长链非编码RNA-SRLR介导肿瘤干细胞化与肾癌靶向药物治疗耐药的相关机制研究

As the first line therapy of metastatic renal cell carcinoma (RCC), targeted drugs significantly improved patients’ prognosis. However, its benefits have been limited due to frequent drug resistance. As a small subpopulation in tumor entity, there is increasing evidence that tumor stem cells (TSCs) may promote tumor drug resistance. Previously, we identified a novel lncRNA named lncRNA-SRLR (sorafenib resistance-associated lncRNA in RCC) by lncRNA array, which was required for sorafenib resistance. We also detected the positive correlation between lncRNA-SRLR and TSC-related genes expression (Nanog, et al.). Therefore, we hypothesize that lncRNA-SRLR may promote sorafenib resistance in RCC through TSC-related signal pathway. In the present study, we will further explore the function of lncRNA-SRLR in inducing TSC phenotype and explain the potential mechanisms of drug resistance. Hence, lncRNA-SRLR may serve as a novel molecule for drug resistance prediction and intervention.

靶向药物治疗是晚期肾癌的有效治疗手段，耐药的频繁出现限制了其临床应用。已有研究表明肾癌组织中存在肿瘤干细胞亚群，具有多项分化、自我更新能力，在靶向药物耐药中发挥重要作用。我们前期对接受索拉非尼治疗敏感和耐药肾癌患者的组织标本进行高通量测序，筛选出一条差异性表达的lncRNA-SRLR(sorafenib resistance-associated lncRNA in RCC)，细胞实验表明lncRNA-SRLR能促进肾癌细胞索拉非尼耐药，同时检测到lncRNA-SRLR与Nanog等肿瘤干细胞基因表达呈正相关。由此，我们推测lncRNA-SRLR是通过诱导肾癌干细胞化促进索拉非尼耐药。本研究拟应用高通量筛选、免疫共沉淀等技术，筛选出lncRNA-SRLR调控肾癌干细胞表型的关键分子及信号通路，阐明lncRNA-SRLR在肾癌靶向治疗耐药中的作用机理，为预测预后、逆转耐药提供新的理论依据。

肾癌是泌尿系统常见的恶性肿瘤之一，靶向药物治疗是晚期肾癌的有效治疗手段，但耐药的频繁出现限制了其临床应用。已有研究表明肾癌组织中存在肿瘤干细胞亚群，具有多项分化、自我更新能力，在靶向药物耐药中发挥重要作用。我们前期对接受索拉非尼治疗敏感和耐药肾癌患者的组织标本进行高通量测序，筛选出一条差异性表达的长链非编码RNA并将其命名为lncRNA-SRLR(sorafenib resistance-associated lncRNA in RCC)。我们的研究表明下调lncRNA-SRLR可以增强肾癌细胞对索拉非尼的敏感性，过表达lncRNA-SRLR可促进肾癌细胞对索拉非尼的耐药性。lncRNA-SRLR过表达促进肾癌细胞肿瘤干细胞表型，且肾癌肿瘤干细胞中lncRNA-SRLR表达上调。体内外实验证实，肾癌肿瘤干细胞与正常肾癌细胞相比，对索拉非尼的药物敏感性降低。我们猜测lncRNA-SRLR对肾癌索拉非尼耐药的影响可能与肿瘤干细胞相关。经过深入研究，团队发现lncRNA-SRLR过表达导致肿瘤干细胞相关基因Sox2基因表达上调，激活Wnt/β-catenin通路，促进肾癌细胞对索拉非尼耐药。最后，我们利用肾癌患者肿瘤组织样本进一步验证发现，lncRNA-SRLR、Sox2、Wnt/β-catenin通路与肾癌患者索拉非尼治疗的无进展生存期存在相关性。在此基础上，我们提出lncRNA-SRLR可能是靶向治疗新的疗效评估标志物，也可能是靶向治疗新的辅助治疗靶点。