化疗耐药是导致肺癌治疗失败的主要原因。肺癌干细胞的干性维持是肺癌耐药产生的关键，自噬在干性维持中的作用至关重要。本项目聚焦的科学问题是自噬溶酶体相关蛋白-组织蛋白酶L（Cathepsin L）对肺癌干细胞干性维持及耐药的作用机制和干预策略。前期工作及预初实验发现耐药患者肺癌组织和肺癌干细胞中，组织蛋白酶L、干性基因SOX2、生存基因Bcl-XL和耐药蛋白ABCG2均高表达；抑制组织蛋白酶L后，干细胞标志物CD133表达下调，干细胞球形成率降低，并可逆转肺癌干细胞对顺铂的耐药；此外，突变p53的肿瘤细胞中组织蛋白酶L异常活化。本项目拟以肺癌干细胞干性维持为切入点，系统研究和明晰组织蛋白酶L通过激活干性基因和生存基因途径调控肺癌干细胞干性维持及耐药的机制；揭示突变p53激活组织蛋白酶L转录调控机制及其与肺癌干细胞干性维持和耐药的关联性，探索和建立靶向干预抑制组织蛋白酶L逆转肺癌耐药的新策略。

Drug resistance remains the major cause of treatment failure among the lung cancer patients. Keeping stemness of lung cancer stem cells give them higher natural drug resistance to chemotherapy. Autophagy is the key of the stemness maintenance. The scientific problem of this project which focus on is the mechanism of Cathepsin L, a autophagy-lysosomal protein, acts on the stemness maintenance of lung cancer stem cells and the strategy for drug resistance. Our preliminary study found the expressions of Cathepsin L, stemness gene SOX2, survival gene Bcl-XL and ABC transporter ABCG2 were extraordinarily elevated in both drug resistant human lung cancer tissues and lung cancer stem cells. After Cathepsin L inhibition, the expression of CD133 significantly reduced, the sphere formation efficiency decreased, and eventually the drug resistance of lung cancer stem cells to cisplatin reversed. Furthermore, Cathepsin L was abnormal activated in p53 mutation type cancer cells. Building on these results, we propose to study the regulatory mechanisms of Cathepsin L on stemness maintenance of lung cancer stem cells and drug resistance through both the stemness gene signaling pathway and the survival gene signaling pathway. Our study will provide new insights into the essential roles of mutant p53 on transcriptional regulation of Cathepsin L. Thus, targeting Cathepsin L might be explored as a novel target and theoretical basis for individualized treatment of lung cancer patients.