肺癌的发病率及死亡率在我国恶性肿瘤中最高，且日趋增多，危害巨大。化疗药物早期多有效，但容易产生耐药且预后很差，故阐明潜在的分子基础对破解临床肺癌化疗抵抗的难题意义重大。有研究提示肿瘤干细胞或lncRNA参与了化疗抵抗，但该方面研究尚处于初期。申请者长期致力于肺癌相关机制的研究，前期研究已揭示了多个lncRNAs调控肿瘤的表观遗传机制。为寻求肺癌耐药的关键“因子”，基于前期建立的耐药细胞模型及二次活检肺癌标本进行的肺癌干细胞和lncRNA的双重筛选，申请者发现：一个新分子lncRNA-CSCL，可通过调控肺癌干细胞与巨噬细胞的“crosstalk”重塑肺癌干细胞niche（微环境），并介导了肺癌化疗抵抗，而PI3K/Akt信号通路可能发挥了关键的“枢纽”作用。本研究拟通过细胞及小鼠模型，结合临床样本，探讨lncRNA-CSCL分子网络调控肺癌干细胞介导耐药的关键机制，为肺癌防治提供新策略。

Lung cancer is the most common malignant cancer both in incidence and mortality in China. Although chemotherapy drugs initially effective, but most patients will subsequently relapse and the prognosis is poor. So looking for the underlying molecular basis is of great significance for overcoming the barrier of drug resistance.At present,it has been suggested that cancer stem cells or lncRNA may mediate the therapy resistance, but these researches are still in their early stage. Our group persists in the research of lung cancer recurrence and metastasis and our previous works showed key role of several lncRNAs in the epigenetic regulation of tumor.To explore the key molecular involved in the recurrence and therapy resistance of lung cancer, our previous works performed high-through gene screening base on both of the drug-resistant lung cancer cell lines and lung cancer biopsy specimens. We found a new molecular, named as lncRNA-CSCL, remodels tumor microenvironment (niche) through regulation of "crosstalk" between lung cancer stem cells and macrophages, which possibly leads to lung cancer chemotherapy resistance. While PI3K/Akt signaling pathway plays a key role in the "hub". In this study, we will explore the key mechanisms of lncRNA-CSCL molecular network/lung cancer stem cell mediated drug resistance by cell and mouse model,and even clinical specimens, eventually to provide new strategies for the prevention and treatment of lung cancer.