前列腺癌是男性最常见的恶性肿瘤之一，是全球范围内男性第二大被诊断和第五大致死性肿瘤。雄激素受体（AR）是前列腺癌进程的关键因子,敲除AR基因对肿瘤进程的影响仍未可知。我们的前期研究表明：1.CRISPR-Cas9系统可体外高效敲除肿瘤细胞AR基因，显著抑制前列腺癌进程，并显著下调AR靶基因表达水平；2.重组腺相关病毒（rAAV）7可高效安全转导人和小鼠前列腺癌细胞。本课题拟包装rAAV7-SaCas9和sgAR病毒，注射TRAMP小鼠前列腺（肿瘤）和裸鼠皮下移植瘤，分析肿瘤细胞内AR基因敲除对荷瘤小鼠生存周期，肿瘤细胞增殖，凋亡，转移等的影响。另外，检测AR靶基因（SGK1/TMPRSS2）及肿瘤恶性相关基因的表达变化，和TMPRSS2/HGF/MET/PI3K/SGK1/ERK1/2信号通路活性。研究结果将为前列腺癌基因治疗和分析前列腺癌发生发展的分子机制提供重要体内实验基础。

Prostate cancer is one of the most common malignancies among male population, it is also the second most diagnosed malignancy and fifth leading cause of cancer-related death. Many studies indicated that androgen receptor (AR) plays a very important role in prostate cancer progression, and the effect of AR deletion on tumor progression is largely unknown. Our preliminary data suggest that clustered regularly interspaced short palindromic repeats (CRISPR) associated nuclease 9 (CRISPR-Cas9) system can effectively delete AR gene. AR deletion significantly inhibits prostate cancer progression and downregulates the expression of its target genes in vitro. Furthermore, recombinant adeno-associated virus (rAAV) 7 can transduce human and mouse prostate cancer cells with high transduction efficacy and safety. This study will firstly package rAAV7-SaCas9 and sgAR viruses, and then the effect of AR deletion on survival rate of tumor bearing mice, tumor cell proliferation, apoptosis as well as tumor metastasis will be observed using transgenic adenocarcinoma mouse prostate (TRAMP) and xenograft mouse models. Simultaneously, the expression of AR target genes (SGK1/TMPRSS2) and tumor malignancy related genes will be detected. The activity of TMPRSS2/HGF/ MET/PI3K/SGK1/ERK1/2 will be evaluated. Taken together, our findings will provide critical foundation for investigating mechanism of prostate cancer progression and its gene therapy.