PHF8增强β-catenin/BRN2信号在去势诱导前列腺癌神经内分泌分化中的作用及机制研究

Emerging evidences suggest that castration treatment-induced neuroendocrine differentiation of prostate cancer plays crucial roles in the pathogenesis of castration resistant prostate cancer (CPRC) and disease progression. Previous studies demonstrated that the activation of β-catenin/BRN2 signaling is the main event during trans-differentiation from the adenocarcinoma to neuroendocrine carcinoma after long time of androgen deprivation therapy. However, the underlying molecular mechanism by which castration treatment activates β-catenin/BRN2 signaling still remains unclear. Our previous findings showed that PHF8 is upregulated by HIFs （hypoxia inducible factors）in the condition of hypoxia induced by castration treatment. PHF8 knockdown could repress castration-induced upregulation of β-catenin, BRN2 and neuroendocrine phenotype biomarkers such as CgA, Syn and CD56. Taken all together, we hypothesized that PHF8, as a ‘switch molecule’, might play an important regulatory role in the pathogenesis of neuroendocrine differentiation induced by castration treatment via activating β-catenin/BRN2 signaling. In this study, by using prostate cancer cell lines, xenografts and a new mice model of prostatic carcinoma with PHF8 knockout background (TRAMP/PHF8-/Y) by crossing TRAMP (Transgenic Adenocarcinoma of the Mouse Prostate) with PHF8 knockout mice, we will investigate how PHF8 regulates the expressions of β-catenin and BRN2, as well as their effects on castration treatment-induced neuroendocrine differentiation. These studies will shed a new insight into understanding the molecular mechanisms underlying the development of neuroendocrine prostate cancer (NEPC) as well as looking for the potential molecular target for therapeutic intervention of NEPC, which is of very important scientific significance as well as clinical value.

去势治疗诱导的神经内分泌分化改变是前列腺癌CRPC发生及疾病进展重要原因。研究证实，β-catenin/BRN2信号激活在其中发挥关键调节作用。但去势治疗激活β-catenin/BRN2信号的具体机制尚不清楚。我们既往研究发现，PHF8受去势诱导的缺氧调控，敲低PHF8显著抑制去势对β-catenin，BRN2及神经内分泌表型相关分子的上调作用。结合以往及我们的前期研究，我们推测：PHF8作为去势诱导的β-catenin/BRN2信号激活的“开关”调节分子，在前列腺癌神经内分泌分化中发挥重要作用。本项目拟以前列腺癌细胞、裸鼠移植瘤及PHF8基因敲除前列腺癌小鼠模型为研究对象，研究PHF8对β-catenin/BRN2信号通路的调节机制及其在去势诱导的前列腺癌神经内分泌分化中的作用。研究结果将揭示前列腺癌神经内分泌分化新的调控机制，提高前列腺癌治疗效果，具有重要科学意义及潜在的临床应用价值。

神经内分泌前列腺癌是去势抵抗性前列腺癌中恶性程度最高的一类亚型，有更强的侵袭性和高度致死性。伴有神经内分泌前列腺癌或存在神经内分泌分化患者预后更差，可能原因是对于驱动神经内分泌进展的机制目前仍不十分清楚，因而缺乏有效的治疗。在本研究中，我们采用TRAMP小鼠和PHF8敲除小鼠，不同前列腺癌细胞系，病人源移植瘤组织系，病人样本等，系统性地探讨了PHF8在神经内分泌前列腺癌和神经内分泌分化中作用及机制。我们研究发现PHF8在神经内分泌前列腺癌中及神经内分泌区域中明显高表达；PHF8敲除后不仅抑制NEPC的发生，同时也抑制前列腺癌细胞生长增殖、侵袭和迁移。机制上，PHF8与β-catenin形成复合体，转录调控神经内分泌特异性转录因子FOXA2。我们的研究结果揭示了前列腺癌神经内分泌分化的重要调控因子PHF8，为神经内分泌前列腺癌诊断提供了可能标志物，同时也为神经内分泌前列腺癌治疗提供了重要靶点。