PSGL-1缺失促进前列腺癌神经内分泌分化及机制研究

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.

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。

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。本项目主要研究内容包括：1.证实PSGL-1缺失与前列腺癌发展相关性；2.确定PSGL-1缺失促进前列腺癌神经内分泌分化；3.揭示PSGL-1缺失促进前列腺癌神经内分泌分化的分子机制。通过研究发现，与临床前列腺腺癌相比，前列腺神经内分泌癌肿瘤微环境中浸润的PSGL-1阳性白细胞显著减少，并且前列腺神经内分泌癌中PSGL-1表达降低，PSGL-1表达与神经内分泌标志物CgA表达呈负相关。PSGL-1缺失可以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。主要是通过减少肿瘤微环境中T细胞浸润，抑制其分泌TNF-α，进而抑制肿瘤细胞miR-200c，促进其靶基因CXCL-1表达，影响AR/RMPRSS2。与临床前列腺腺癌相比，前列腺神经内分泌癌中CXCL-1表达显著升高，且其表达与神经内分泌标志物CgA表达呈正相关。另外，通过CXCL-1抗体治疗PSGL-1缺失的TRAMP小鼠，小鼠不发生神经内分泌分化。通过以上研究，我们证明了PSGL-1缺失调控前列腺癌发生神经内分泌分化机制，并且CXCL-1有望作为前列腺神经内分泌癌治疗靶点。