miR-181c靶向调控OPN介导乳腺癌化疗耐药的机制研究

Multiple-drug resistance to chemotherapy is a common phenomenon in clinics，and thus one of the main causes for failures of breast cancer treatment. To date, the exact mechanisms of chemoresistance are poorly understood. Previous studies indicate that osteopontin (OPN) overexpression is associated with resistance to conventional chemotherapeutic drugs and poor prognosis. OPN is highly expressed in MCF-7/MDR cells, whereas the expression of miR-181c is very low. Luciferase reporter assays have proved that OPN gene contains the binding sites of miR-181c. Therefore, we hypothesize that miR-181c negatively regulates OPN expression and thus reverses chemotherapy resistance in breast cancer. In the project, we plan to use breast cancer tissue samples, cell lines, and nude mice model to study the important role of miR-181c on chemoresistance, to elucidate the mechanisms that miR-181c regulates OPN expression and affects chemotherapy resistance by molecular biological technique from the molecules, cells, tissues and animals level. From the new perspective of miR-181c, this study will lay the foundation to reveal the mechanisms of breast cancer chemoresistance and provide new theoretical basis and molecular target for individual therapy of patients.

乳腺癌化疗耐药是临床上常见的问题，也是乳腺癌治疗失败的主要原因之一。目前乳腺癌化疗耐药的机制尚未完全阐明。前期研究中我们发现OPN表达上调与乳腺癌化疗耐药及预后不良密切相关；MCF-7/MDR细胞系中证实OPN高表达，miR-181c低表达，两者表达呈负相关；荧光素酶报告基因实验已确认miR-181c与OPN有靶向结合位点。由此推测miR-181c通过靶向调控OPN表达进而参与乳腺癌化疗耐药。本项目拟利用乳腺癌组织标本、乳腺癌细胞系、荷瘤鼠模型，采用分子生物学技术，从分子、细胞、组织及动物水平多个方面探讨miR-181c在乳腺癌耐药中的作用，明确miR-181c靶向调控OPN介导乳腺癌化疗耐药的机制。本研究将从miR-181c这个新视点，为进一步揭示乳腺癌耐药的发生机制奠定基础，为临床患者个体化治疗提供新的理论依据和分子靶点。

化疗耐药是临床常见现象，也是乳腺癌治疗失败的主要原因之一。由于越来越多的临床和实验证据表明microRNAs（miRNAs）在肿瘤耐药中发挥了重要作用，本研究旨在探讨miR-181c及其在乳腺癌化疗敏感性和转移中的作用机制。本研究中，我们发现与MCF-7细胞相比，MCF-7 / ADR中的miR-181c表达水平较低。功能实验结果表明，miR-181c的过表达抑制了细胞增殖，对阿霉素的化疗敏感性增强，并且抑制了细胞迁移，侵袭和转移。此外，研究证实了将OPN作为miR-181c的直接和功能性靶标。我们检测了MCF-7 / ADR细胞株和MCF-7细胞株中miR-181c和OPN的表达，发现miR-181c在MCF-7 / ADR中的表达低于MCF-7。相反，在MCF-7中OPN的表达低于在MCF-7 / ADR细胞系中的表达。我们推测miR-181c可能通过下调靶基因OPN来调节化疗敏感性，也增强乳腺癌细胞中p53的活性，促进了凋亡。本篇文章从miR-181c的新视角，为揭示乳腺癌化疗耐药机制奠定基础，为个体化治疗提供新的理论依据和分子靶点。