胃癌微环境中巨噬细胞EGFR-PI3K-AKT通路影响SOCS-1表达及细胞M2型极化的机制研究

Tumor microenvironment plays an important role in tumorigenesis and tumor progression. Macrophages with M2 polarization produce various mediators in tumor microenvironment to promote tumor invasion, angiogenesis, immunosuppression, and epithelial to mesenchymal transition (EMT). It is well known that IL-4 stimulates the phosphorylation of STAT-6, thereby inducing the M2 polarization in macrophages. SOCS-1 can suppress the activation of STAT-6 and reduce M2 polarization in macrophages. Our preliminary data showed that IL-4 could transactivate EGFR through activation of MMP to release EGFR ligands, such as HB-EGF. However, distinct from that in tumor cells, transactivation of EGFR in macrophage stimulated the expression of SOCS-1, which in turn suppressed STAT-6 expression and M2 polarization, resulting in inhibited production of growth factors for gastric epithelial cell growth and EMT. Thus, we hypothesize that in macrophages, the express of SOCS-1 stimulated by EGFR through PI3K-AKT signaling pathway, which negatively regulates STAT-6 activation and M2 polarization. In this study, we will further elucidate the underlying molecular mechanisms of EGFR in regulation of SOCS-1 via IL-4, using cell line and mouse peritoneal macrophages. Furthermore, we will evaluate the association between EGFR/SOCS-1 levels in macrophages and the TNM stage as well as the overall survival of gastric cancer patients to establish a novel prognostic model based on the biomarkers from macrophages.

巨噬细胞的M2型极化对胃癌的进展起到促进作用。前期研究发现：巨噬细胞EGFR活化，可下调IL-4诱导的STAT-6磷酸化及细胞的M2型极化，最终抑制肿瘤增殖及转移；同时EGFR促进SOCS-1的表达，后者可抑制巨噬细胞M2型极化。巨噬细胞EGFR通过何种通路调控SOCS-1表达及其在实际肿瘤中的作用有待研究。因此提出假设：巨噬细胞内EGFR通过PI3K-AKT通路诱导SOCS-1表达；后者抑制STAT-6活化，进而下调细胞M2型极化及功能。本研究将分析胃癌标本中巨噬细胞上EGFR及SOCS-1表达及与预后的关系；以不同EGFR背景小鼠巨噬细胞为模型，体内外深入研究EGFR调控SOCS-1的分子机制，探讨其对肿瘤细胞增殖转移及西妥昔单抗疗效的影响。研究希望发现新的调控巨噬细胞极化的分子机制，揭示EGFR在肿瘤细胞及巨噬细胞上挥发的截然相反的作用，为新靶点药物的研发及个体化治疗提供理论基础。

巨噬细胞的M2型极化对胃癌的进展起到促进作用，本研究旨在探讨上皮细胞表皮因子受体（Epidermal Growth Factor Receptor，EGFR）在巨噬细胞及肿瘤细胞中发挥截然不同功能的具体分子机制，从而为探讨巨噬细胞表面EGFR 表达及活性作为胃癌药物治疗评价及临床预后预测标志物的可行性。研究结果提示：在IL-4诱导的巨噬细胞M2表型极化中，EGFR被IL-4激活后，可上调胞内Jak-2磷酸化水平，进而促进STAT-3入核并最终诱导SOCS-3表达；后者对IL-4/Jak-1/STAT-6诱导的巨噬细胞M2型极化发挥了负向调控作用。研究阐明IL-4在巨噬细胞中，除了经典的Jak-1/STAT-6/M2 polarization信号通路外；在EGFR介导下，可通过Jak-2/STAT-3上调SOCS-3表达，从而抑制巨噬细胞的M2表型极化。同时，研究发现炎症背景下巨噬细胞M1表型极化受2-岩藻糖基乳糖（2'-FL）所显著抑制，从而缓解了靶向抑制HER胞内酪氨酸激酶活性的吡咯替尼引发的消化道炎症及腹泻。上述研究揭示出巨噬细胞表面EGFR在其极化（M1及M2）过程中均发挥重要作用，这为后续完善靶向EGFR治疗提供了理论依据。