miRNA-21调控胆管癌EMT进程及其信号通路的研究

Exploring the invasive and metastatic mechanisms of cholangiocarcinoma, one of the most direct prognostic favtors, is a hot and difficult topic of cholangiocarcinoma research at present. Invasive Cholangiocarcinoma becomes metastatic through the abnormal expression of correlated metastasis genes. Therefore, the focus of the present study is to investigate the regulatory correlated metastasis genes in cholangiocarcinoma. The miRNAs, which regulate the development of tumor and correlated metastasis genes, are an upstream regulatory factor of mRNAs. miRNA-21 is one of these important genes. . Epithelial-mesenchymal transition (EMT) process is a major contributing factor in cancer metastasis. Our present findings indicate that miRNA-21 can regulate the EMT process of organ fibrosis. We have previously shown that miRNA-21 was correlated with the invasiveness and metastasis of cholangiocarcinoma, as abnormal expression of miRNA-21 was associated with the progression of chalongiocarcinoma EMT. Therefore, we hypothesize that miRNA-21 influences the chalongiocarcinoma to become invasive and metastatic by regulating the progression of EMT. Patient tissue samples will be screened for the signal regulatory path using Oligo Signal Transduction PathwayFinder Microarray and our findings will provide the basis for therapeutic targets of cholangiocarcinoma.

明确胆管癌侵袭转移机制将直接影响胆管癌的预后，也是目前胆管癌基础研究的热点和难点，转移相关基因的异常表达是胆管癌侵袭转移机制的基础，因此，研究调控该类基因的分子是目前研究的重点。miRNA作为mRNA的上游调控因子，调控着肿瘤发生和转移相关基因的表达，miRNA-21即是该类重要的调控因子，EMT过程被认为是肿瘤浸润转移的最主要因素，同时研究发现miRNA-21能够调控脏器纤维化中的EMT过程。我们前期研究发现miRNA-21的表达与胆管癌的侵袭转移相关，并且其异常表达与胆管癌的EMT进程相关。因此，我们提出"miRNA-21可能通过调控EMT进程影响胆管癌的侵袭转移"的假设，本项目欲通过标本检测及体内外实验进行验证该假设，并运用信号传导通路基因芯片筛选出该调控作用的信号通路及关键分子，为胆管癌的靶向治疗提供研究基础。

miRNA作为mRNA的上游调控因子，调控着肿瘤发生和转移相关基因的表达，miRNA-21即是该类重要的调控因子，EMT过程被认为是肿瘤浸润转移的最主要因素，同时研究发现miRNA-21能够调控脏器纤维化中的EMT过程。而“miRNA-21能否通过调控EMT进程影响胆管癌的侵袭转移”仍不明确，本项目通过临床标本检测和体内外实验证实miRNA-21可以抑制Ecadherin的表达，上调N-cadherin和Vimentin，促进胆管癌的EMT进程，从而促进其侵袭转移。而通过全基因组芯片筛选及IPA分析得出miRNA-21并没有直接调控EMT相关基因的作用，但发现其与EMT相关基因KLF4和ERK1/2基因相关，遂通过实验证实发现miRNA-21可以间接影响KLF4的表达，并通过AKT/ERK1/2信号通路影响胆管癌的EMT进程，从而完整解释了miRNA-21调控胆管癌EMT的机制及关键分子。