miR-17/Let-7调控Jab1信号网络介导乳腺癌化疗抵抗的研究

Chemoresistance severely affects the efficacy of chemotherapy in breast cancer, thus, it's essential to clarify the mechanism of chemoresistance. Increasing attention are focused on microRNA and Jab1 due to their widely targets. Our previous studies demonstrated that Jab1 plays a pivotal role in the pathogenesis and prognosis of breast cancer. We also found that Jab1 regulates the chemoresistance in breast cancer, which was associated with miR-17 and Let-17. In order to clarify the molecular mechanisms of miR-17/Let-7 targeting Jab1 and regulating the chemoresistance of breast cancer, based on our breast cancer models in vitro and in vivo, we plan to get the directly evidence that miR-17/Let-7 mediates the chemoresistance by targeting Jab1. Then we would like to clarify the mechanism of miR-17/Let-7 in regulating Jab1 signal pathway and contributing to the chemoresistance of breast cancer. Finally, we will demonstrate the clinical significance of miR-17/Let-7 and Jab1 signal pathway in chemoresistance of breast cancer. Our project will provided a novel insight of chemoresistance and novel targets in reversing the chemoresistance of breast cancer.

化疗抵抗严重影响乳腺癌化疗疗效，阐明化疗抵抗机制至关重要。微小RNA（microRNA）和Jab1作为肿瘤研究靶点备受关注，但尚未见两者相互作用调控化疗抵抗的报道。本课题组既往研究证实Jab1与乳腺癌的发生，发展和预后密切相关，我们前期研究验证了Jab1是调控乳腺癌化疗耐药的关键分子，并与miR-17和Let-7相关。为了进一步探索miR-17/Let-7调控Jab1介导乳腺癌化疗抵抗的分子机制，本项目拟在乳腺癌体内外研究模型中，通过干预miR-17/Let-7及其Jab1，获得它们调节乳腺化疗敏感性的直接实验依据，揭示miR-17/Let-7通过靶向Jab1信号网络导致乳腺癌化疗抵抗的分子机制，阐明miR-17/Let-7调控Jab1信号网络在乳腺癌化疗抵抗中的作用和临床意义，为逆转肿瘤耐药提供新思路和新靶点。

化疗耐受和复发严重影响乳腺癌患者生存预后。我们前期研究表明新型癌基因Jab1在肿瘤中异常高表达。但是Jab1在肿瘤中高表达的原因尚未研究。本项目表明肿瘤中异常高表达的Jab1是调控乳腺癌化疗耐药和生存预后的关键靶点，并且Jab1的表达受let-7d调控。为了进一步探索let-7d调控Jab1介导乳腺癌化疗抵抗的分子机制，本项目在乳腺癌体内外研究模型中，通过干预let-7d等miRNA及Jab1，获得它们调节乳腺化疗敏感性的直接实验依据，揭示乳腺癌中低表达的let-7d通过靶向Jab1信号网络导致乳腺癌化疗抵抗的分子机制，阐明let-7d调控Jab1信号网络在乳腺癌化疗抵抗中的作用和临床意义，为逆转肿瘤耐药提供新思路和新靶点。