组胺H2受体在去势抵抗性前列腺癌多西他赛耐药中的作用及机制研究

Castration resistance is a major clinical problem in advanced prostate cancer. Docetaxel is highly recommended for the treatment of castration resistance prostate cancer (CRPC). However, undesirable therapeutic respond caused by acquired drug resistance, urging us to find mechanisms and potential therapeutic targets. We focus on potential biological function of histamine and its receptors for a long time and found high level histamine 2 receptor (H2R) in prostate cancer. The expression of H2R is positive correlated with Gleason score、serum total PSA and metastasis. Combination of H2R antagonist and docetaxel can suppress cell proliferation、migration and invasion, whereas the in-depth mechanism is still unclear. Our project will investigate the mechanism of H2R through interacting with β-catenin to regulate the Wnt/β-catenin pathway by prostate specific transgene mouse model、conditional knockout/knockin β-catenin mouse model、protein spectrometry and co-immunoprecipitation. This project is aimed to give more evidence to elucidate the mechanism of drug resistance to docetaxel, and to provide new target for the treatment of docetaxel resistance in CRPC.

中晚期前列腺癌患者往往在内分泌治疗后逐渐发展为去势抵抗前列腺癌（CRPC），多西他赛化疗是CRPC重要治疗手段，但由于获得性耐药的发生严重影响了其临床治疗效果，因此非常有必要阐明其耐药机制并寻找新的治疗靶点。申请人所在课题组长期从事组胺及受体的生物学功能研究。前期研究发现前列腺癌中组胺H2受体（H2R）表达升高，其表达量与Gleason评分、血清PSA水平及转移呈正相关，H2R拮抗剂与多西他赛联合应用能够通过抑制细胞增殖、迁移和浸润发挥抗肿瘤作用，但具体机制不明。本课题将利用多种前列腺组织特异性转基因小鼠，结合病毒干扰或过表达、蛋白质谱和免疫共沉淀等技术，阐明耐药细胞中H2R通过与β-catenin相互作用调控Wnt/β-catenin信号通路的作用机制。本研究将进一步揭示CRPC多西他赛耐药的病理机制，并为CRPC多西他赛耐药的治疗提供非常具有临床应用价值的药物治疗靶点。

中晚期前列腺癌患者往往在内分泌治疗后逐渐发展为去势抵抗前列腺癌（CRPC），多西他赛化疗是CRPC重要治疗手段，但由于获得性耐药的发生严重影响了其临床治疗效果，因此非常有必要阐明其耐药机制并寻找新的治疗靶点。我们课题组长期从事组胺及受体的生物学功能研究。前期研究发现前列腺癌中组胺H2受体（H2R）表达升高，其表达量与Gleason评分、血清PSA水平及转移呈正相关。因此本课题利用多西他赛耐药荷瘤鼠，结合药理学手段、病毒干扰、蛋白质谱和免疫共沉淀等技术研究发现，H2R拮抗剂与多西他赛联合应用能够通过抑制细胞增殖、迁移和浸润发挥抗肿瘤作用，其可能的机制是通过与β-catenin相互作用激活Wnt/β-catenin通路及下游信号分子，调节细胞周期G1/S转换。从而抑制前列腺癌细胞增殖和侵袭能力调控CRPC多西他赛耐药进展。本研究将进一步揭示CRPC多西他赛耐药的病理机制，并为CRPC多西他赛耐药的治疗提供非常具有临床应用价值的药物治疗靶点。