外泌体介导ANRIL在三阴性乳腺癌阿霉素耐药中的机制研究

Chemotherapy is the main method of systemic treatment for triple negative breast cancer (TNBC)，but Chemotherapy resistance is a major challenge for clinical efficacy of it. Exosomal long non-coding RNA (lncRNA) is associated with chemotherapy resistance. Our preliminary study shown that exosomes secreted by adriamycin-resistant TNBC cells (TNBC-ADR) could cause drug resistance in other sensitive cells, which is attributed to the lncRNA ANRIL carried in secreted exosome by TNBC-ADR. Autophagy is also observed. The aim of this study is to: determine the biological function of ANRIL in TNBC adriamycin resistance through the loss-of-funtion and gain-of-function experiments with adriamycin-resistant TNBC cell lines; confirm that exosome was the main carrier for extracellular ANRIL and involved in the transmission of drug resistance with animal models and clinical samples; investigate the role of exosomal ANRIL-regulated autophagy in TNBC adriamycin resistance and to clarify its specific molecular mechanism. This study will reveal the molecular regulatory network of TNBC chemotherapy resistance, which provided theoretical basis and potential drug target for reversing TNBC chemotherapy resistance.

化疗是三阴性乳腺癌（TNBC）的主要全身治疗手段，但耐药是限制其临床疗效的核心问题。既往研究表明外泌体中携带的长链非编码RNA（lncRNA）可能与化疗耐药有关。我们前期实验结果显示阿霉素耐药的TNBC细胞分泌的外泌体可以引起敏感细胞耐药，且耐药性的产生与外泌体携带的lncRNA ANRIL可能有关;同时我们还观察到耐药细胞自噬活性呈明显增加。本项目拟在前期基础上利用阿霉素耐药的TNBC细胞系通过功能获得与缺失实验，确定ANRIL在TNBC阿霉素耐药中的生物学功能；结合动物模型及临床样本证明ANRIL为外泌体包裹，并且参与耐药性的传递；探究外泌体ANRIL调控的自噬在TNBC阿霉素耐药中的作用并阐明具体分子机制。本研究将为临床逆转TNBC化疗耐药提供理论依据和潜在的药物作用靶点。

化疗是三阴性乳腺癌（TNBC）的主要全身治疗手段，但耐药是限制其临床疗效的核心问题。既往研究表明外泌体中携带的长链非编码RNA（lncRNA）可能与化疗耐药有关。我们前期实验结果显示阿霉素耐药的TNBC细胞分泌的外泌体可以引起敏感细胞耐药，且耐药性的产生与外泌体携带的lncRNA ANRIL可能有关;同时我们还观察到耐药细胞自噬活性呈明显增加。本项目在前期基础上利用阿霉素耐药的TNBC细胞系通过功能获得与缺失实验，确定ANRIL在TNBC阿霉素耐药中的生物学功能；结合动物模型及临床样本证明ANRIL为外泌体包裹，并且参与耐药性的传递；探究外泌体ANRIL调控的自噬在TNBC阿霉素耐药中的作用并阐明具体分子机制。本研究为临床逆转TNBC化疗耐药提供了理论依据和潜在的药物作用靶点。