STAG2-NIPBL-STAT3信号通路调节EMT参与膀胱癌转移的分子机制

Metastasis is one of main cause of death in patients with bladder cancer. Our previous work found that the gene mutation or abnormal protein expression of stromal antigen 2 (STAG2), a subunit of Cohesin, is associated with bladder cancer metastasis, but the underlying mechanisms have not been yet clear. Research showed that NIPBL, the Cohesin loader protein, regulates the expression of oncogene STAT3, and STAT3 participates in malignant of tumor by adjust Epithelial-mesenchymal transition (EMT). Using genomic sequencing of human bladder cancer tissue samples or bioinformatics data analysis showed that there is correlation between STAG2 and NIPBL. Hence, whether STAG2 mediate STAT3 signaling pathways to regulate EMT by interaction with NIPBL, and participate in bladder cancer metastasis? This project will exploy chromatin immune co-precipitation, site-directed mutagenesis, reporter gene, transcriptomics and bioinformatics methods from three levels of bladder cancer tissues, bladder cancer cell knockdown or overexpression STAG2, metastasia model of nude mice in vivo to analysis comprehensive the molecular mechanisms of STAG2 - NIPBL - STAT3 - EMT signal in bladder cancer metastasis. This study will provide new evidence for further perfecting the bladder cancer metastasis theory.

转移是膀胱癌患者致死的主要原因。本课题组前期研究发现粘连体(Cohesin)的亚基-基质抗原2(STAG2)基因突变或蛋白表达异常与膀胱癌转移相关，但其作用机制尚未明确。研究表明，Cohesin的负载蛋白NIPBL调控癌基因STAT3的表达；而STAT3通过调节上皮间质转化(EMT)参与肿瘤恶性演进。我们对人膀胱癌组织样本基因组测序及生物信息学数据分析均显示：STAG2与NIPBL存在相互关联。那么，STAG2是否是通过与NIPBL相互作用调控STAT3介导的相关信号通路调节EMT，进而参与膀胱癌转移？本项目拟分别从人膀胱癌组织、敲降或过表达STAG2的膀胱癌细胞株、膀胱癌裸鼠体内转移模型三个层面，利用染色质免疫共沉淀，定点突变，报告基因，转录组学及生物信息学分析等方法全面解析STAG2-NIPBL-STAT3-EMT参与膀胱癌转移的分子机制。该研究将为日后完善膀胱癌转移理论提供新的证据。

转移是泌尿系统肿瘤膀胱癌患者致死的主要原因。课题组前期发现粘连体(Cohesin)的亚基-基质抗原2 (STAG2) 基因在膀胱癌患者中存在高频突变，为了探讨该基因在膀胱癌转移中的作用，我们收集了403例膀胱癌病人样本，免疫组化结果显示在癌组织样本中，STAG2表达缺失，且其突变或蛋白表达异常与膀胱癌转移相关，实验检测发现STAG2通过STAT3信号通路调控EMT的发生，我们建立了敲低和过表达STAG2基因的细胞和动物模型，发现不同细胞模型在敲低STAG2后细胞恶性表型不一致，目前仍在继续探索。同时，我们采用生物信息学分析和实验验证的方法，发现了另外一种泌尿系统肿瘤—肾透明细胞癌的潜在诊断治疗靶标：CDKN2B和THBS3，相关论文分别发表在“Cell Death and Disease” 和“Investig Clin Urol”杂志上。本项目的研究对于揭示泌尿系统肿瘤：膀胱癌和肾癌转移的分子机制具有重要的意义，将为日后完善泌尿系统肿瘤转移理论提供新的实验依据，希望能为其诊断及基因治疗提供新的靶点。