miR-301a在缺氧诱导胰腺癌EMT中的功能机制研究

课题组前期的研究发现缺氧微环境上调miR-301a的表达，miR-301a又可能通过其靶基因Smad4影响TGF-β信号通路，并通过串扰效应引起STAT3过活化，诱导胰腺癌EMT。但目前尚不知miR-301a如何调控TGF-β信号相关的STAT3过度活化，也不知缺氧诱导的HIF-1α是否可调控miR-301a的表达。本课题拟分析miR-301a及其下游分子对胰腺癌分期及转移的关系，研究miR-301a在缺氧诱导胰腺癌EMT的功能，分析miR-301a调控TGF-β信号通路与STAT3信号通路串扰关系及相关机制，并初步探讨HIF-1α对miR-301a表达的影响。我们的研究结果将首次揭示miR-301a在缺氧条件下通过TGF-β通路诱导胰腺癌EMT中的功能及机制,可为揭示胰腺癌发病机理提供依据，也为基于microRNAs临床靶向性治疗奠定基础。

Our preliminary studies have shown that hypoxia up-regulated miR-301a expression, which targeted Smad4 expression. Given that hypoxia induces HIF-1α expression, we hypothesize that hypoxia induces HIA-1 expression and promotes miR-301 expression, which targets Smad4 and other unknown molecules to regulate TGF-β-mediated Smad dependent and independent signaling, promoting STAT3 aberrant activation and EMT process in pancreatic cancer. In this proposal, we will analyze the potential association of miR-301 and its downstream molecules with pancreatic cancer metastasis in clinical samples, determine the molecular mechanisms underlying the role of miR-301a in hypoxia-induced EMT in pancreatic cancer, and investigate the potential cross-talk between the TGF-β and STAT3 pathway in the absence of Samd4, and finally identify the regulatory effect of HIF-1α on hypoxia-induced miR-301a expression. Our data may demonstrate that miR-301a is valuable biomarker for the prognosis of pancreatic cancer and reveal molecular mechanisms underlying the action of miR-301a in regulating EMT and metastasis of pancreatic cancer. Potentially, our findings may provide a basis for the design of new therapeutic strategy for the intervention of pancreatic cancer in the clinic.