肿瘤微环境中IL-6导致前列腺癌神经内分泌分化的机制研究

前列腺癌神经内分泌分化，是导致晚期前列腺癌耐药的重要机制，目前尚无有效治疗方法。在前期研究中我们发现，肿瘤微环境中IL-6与前列腺癌神经内分泌分化及其恶性程度密切相关，机制与下游重要通路受到抑制相关，与本项目将深入探讨其生物学机制：（1）构建前列腺癌神经内分泌分化细胞系的3D培养体系，模拟肿瘤微环境情况；（2）通过分子生物学研究方法，研究IL-6通过STAT3-FOXO通路影响DNA同源重组修复基因与细胞周期（检查点）蛋白相关基因表达及蛋白活性的生物学机制；（3）通过细胞学及动物学研究手段，研究上述机制所导致的CRPC细胞表型及动物体内的改变，并研究DNA同源重组修复基因通路受到抑制（表达及蛋白活性的抑制）后，对PARP抑制剂的治疗反应，为神经内分泌分化CRPC的治疗提供理论依据；（4）在人群样本中进行初步探索，利用组织库中的样本，验证上述机制的存在，为进一步临床转化研究提供理论基础。

Prostate cancer (PCa) neuroendocrine differentiation (NED-PCa) is one of the most important mechanisms of drug resistance in late-stage PCa. Currently, there is no effective therapeutic method against NED-PCa. In the previous study, we found that tumor microenvironment interleukin-6 (IL-6) is associated with PCa neuroendocrine differentiation and its progression via regulating the downstream pathways. In this study, we propose to investigate this regulation mechanism: (a) To improve the current method of inducing NED, to establish 3D culture system for NED-PCa; (b) To investigate the mechanism of DNA homology recombination/cell cycle (check point) regulation by IL-6 via STAT3-FOXO pathway; (c) To study this mechanism in vivo and in vito, and to evaluate the efficacy of PARP inhibitor for treating NED-PCa; (d) To further evaluate the up-/down-regulation of the genes in the pathway in a population level.