Hedgehog通路异常激活导致的肿瘤干细胞增殖是肺癌耐药形成的重要原因。近期研究表明，长链非编码RNA（lncRNA）的异常调控与耐药产生密切相关。本课题组发现，lncRNA SOX2-OT在肺癌干细胞和耐药细胞中高表达且与Hedgehog通路关键转录因子GLI1存在正反馈调控效应；FISH染色显示SOX2-OT主要位于细胞浆，生物信息分析提示其作为ceRNA调节GLI1上游调控分子SOX2表达。因而，我们推测SOX2-OT通过SOX2/Hedgehog信号轴调控肺癌干细胞介导的耐药性。本项目拟采用ChIP、RIP和报告基因定点突变等方法深入解析SOX2-OT与Hedgehog通路形成正反馈环路的分子机理；分析SOX2-OT表达水平与患者预后的相关性；在体内外评估SOX2-OT对肺癌干细胞增殖、耐药性及相关标记物表达水平的影响。旨在丰富肺癌耐药形成的分子机理并为临床提供新的治疗靶点。

Hedgehog pathway-mediated proliferation of cancer stem cells (CSCs) is a major cause of drug resistance development in lung cancer therapy. Recent studies have shown that dysregulation of long non-coding RNAs (lncRNAs) is closely associated with drug resistance. Our group found that lncRNA SOX2-OT which is aberrantly expressed in lung CSCs and drug resistant cells reciprocally and positively interacts with GLI1, a key transcription factor of the Hedgehog cascade. Fluorescent in situ hybridization (FISH) indicated that SOX2-OT transcripts are mainly located in the cytoplasm and bioinformatics analysis suggested that SOX2-OT, as a ceRNA could upregulate expression of SOX2, a molecule upstream of GLI1. Thus, we propose that SOX2-OT plays an important role in lung CSCs-mediated drug resistance through regulating the SOX2/Hedgehog signaling axis. This project is designed to dissect the molecular mechanism of SOX2-OT/Hedgehog positive loop by employing ChIP, RIP and other target analysis techniques; to correlate the expression level of SOX2-OT with prognosis of patients; and to validate regulatory roles of SOX2-OT in CSC proliferation, drug resistance and expression of relevant markers in vitro and in vivo. We aim to take novel insight into molecular mechanisms of drug resistance development in lung cancer and provide novel therapeutic targets for clinic.