CD147参与AR调控雄激素非依赖性前列腺癌的作用及机制研究

Androgen-independent prostate cancer (AIPC) is the lethal stage of prostate cancer, for which there is no curative therapy. Androgen receptor (AR) plays a central role in the development of AIPC. We find out that CD147 is associated with the invasion and migration of AIPC. The nuclear fractions for up-expression CD147 cells also contained a increased level of the β-catenin that is a AR co-activator in process of AIPC. But the functions of CD147 are not clear. A recent study confirms that the CD147 in lung cancer cells can elevate the level of β-catenin in the nucleus and promote the proliferation and invasion of cells. Therefore, we, for the first time, propose the hypothesis: up-regulated expression of CD147 could increase the level of β-catenin in the nucleus and then promote the AR expression and activation, which results in AIPC occurence. In this study, we detect the interaction of CD147, β-catenin and AR in the cellular and molecular level and clarify the functions and mechanisms of CD147 which positively participate in the AR regulated AIPC by technology of molecular biology, cell biology and immunology methods. The tumor xenograft model mouse with castration is adopted to testify the role of CD147. The aim of our study is to explore the pathogenesis of AIPC and provide the new theoretical basis and drug targets for clinical treatment.

雄激素非依赖性前列腺癌(AIPC)是前列腺癌病程中的致死性阶段，目前无法治愈。AIPC发生与雄激素受体(AR)密切相关。我们研究发现，CD147与AIPC侵袭和转移相关；AIPC发生过程中CD147和细胞核内AR共激活因子β-catenin表达水平升高，但CD147的作用尚不清楚。新近研究证实，肺癌中CD147能促进β-catenin的细胞核内水平，导致癌细胞增殖和侵袭。因此，我们首次提出假说：CD147表达升高上调细胞核内β-catenin水平，继而促进AR表达和活化，导致AIPC发生。本研究拟采用分子生物学、细胞生物学和免疫学等技术，在细胞和分子水平上检测CD147、β-catenin和AR的相互作用，阐明CD147正向参与AR调控AIPC发生的作用和机制。采用公认的荷瘤裸鼠去势模型，在体内水平进一步验证。本项目旨在深入探讨AIPC的发病机制，为临床治疗提供新的理论依据和药物靶点。

雄激素非依赖性前列腺癌(androgen-independent prostate cancer, AIPC)是前列腺癌病程中的致死性阶段，目前无法治愈。近年来的研究表明，前列腺癌的发生和发展与雄激素受体（androgen receptor, AR）和自噬密切相关。本项目研究发现，RNAi沉默CD147表达能够抑制PI3K/Akt信号途径。因此，我们详细的研究了CD147通过PI3K/Akt信号途径调节前列腺癌细胞AR的功能及自噬的作用。研究表明，沉默CD147能够抑制PI3K/Akt信号途径导致p-GSK3-β表达下降，使β-catenin在胞浆中被降解，入核减少，降低β-catenin与AR相互作用，最终导致AR靶基因PSA表达下降，抑制前列腺癌的发展进程。此外，沉默CD147能够抑制PI3K/Akt信号途径降低Snail的表达，促进E-cadherin水平，逆转前列腺癌细胞上皮间质转化(epithelial-mesenchymal transition，EMT)的特征。沉默CD147通过抑制PI3K/Akt信号途径减少前列腺癌细胞基质金属蛋白酶2(Matrix metalloproteinase2，MMP-2)和MMP-9的分泌，抑制细胞侵袭。进一步研究表明，沉默CD147能够促进Beclin-1表达及抑制PI3K/Akt信号途径降低p-mTOR的水平，促进饥饿诱导的前列腺癌细胞自噬性死亡。. 胡桃醌是从核桃楸中提纯的一种天然成分，是胡桃揪中的主要的毒性物质。为了寻找理想的抗肿瘤药物，本研究探讨了胡桃醌对前列腺癌等细胞的作用及其机制。本课题研究发现，胡桃醌通过细胞周期阻滞和诱导细胞凋亡，抑制肿瘤细胞生长。此外，胡桃醌通过降低肿瘤细胞分泌MMP-2和MMP-9抑制肿瘤细胞侵袭。