CHI3L1通过PI3K/AKT/mTOR信号通路调节髓源抑制性细胞在肺癌发展及转移过程中的作用

It is well known that IL-6/Stat3 signaling pathway is the important mechanism linking chronic pulmonary inflammation to lung cancer. As Stat3 and downstream genes were studied further, we found that Chitinase 3-like 1(CHI3L1) was expressed on lung cancer cells and macrophages surround those cancer cells, and was revealed as one diagnostic biomarker for early detection of lung cancer. The preliminary data demonstrated that CHI3L1 promoted the growth and immune suppressor function of Myeloid-Derived Suppressor Cells (MDSCs), which infiltration played important roles in the development of lung chronic inflammation into lung cancer. In the project, we will investigate that CHI3L1 promotes the pathologic growth and suppression function of MDSCs and the function of MDSCs on the conversion of T effector cells (Teff) into regulatory T cells (Treg), and regulates MDSC-mediated metastasis of cancer cells and tumor angiogenesis by activating PI3K/ AKT/mTOR signaling pathways, using transgenic mouse tumor models and tumor metastasis models and samples from lung cancer patients. The correlations between the distribution of CHI3L1 positive MDSCs and clinico-pathologic factors among lung cancer tissue samples will be investigated further. The results are expected to provide new theoretical basis for the prevention and treatment of lung cancer.

前期研究证实IL-6/stat3信号通路为肺慢性炎症发展到肺癌的重要机制。在此基础上，我们进一步研究了stat3及其下游基因，发现几丁质酶3样蛋白1 (CHI3L1)表达在肺癌细胞及癌周巨噬细胞，可以作为肺腺癌的早期诊断标志。预实验结果显示在以髓源抑制性细胞（MDSCs) 侵润为主的肺慢性炎症到肺癌的慢性发展过程中，CHI3L1促进MDSCs的增殖及免疫抑制功能。本课题拟采用小鼠转基因肿瘤模型、小鼠肿瘤转移模型及肺癌患者样本，研究CHI3L1激活PI3K/AKT/mTOR信号通路促进MDSCs的病理性扩增，扩增的MDSCs一方面通过促进效应T细胞向Treg转换，加强MDSCs对机体免疫抑制能力；另一方面通过促进肿瘤血管形成和增强肿瘤细胞侵袭性，促进肺癌的发展和转移的机制。分析肺癌患者肺癌组织内的CHI3L1+MDSCs与临床病理参数之间的相关性。为肺癌的预防和阻断治疗提供理论基础。

本课题采用动物肿瘤模型、肿瘤转移模型及肺癌患者样本，通过siRNA干扰、抗体阻断等技术，研究CHI3L1激活PI3K/AKT/mTOR信号通路促进MDSCs的病理性扩增、肿瘤免疫抑制，调节MDSCs介导肺肿瘤转移及对调节性T细胞的作用。我们发现体外用CHI3L1抗体阻断CHI3L1在分离自荷瘤小鼠的MDSCs的表达，能够抑制MDSCs的增殖，增加MDSCs的凋亡， 并且对 T 细胞的免疫抑制功能明显弱于IgG 对照组的MDSCs, 实验组的T 细胞活性则相对增强, 同时减少MDSCs所介导的肿瘤转移。 Western blotting结果显示CHI3L1 激活 MDSCs的AKT/mTOR信号分子；如果体外用PI3K siRNA、AKT siRNA 或Rapamycin (mTOR 阻断化合物) 阻断AKT 和mTOR表达，则CHI3L1不能调节MDSCs的功能。利用多因素相关统计学方法分析肺癌患者的CHI3L1+MDSCs与临床肿瘤病理参数之间的相关性。我们的结果显示，HI3L1、PI3K、Akt、mTOR在非小细胞肺癌组织中的表达明显高于癌旁正常组织，其表达水平与肺癌分化程度、临床分期及淋巴结转移有显著相关性。CHI3L1与Akt1、PIK3CA、mTOR三者在MDSCs和肿瘤细胞的表达水平呈现显著相关性。这些结果初步证明了CHI3L1 通过PI3K/AKT/mTOR 信号通路调节肿瘤MDSCs的增殖和免疫抑制功能。