TXNDC5在前列腺癌中的功能及关键机制的研究

In general, primary PCa is an androgen-dependent disease and is highly responsive to androgen ablation therapy. However, PCa eventually will recur and progress to castration-resistant prostate cancer (CRPC) after hormone therapy. CRPC is the lethal form of PCa. Our previous results showed that TXNDC5 expression, which was up-regulated by hypoxia and androgen, overexpressed in Pca tissues. In order to study the function of TXNDC5 in tumorigenesis and whether or not, it was accounted for castration-resistant Pca progression, the following studies are needed. Firstly,we would clarify the characters and clinical significance of TXNDC5 expression in different kinds of Pca. Secondly,under the androgen-deprivation and/or hypoxia conditions,the functions of TXNDC5 on PCa cells would be studied after up/down-regulation of its expression in vitro and vivo. Furhermore, the relationship between TXNDC5 and androgen receptor would be studied as well. Proteomics would also be applied to screen proteins interacting with TXNDC5. All together, we would study the effects of TXNDC5 on cell biological functions from different aspects as well as the molecular mechanism of the progression from androgen-dependence to castration-resistant to make diagnosis and targeting treatment feasible and applicable.

前列腺癌一旦由雄激素依赖性向非依赖性生长转变，临床预后极差。研究表明，雄激素剥夺治疗过程中肿瘤局部出现的缺氧环境会导致该转变的发生。本项目组前期发现，TXNDC5在前列腺癌中过表达，并可受缺氧和雄激素的双重调控表达上调。为了进一步明确TXNDC5的功能以及在雄激素非依赖性生长转变过程中发挥的作用，我们拟通过检测TXNDC5在不同类型前列腺癌中的表达特点和临床意义；在雄激素剥夺和/或缺氧诱导条件下，采用强制性高表达/沉默TXNDC5的方法，体内外实验证明它对细胞功能的影响，并检测雄激素受体和TXNDC5是否存在相互作用和调控关系；蛋白质组学法寻找与TXNDC5相互作用蛋白等方面，多角度验证TXNDC5在前列腺癌中高表达的意义，进一步揭示癌细胞发生雄激素非依赖性生长转变的分子机制，为临床诊断以及靶向性治疗提供实验线索和理论依据。

去势抵抗性前列腺癌(Castration-resistant prostate cancer, CRPC)仍然是困扰当前临床治疗的问题，其机制尚不十分明确。硫氧还原蛋白5（Thioredoxin domain containing protein 5，TXNDC5)属于分子伴侣，参与二硫键形成和蛋白折叠，在分子在多种恶性肿瘤中都有过表达。本课题探讨了TXNDC5在前列腺癌（Prostate cancer, PCa）进展和CRPC发生中的作用和机制。首次发现：（1）TXNDC5在CRPC组织中的表达明显高于局限性前列腺癌；长期雄激素剥夺会上调TXNDC5表达；（2）体内外实验证实，TXNDC5在前列腺癌病变中发挥癌基因的作用，并可促进PCa细胞在激素剥夺或去势条件下的增殖和成瘤；（3）TXNDC5可与AR相互结合，并通过调控AR的蛋白稳定性和入核，促进肿瘤进展；阻断AR信号通路会抑制TXNDC5的促癌作用；（4）TXNDC5可调控AR对雄激素抑制剂和雌激素的敏感性，提示与肿瘤耐药相关；（5）TXNDC5还可与HSP70相互结合，而后者可调控TXNDC5的蛋白稳定性；（6）长期雄激素剥夺条件下引起的乏氧环境会通过miR-200b依赖性途径调控TXNDC5的表达，而且该乏氧状态也会加强TNXDC5和AR的相互作用。本研究发现TXNDC5在促进CRPC发生和进展过程中发挥重要作用，有必要研发针对它的抑制剂，作为治疗手段用于前列腺癌，特别是CRPC患者的治疗。