BCOX1调控STAT3信号通路在内分泌治疗诱发的前列腺癌神经内分泌转化中的作用机制研究

At present, patients with metastatic prostate cancer initially respond to hormonal therapy, but most eventually develop castration-resistant prostate cancer. At least 30% of patients with lethal castration-resistant prostate cancer are neuroendocrine prostate cancer (NEPC). However, the mechanism by which NED is induced after hormonal therapy still remains largely unclear. Our previous studies showed BCOX1 was a potential metastasis-associated gene and was associated with PCa progression. The increased BCOX1 can drive PCa progression by promoting PCa proliferation, migration and invasion. Our further observations showed that BCOX1 was significantly increased in neuroendocrine-like prostate cancer (NEPC) cell. It is well known that STAT3 signaling plays an important role in neuroendocrine differentiation. The BCOX1 expression levels were additionally found to be correlated with STAT3 and pSTAT3 levels in NEPC cell. We subsequently suppose BCOX1 can regulate STAT3 signaling in NEPC cell and affect the cell biological behavior. In preliminary study, we constructed the model of NEPC cell by inducing the LNCaP cell in medium with deprivation of hormone in vitro. We will establish a human prostate carcinoma xenograft model by orthotopicly injecting NEPC cells into SCID mice. Collectively, We will investigate possible molecular mechanisms and biological functions of the interaction between BCOX1 and STAT3 signaling at cell and animal model levels respectively. In addition, we examine expression and correlation of BCOX1 and STAT3 in clinical PCa tissues. Our study will advance our knowledge of the molecular mechanisms of NED, provide potential effective molecular and developed effective potential therapeutic targets for the treatment of PCa.

大多数转移性前列腺癌经内分泌治疗后进展为去势抵抗型。研究表明致死性去势抵抗前列腺癌中，神经内分泌表型的发生率为30%甚至更高。然而内分泌治疗诱发前列腺癌神经内分泌转化的机制尚不明确。我们前期研究证实BCOX1与前列腺癌的发生发展密切相关，对其增殖、侵袭和转移具有调控作用。预实验结果提示BCOX1在神经内分泌样前列腺癌细胞中高表达，且与在调节神经内分泌分化中具有重要作用的STAT3信号通路相关。本课题组设想，BCOX1可能参与激活STAT3信号通路，调控内分泌治疗中前列腺癌神经内分泌转化。我们拟采用体外去雄激素诱导神经内分泌样前列腺癌细胞模型和裸鼠动物模型，在细胞、组织和整体水平明确BCOX1对STAT3信号通路的调控及其在前列腺癌神经内分泌分化中的作用，并在前列腺癌临床标本中对其进行验证。本项目的研究发现可能为预防和逆转前列腺癌神经内分泌转化、探索去势抵抗性前列腺癌的治疗靶点提供新的思路。

大多数转移性前列腺癌经内分泌治疗后进展为去势抵抗型。研究表明致死性去势抵抗前列腺癌中，神经内分泌表型的发生率为30%甚至更高。神经内分泌前列腺癌（NEPC）预后极差，随着新一代内分泌治疗药物的使用，其实际发生率将进一步升高。阐明去势治疗诱导的前列腺癌神经内分泌分化的分子机制对探索新的前列腺癌预防和治疗靶点有着非常重要的临床意义。本课题组研究发现在去势治疗中LncRNA-565686可能作为ceRNA竞争性抑制miR-195表达，进而激活BCOX1下游通路，影响前列腺癌细胞的生物学行为、促进前列腺癌神经内分泌分化的过程；同时研究发现前列腺癌中异常表达的LncRNA-565686 可特异性的结合 SOX2蛋白，促进前列腺癌神经内分泌分化的过程。SOX2作为干细胞功能基因的分子标志，在前期研究中已发现可调控肿瘤细胞表型及NED过程。本项目组进一步在人体前列腺组织水平明确LncRNA-565686对miR-195及其下游BCOX1通路表达的调控；明确LncRNA-565686与SOX2在前列腺癌组织中的正相关，在神经内分泌前列腺癌临床标本进行验证。在前列腺癌组织中高表达的BCOX1，其表达水平与前列腺癌术前PSA水平、术后Gleason评分有关，与前列腺癌患者预后密切相关，可为筛选高风险前列腺癌患者提供重要的信息，而这些具有潜在复发风险和不良预后的患者将受益于早期综合治疗。BCOX1可能成为监测前列腺癌患者预后的理想指标。本研究结论：前列腺癌中上调的LncRNA-565686可引起BCOX1通路抑制和促进SOX2表达，引起前列腺癌向神经内分泌转化。研究结果为晚期前列腺癌的发展机制提供重要的理论，也为去势抵抗性前列腺癌的治疗开辟新的途径。