核受体辅调节因子SRC-2在前列腺癌中的功能研究

Prostate cancer (PCa), the second most common cancer in man worldwide, has now become the most common malignant tumor of the urinary system in China. Despite recent progress, two important and largely unresolved clinical challenges are the major hurdles for managing advanced PCa patients. The first is what biomarker can be used for appropriate risk stratification of patients? The second is how does PCa progresses to an androgen refractory state subsequent to androgen deprivation therapy (ADT). Therefore, it is important to elucidate the underlying mechanism causing metastatic PCa and castration resistant prostate cancer (CRPC). Based on patient specimen analysis, our preliminary studies employed genetically engineered mouse models to show that Steroid Receptor Coactivator-2 (SRC-2, or NCoA2), which is frequently amplified or overexpressed in metastatic prostate cancer patients, might be critical for PCa metastasis and the development of CRPC. In this application, we propose to utilize the genetically engineered mouse models, a PTEN prostate cancer model and cell culture assay, together with patient sample analysis to define the pivotal role of SRC-2 in prostate cancer progression and metastasis. We will address whether SRC-2 serves as an important player to potentiate the indolent tumors to become more aggressive tumors, which will lead to future development of potential biomarkers for clinical diagnosis. In addition, we will define whether SRC-2 plays a causal role in castration resistance. Further mechanistic investigation will also uncover the pivotal regulators and signal circuits involved in these two processes. At the same time, comparative analysis of patient samples will strengthen the rational basis for translating our findings for clinical diagnosis and treatment. Together, our studies are innovative and highly significant. Success accomplishment of the proposed goals will provide new insights on the etiology of this disease and pave the way for the development of new therapeutic strategies for disease intervention.

前列腺癌已成为我国男性泌尿系统最常见的恶性肿瘤，并且其发病率正呈现快速增长的趋势。前列腺癌的高侵袭性转移和去势难治性是目前临床治疗所面临的两个难题也是基础研究重点关注的方面。本课题组前期工作通过对临床病人样品数据的分析以及运用遗传小鼠模型，发现P160类固醇受体辅助调节因子SRC-2可能在前列腺癌转移以及去势难治性中发挥重要作用。因此，本研究中将以遗传小鼠作为模式生物，通过分子生物学，细胞生物学，病人样品分析等实验手段，在多个层面系统地解析SRC-2在前列腺癌侵袭和转移以及去势难治性前列腺癌中的功能及其分子机制。本项目的成功实施将有助于进一步阐明前列腺癌高侵袭性转移和对雄激素剥夺疗法抵抗的分子机制，从而最终为临床诊断和治疗提供有益的思路和靶点。

前列腺癌已成为我国男性泌尿系统最常见的恶性肿瘤，并且其发病率正呈现快速增长的趋势。前列腺癌的高侵袭性转移和去势难治性是目前临床治疗所面临的两个难题也是基础研究重点关注的方面。本课题组通过对临床病人样品数据的分析以及运用遗传小鼠模型阐明核受体辅调节因子SRC-2响应雄激素内分泌剥夺治疗，反馈激活AKT及MAPK信号导致内分泌治疗耐受前列腺癌的形成（Journal of Clinical Investigation，2014）。研究结果提示在SRC-2高表达的肿瘤患者在进行内分泌治疗时需要考虑同时靶向AKT及MAPK信号。在接下来研究中，我们以SRC-2相互作用蛋白着手，发现组蛋白H3K36二甲基化修饰在前列腺癌高侵袭转移中的重要功能。H3K36二甲基转移酶WHSC1与胞内重要的信号分子AKT、Rictor、Rac1相互“作用”，促进PTEN缺失的“惰性”肿瘤发展成为高转移性前列腺癌（Journal of Clinical Investigation, 2017）。研究揭示PTEN缺失肿瘤可以通过AKT和EZH2信号上调H3K36二甲基转移酶WHSC1的表达，重塑细胞内染色质“信息”，获得高转移的潜能。上述研究发现揭示SRC-2和WHSC1在前列腺转移及内分泌治疗耐受中的重要功能及调控机制，为临床诊断和治疗提供有益的思路和靶点。