长链非编码RNA介导的肿瘤干细胞样表型在肾癌舒尼替尼耐药中的作用及机制研究

Sunitinib are currently approved for the therapy of metastatic renal cell cancer (RCC), but their benefits are limited by inherent and acquired resistance, whose mechanisms are the subject of intense investigation. Cancer stem cells (CSCs) are believed to have a crucial role in the heterogeneity of RCC. Long non-coding RNAs (lncRNAs) have been recently found to be pervasively transcribed in human genome and link to diverse human diseases. We hypothesize that lncRNA may be involved in reprogramming renal tumor cells towards a stem-like phenotype with specific resistance to RTK inhibitors. Here, we showed that cancer cells derived from recurrent RCC with resistance to sunitinib are endowed with CSC-liked capacity, and we identified a novel lncRNA named lncRNA-ARSR (Activated in sunitinib Resistant Stem-like RCC cells, ARSR) which was required for resistant RCC cells survival by lncRNA Array. On this basis we will further explore the function and mechanism of lncRNA-ARSR, which laying the theoretical foundations and preliminary experimental evidence for the future clinical transformation. The level of lincRNA-ARSR in plasma may be a potential biomarker for VEGFR TKI resistance as its level significantly elavated during sunitinib resistance. Hence, plasma lincRNA-ARSR kinetic change might serve as new surrogate end points for guiding early treatment decisions, monitoring patients on therapy and offering prognostic information.

舒尼替尼广泛应用于晚期肾癌的一线治疗，但药物耐药的频繁出现限制了其临床应用和疗效。鉴于肾癌具有高度的肿瘤异质性，我们推测肿瘤干细胞的存在可能参与了舒尼替尼耐药的发生，而在肿瘤发生发展中具有重要调节功能的长链非编码RNA(long non-coding RNA,lncRNA)可能参与对肾癌细胞的重塑，赋予其肿瘤干细胞样特征和耐药表型。我们前期建立了肾癌舒尼替尼耐药细胞株，发现其具有肿瘤干细胞样的特征，并利用lncRNA表达谱芯片检测耐药株和亲本之间差异表达的lncRNA，筛选鉴定出一条调控耐药细胞株肿瘤干细胞样特征与舒尼替尼耐药的新的lncRNA，并命名为lncRNA-ARSR (Activated in sunitinib Resistant Stem-like RCC cells, ARSR)，在此基础之上，我们拟进一步探索lncRNA-ARSR参与的调控网络，解析肾癌靶向药物耐药机制，为逆转肾癌靶向药物耐药提供新的治疗策略。

近年来，在世界范围内肾细胞癌(RCC)的发生率逐年上升。由于肾癌的不良预后和对细胞异质性认识的不断深入，人们开始关注一种独特的肾癌细胞亚群，即肾癌中的肿瘤起始细胞(T-ICs)或癌症干细胞(CSCs)。肾癌起始细胞(T-ICs)参与了肾细胞癌(RCC)的发生、发展和耐药过程。然而，其增殖的潜在机制仍不清楚。我们的研究表明，长链非编码RNA lncARSR在原发性肾癌起始细胞中表达升高，并与透明细胞癌(ccRCC)的不良预后相关。lncARSR的下调减弱了肾癌起始细胞的自我更新、致瘤性和转移。相反，lncARSR的过表达增强了肾癌细胞的T-IC特性。从机理上讲，lncARSR与YAP的结合阻碍了lats1诱导的YAP磷酸化，促进了YAP核的转位。相反，YAP/TEAD促进lncARSR转录，从而形成正反馈通路。lncARSR和YAP之间的相关性在肾透明细胞癌队列中得到了验证，这两个参数的组合可以提高预后准确性。我们的研究结果表明，lncARSR在肾癌起始细胞的传播中起着关键作用，可能作为一种预后生物标志物和潜在的治疗靶点。