PSGL-1 is an inflammatory cytokine and expressed on the surface membranes of all leukocytes. However, the effect of PSGL-1 on NED in prostate cancer is still unknown. Our results showed that the expression of PSGL-1 on tumor infiltrating T cells was decreased in cancer tissues compared with paracancerous tissues. Meanwhile, we also found that PSGL-1 deficency can promote NED in prostate cancer and decreased the number of tumor infiltrating T cells in TRAMP mice. Moreover, PSGL-1 deficency can decreased the expression of IL-2, TNF-α, AR and TMPRSS2 and up-regulated the expression of CXCL-1 in tumor tissues of TRAMP mice. However, PSGL-1 deficency whether promote NED in prostate cancer through regulated the secretion of IL-2 and TNF-α in tumor infiltrating T cells to affect CXCL-1/AR/TMPRSS2 signaling？We will clarify the molecular mechanism of PSGL-1 deficency in the promotion of NED in prostate cancer through clinical specimen of prostate cancer, tumor cells and transgenic mice. This study will provide the basis for investigate the new target for the treatment of prostate cancer.

英文关键词： PSGL-1;prostate cancer;neuroendocrine differentiation