抑制TGF-β/IL-6/JAK2/Stat3信号通路对肌纤维母细胞促进肺癌生长的影响

Tumor microenviroment myofibroblasts(MFs) play an important role in the development and progression of lung cancer. However, it is still unclear how MFs interact with tumor cells and affect their growth. Our previous studies found that in the tumor microenvironment, MFs secreted IL-6 which had the ability to promote lung cancer cell proliferation by activating the JAK2/Stat3 signaling pathway. The lung cancer cells secreted transformation growth factor-β (TGF-β) which activated MFs, resulting in inducing MFs to secret more IL-6. These findings indicate the key role of "TGF-β/IL-6/JAK2/Stat3" signaling pathway on the interactions between MFs and lung cancer cells, but the mechanisms are still unclear. To futher characterize the role of this TGF-β and IL-6/JAK2/Stat3 signaling pathway in promoting lung cancer growth by MFs, we propose to generate IL-6 receptor gene stable knock down lung cancer cells and TGF-β receptor gene stable knock down MFs and investigate the effects of the blockage of different signaling molecules of this signaling pathway loop on the interactions between MFs and lung cancer cells and tumor biological properties in vitro and in vivo. Our study will demontrate that TGF-β/IL-6/JAK2/Stat3 signaling pathway plays critical role in mediating the interactions of lung cancer cells with MFs and that targeting this signaling pathway loop will be a new approach for lung cancer therapy.

肿瘤微环境中肌纤维母细胞（MFs）在肿瘤发生发展中起重要作用，但MFs如何影响肿瘤细胞的生长及其相互作用机制尚不清楚。我们前期研究发现，MFs能分泌IL-6，激活肺癌细胞JAK2/Stat3通路，促进其增殖；而肺癌细胞分泌TGF-β激活MFs，使其分泌高水平IL-6；显示TGF-β和IL-6/ JAK2/Stat3信号通路可能介导了MFs与肺癌细胞的相互作用，但其机制仍不明了。为进一步研究该信号通路在MFs促进肺癌生长的作用和探讨阻断该信号通路对MFs促进肺癌生长的影响，本项目通过建立TGF-β受体基因静默的MFs和IL-6受体基因静默的肺癌细胞，采用肺癌细胞和MFs共培养体系和裸鼠移植瘤模型，研究抑制该信号通路不同环节对肺癌细胞和MFs相互作用及肺癌细胞生物学行为的影响；并研究该通路的特异性抑制剂体内抑制MFs促进肺癌生长的作用，从而为肺癌靶向治疗提供新策略。

肿瘤微环境中肌纤维母细胞（MFs）在肿瘤发生发展中起重要作用，TGF-β和IL-6/JAK2/Stat3信号通路可能介导了MFs与肺癌细胞的相互作用，但其机制仍不明了。本项目采用肺癌细胞和MFs共培养体系和裸鼠移植瘤模型，研究抑制该信号通路对肺癌细胞和MFs相互作用及肺癌细胞生物学行为的影响；并研究该通路的特异性抑制剂体内抑制MFs促进肺癌生长的作用。结果发现①应用JAK2特异性抑制剂阻断IL-6/JAK2/Stat3信号通路，能够抑制MFs对肺癌细胞生物学行为的影响和减少肺癌细胞表达TGF-β，表明MFs通过IL-6促进肺癌生长；②应用TGF-β受体特异性抑制剂阻断TGF-β信号，能够抑制肺癌细胞对MFs的激活作用和细胞因子的分泌，表明肺癌细胞分泌的TGF-β是激活MFs的关键因子；③在JAK2水平和TGF-β受体水平阻断该信号通路，能够对MFs促进体内移植瘤生长起到抑制作用。这些实验结果初步为肺癌靶向治疗提供了新的实验依据。