PC-1通过协调FLNa和Talin1功能促进整合素β1激活：一种促进前列腺癌转移的新机制

PC-1 a TPD52 protein family member is frequently upregulated in advanced prostate cancer cells and may be a potential therapeutic target of aggressive prostate cancer (PCa). Here, our data showed that PC-1 enhances the mobility and metastasis of prostate cancer cells. We further identified that PC-1 interacts with cytoskeleton protein FLNa. The increased expression of PC-1 significantly promotes integrin β1 activation and phosphorylation of Talin1 suggesting that PC-1 overexpression in prostate cancer may play an important role. Based upon the preliminary data, We will further determine how PC-1 activates integrinβ1 through regulating interaction of FLNa/Talin1/integrinβ1 complex; We will examine the effect of PC-1 on promoting prostate cancer cell metastasis in vitro and in vivo; Using prostate cancer specimens, we will define the correlation between PC-1 expression and metastasis as well as its clinical significance; We will investigate therapeutic strategies against PC-1 highly expressed aggressive PCa; This study will lay a solid foundation for elucidation of molecular mechanisms of prostate cancer cell metastasis and identification of novel targets of breast cancer therapy.

PC-1属于TPD52家族成员，在恶性前列腺癌中特异性高表达，可能作为前列腺癌治疗的潜在靶标。我们前期研究发现PC-1与细胞骨架蛋白FLNa相互作用并共定位于细胞突触，能够激活Talin1和整合素β1，促进前列腺癌细胞的运动、迁移，提示PC-1可能在前列腺癌转移中发挥重要作用。本申请拟在此基础上，进一步确定PC-1如何通过与FLNa/整合素β1/Talin1复合物相互作用激活整合素β1；体内外检测PC-1对前列腺癌细胞运动、迁移的影响；利用前列腺癌标本，确定PC-1和肿瘤转移的相关性及临床意义；探索针对PC-1高表达恶性前列腺癌的治疗策略，为阐明前列腺癌转移的分子机制及发现新的治疗靶标打下坚实基础。

随着我国步入老龄化大国和生活水平的改善，目前前列腺癌已成为男性生殖系统第一位的恶性肿瘤，一旦出现转移，患者5年存活率仅为28% 。我们研究发现PC-1参与调控前列腺癌细胞运动，与前列腺癌的转移密切相关，是前列腺癌侵袭、转移的重要促进因子。研究证明PC-1能控制FLNa、Talin1和整合素β1相互作用，通过相互作用辅助FLNa募集至黏着斑，由此调节整合素在黏着斑定位和激活，通过激活Cdk5/p35/Talin1信号通路促进整合素β1激活，激活整合素β1诱发微丝重新装配、黏着斑的装配和解聚，由此调控前列腺癌细胞的运动和转移。小鼠体内实验证实PC-1高表达的前列腺癌细胞更容易形成骨转移。利用整合素β1抑制性抗体AIIB2和Cdk抑制剂，对PC-1高表达的肿瘤转移具有较好抑制效果。基于这些研究发现，PC-1通路可能成为转移前列腺癌治疗靶标，将为PC-1高表达的恶性前列腺癌患者提高治疗效果和改善预后提供新的思路，为制定有效的个体化的治疗方案提供理论依据。