DACH2调控Smad4/R-Smad通路介导上皮间质转化促进膀胱癌的侵袭转移

项目名称： DACH2调控Smad4/R-Smad通路介导上皮间质转化促进膀胱癌的侵袭转移

项目编号： No.81502206

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 何娅娣

作者单位： 中山大学

项目金额： 16万元

中文摘要： 淋巴转移是膀胱癌致死的重要原因。我们前期采用基因表达谱芯片筛选膀胱癌转移相关基因，发现DACH2在盆腔淋巴结阳性膀胱癌组织样本中转录和蛋白表达水平均明显上调，DACH2阳性膀胱癌术后无转移生存率和总体存活率明显低于DACH2阴性者[BBRC,2015]，但DACH2促进膀胱癌侵袭转移的机制尚不明确。结合近期预实验结果: DACH2可通过促进上皮-间质转化(EMT)增强膀胱癌细胞转移能力；癌细胞中DACH2与Smad4表达成正相关；DACH2可与Smad4发生直接结合。同时，鉴于Smad4与EMT过程密切关联，我们提出DACH2促进膀胱癌淋巴转移新机制：DACH2可通过Smad4/R-Smad通路，改变EMT相关基因转录活性，促进膀胱癌细胞EMT、侵袭性伪足形成及降解细胞外基质。本研究力图解析DACH2过表达介导EMT促进膀胱癌侵袭转移的机理，有望为临床抑制膀胱癌转移提供重要的分子干预靶点。

中文关键词： 膀胱肿瘤；DACH2；Smad4；上皮间质转化；转移

英文摘要： Lymph node metastasis is the primary cause of mortality from bladder cancer. In our previous studies, using gene expression profile chip we showed that both DACH2 protein and mRNA expression were greatly increased in bladder cancer patients with lymph node metastasis. Patients with primary bladder cancer that did not express DACH2 had a longer metastasis-free survival and overall survival than did those with tumors expressing DACH2 [BBRC, 2015]. However, the molecular mechanisms of DACH2 initiating bladder cancer metastasis still remain obscure. Our recent investigations also showed: (1) DACH2 could contribute to bladder cancer cell metastasis via promoting epithelial-mesenchymal transition (EMT). (2) There is a positive correlation between relative DACH2 expression and its corresponding Smad4 expression in bladder cancer cells. (3) DACH2 could directly bind Smad4 protein. Herein, based on these findings and the close correlation between Smad4 and EMT, we speculate and present the novel mechanisms underlying DACH2-inducing lymph node metastasis in bladder cancer: DACH2 overexpression could alter the activity of EMT-related gene expression via Smad4/R-Smad signal pathway, thus contributes to EMT, the formation of invasive pseudopod, and degrading extracellular matrix. The present study would elucidate the mechanisms of EMT-related gene expression alteration induced by DACH2 overexpression in bladder cancer. Our results may provide novel and imperative molecular targets for the intervention of bladder cancer metastasis.

英文关键词： bladder neoplasm;DACH2;Smad4;epithelial-mesenchymal transition;metastasis