IFN-γ诱导非小细胞肺癌肿瘤干细胞富集的机制研究

The incidence and mortality of lung cancer are at the top of the list in China. Tumor microenvironment (TME) and cancer stem cells (CSC) are closely related to the tumorigenesis and development of lung cancer. IFN-γ mainly secreted by immune cells in the TME is the earliest and most studied cytokine. IFN-γ is considered as a typical anti-tumor cytokine, but the clinical efficacy varies. We have previously shown that the progression of lung cancer patients with IFN-γ low expression was poor, and IFN-γ low expression was correlated with brain metastasis and chemoresistance. In addition, lung cancer cells with low dose IFN-γ treatment increased CSC marker CD133 expression and promoted self-renewal capability and stem-related genes expression in vitro. However, there are few reports currently available regarding interrelation between IFN-γ and lung cancer CSC. The key mechanism of IFN-γ induced CSC enrichment in lung cancer remains to be further explored. We hypothesize that IFN-γ plays a key role in the enrichment of CSC in lung cancer. In order to prove our hypothesis, we will use NSCLC cell lines, nude mice model and molecular biology techniques to explore the role of IFN-γ on the biological characteristics of CSC in lung cancer. This study will lay the foundation for revealing lung cancer progression and provide new ideas for developing more specific therapeutic targets.

肺癌的发病率及死亡率在我国都高居榜首。肿瘤微环境(TME)、肿瘤干细胞(CSC)与肺癌的发生发展有密切的联系。在TME中IFN-γ主要由免疫细胞分泌，是发现最早和研究最多的细胞因子。IFN-γ被认为是一种典型的抗肿瘤细胞因子，但临床疗效不一。我们的前期结果显示肺癌患者IFN-γ低表达者预后较差，与脑转移及化疗耐药等正相关；并且体外实验发现低浓度IFN-γ处理肺癌细胞后，CSC标记物CD133表达明显升高，促进了自我更新能力及干性相关基因的表达。迄今IFN-γ与肺癌CSC的研究仍知之甚少，IFN-γ富集肺癌CSC的机制仍有待进一步探讨。我们假设：IFN-γ在肺癌CSC的富集中发挥关键作用。本项目将利用肺癌细胞系、动物模型、分子生物学技术等手段，从分子、细胞、组织水平及动物实验等多方面探讨IFN-γ对肺癌CSC生物学特性的调控及机制，为揭示肺癌进展机制和开发更具有针对性的治疗靶点提供新思路。

IFN-γ通常被认为是一种炎症细胞因子，在抗肿瘤免疫中起着核心作用。尽管它已被临床用于治疗多种恶性肿瘤，但肿瘤微环境(TME)中低水平的IFN-γ会增加免疫治疗期间肿瘤转移的风险。越来越多的证据表明IFN-γ可以诱导癌症进展，但IFN-γ在肿瘤发展中有争议的作用的机制尚不清楚。在这里，我们揭示了IFN-γ在诱导肿瘤干性以加速各种类型癌症患者的癌症进展方面的剂量依赖效应。低水平的IFN-γ通过细胞间粘附分子-1(ICAM1)-PI3K-AKt-Notch1轴赋予肿瘤干细胞样特性，而高水平的IFN-γ激活JAK1-STAT1-caspase通路诱导非小细胞肺癌(NSCLC)细胞凋亡。在体外和体内实验中，ICAM1的抑制消除了低剂量IFN-γ诱导的NSCLC细胞的干细胞样特性。这项研究揭示了低水平的IFN-γ在赋予肿瘤干性中的作用，并阐明了IFN-γ以剂量依赖的方式激活的不同信号通路，从而为癌症治疗提供了新的见解，特别是对于TME中IFN-γ低表达的患者。