长链非编码RNA LINC00857介导非小细胞肺癌耐药的机制研究

At present, Lung cancer is one of the most frequently diagnosed types of malignant tumor and a leading cause of mortality worldwide. Systemic chemotherapy is still an important treatment option for advanced lung cancer. However, drug resistance acquired by lung cancer cells usually leads to treatment failure. The puzzle of drug resistance can’t be solved from the perspective protein-coding genes, whose mechanisms need to be considered at the non-coding gene level. Our previous study showed that LINC00857 plays a critical role in the development and progression of non-small cell lung cancer (NSCLC). Furthermore, we found that the expression of LINC00857 was significantly increased in the Texotre-resistant NSCLC cells. To understand the underlying molecular mechanisms of chemoresistance in NSCLC and to identify molecular targets for therapy, this project aims to investigate the function of LINC00857 in the chemoresistant NSCLC cells, to determine whether LINC00857 involved in chemoresistance of NSCLC as ceRNA. Our results will not only help to elucidate the underlying molecular mechanisms of docetaxel resistance in lung cancer, but also provide theoretical evidences for clinical personalized medicine, reversal of drug resistance or molecular targeted therapy in lung cancer.

肺癌是目前常见的恶性肿瘤，化疗是治疗中晚期肺癌的重要手段而耐药是化疗失败的主要原因。既往针对编码基因的研究并不能全面阐明肿瘤耐药机制，使得lncRNA在肿瘤耐药中的作用愈发引人重视，但lncRNA在肺癌耐药中的作用尚不完全清楚。前期我们发现lncRNA LINC00857与非小细胞肺癌(non-small cell lung cancer, NSCLC)发生发展密切相关，敲低LINC00857后可增强细胞对紫杉醇的敏感性。提示LINC00857在NSCLC耐药过程中起重要作用，有必要深入研究LINC00857在化疗耐药中的机制。本课题将以竞争性内源性RNA理论作为桥梁，从非编码RNA相互作用角度揭示LINC00857参与NSCLC耐药形成的分子机制。研究结果将为揭示NSCLC耐药分子机制提供新的线索，也可为晚期NSCLC化疗药物的选择及临床预后的判断提供新的理论参考。

化疗耐药问题是导致非小细胞肺癌（Non small cell lung cancer, NSCLC）患者治疗失败的最主要原因。长链非编码RNA（Long non-coding RNAs, lncRNAs）在促进癌症的发生和发展中发挥着重要作用。然而，其在化疗耐药中的调控和作用仍不清楚。在本研究中，我们发现LINC00857在NSCLC化疗耐药细胞中表达上调，且其下调可逆转化疗耐药。高表达的LINC00857与NSCLC术后化疗患者不良预后相关。敲低LINC00857可显著抑制NSCLC耐药细胞体外增殖、迁移、侵袭、克隆形成能力。沉默LINC00857表达后，可降低耐药细胞中CDK2、Cyclin B1表达，增加p21表达，诱导细胞周期阻滞。机制上LINC00857可靶向结合YBX1蛋白并抑制其通过蛋白酶体通路降解，促进YBX1核转位，从而促进肿瘤耐药相关基因ABCB1和BCL2的表达，进而促进NSCLC细胞耐药形成。本项目研究揭示LINC00857靶向结合YBX1从而参与非小细胞肺癌耐药的机制，有望为NSCLC新型化疗药物研发和基因治疗提供实验依据。