miR-4719/miR-6082调控BRIT1信号网络介导乳腺癌化疗耐受的研究

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 BRIT1 due to their widely targets. Our previous studies demonstrated that BRIT1 regulates p53 and plays a role in the DNA damage and repair pathway, which results in the chemoresistance in breast cancer, which was associated with miR-4719/miR-6082. In order to clarify the molecular mechanisms of miR-4719/miR-6082 targeting BRIT1 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 of miR-4719/miR-6082 mediates the chemoresistance by targeting BRIT1. Then we would like to clarify the mechanism of miR-4719/miR-6082 in regulating BRIT1 signal pathway and contributing to the chemoresistance of breast cancer. Finally, we will demonstrate the clinical significance of miR-4719/miR-6082 and BRIT1 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.

化疗耐受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BRIT1及DNA损伤修复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了BRIT1能调控p53，且与DNA损伤修复密切相关。进一步的研究显示，BRIT1是调控乳腺癌化疗耐药的关键分子，且与miR-4719/miR-6082相关。为进一步探索miR-4719/miR-6082靶向BRIT1介导乳腺癌化疗抵抗的分子机制，本项目拟在乳腺癌细胞中，通过干预miR-4719/miR- 6082靶向BRIT1，获得其调节乳腺癌化疗敏感性的直接实验依据，揭示miR-4719/miR-6082通过靶向BRIT1信号通路导致乳腺癌化疗耐受的分子机制，阐明miR-4719/miR- 6082调控BRIT1信号在乳腺癌化疗耐受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。

乳腺癌是女性最常见的恶性肿瘤，在全世界范围内，乳腺癌的发病率处于恶性肿瘤的前首位。三阴性乳腺癌（Triple-negative breast cancer, TNBC）占乳腺癌的15－20％，TNBC的治疗面临很多困境，除了化疗还没有特异性的靶向治疗，大部分都是经验性治疗且没有肿瘤生物学的依据。TNBC的不良临床特征和预后，都促使我们去探索和寻找TNBC治疗的切入点。Palbociclib是CDK4/ 6激酶的高效选择性抑制剂，三阴性疾病患者也受益于这种治疗，但是其主要领用于ER+乳腺癌患者且联合来曲唑应用，而新的证据表明miRNA参与肿瘤化疗抵抗相关蛋白的调控等过程而备受关注。我们通过探索 BRIT1 在乳腺癌中的表达，并验证其与化疗耐受性的关系，组织芯片筛选并确证miR-3613-3p通过介导细胞周期停滞抑制三阴性乳腺癌生长，发现miR-3613-3p增强三阴性乳腺癌对CDK4/6抑制剂的敏感性；并且在体内及体外实验都进行了论证。明确了miR-3613-3p调控SMAD2/EZH2抑制肿瘤增殖及增强三阴性乳腺癌对CDK4/6抑制剂的敏感性的作用机制。这些研究结果显示miR-3613-3p在三阴性乳腺癌中明显表达降低并与临床重要预后指标相关，而且其功能上明显抑制肿瘤增殖，这些特征都使其日后成为三阴性乳腺癌的重要预测指标或肿瘤标记物。更重要的是，miR-3613-3p高表达的TNBC对Palbociclib更加敏感，这使其在以后成为Palbociclib临床应用的指标之一，增加Palbociclib在临床应用的范围，应用更加精准。