DGKα-FAK轴介导食管鳞癌细胞调控巨噬细胞浸润和M2型极化促进肿瘤恶性进展的机制研究

Diacylglycerol kinase α (DGKα) has been verified to play a critical role in cancer malignant progression. However, these studies only paid attention to that DGKα influences characteristics of cancer cells themselves. Based on RNA-Seq and antibody arrays techniques, we recently found that overexpression of DGKα could effectively upregulate the expression of several cytokines, which induce macrophage migration and M2 polarization in ESCC cells. The in vitro data indicated that overexpression of DGKα induced macrophage migration and M2 polarization, which was independent of the direct action of DGKα-produced PA (phosphatidic acid) on macrophages. We have found that DGKα activates FAK (focal adhesion kinase) partially through producing PA. It has been widely accepted that FAK in cancer cells mediates recruitment and M2 polarization of macrophages. Taken together, we hypothesize that DGKα can promote malignant progression of ESCC through inducing infiltration and M2 polarization of macrophages via activating FAK and stimulating the expression and secretion of FAK-activated cytokines. Besides, we put forward a novel biological function that DGKα activates FAK, involving the direct interaction of DGKα with FERM domain of FAK to release the inhibition of FAK autophosphorylation independent of producing PA. This study will provide fundamental evidences for targeting the activity of DGKα and resultantly inhibiting the malignant progression of ESCC from the perspective of inflammatory microenvironment.

DGKα在肿瘤恶性进展中扮演重要角色，但相关研究主要集中于DGKα调控癌细胞本身特性。我们最近基于RNA-Seq及蛋白芯片技术，发现过表达DGKα可上调ESCC细胞中多个诱导巨噬细胞迁移及M2型极化的细胞因子的表达。细胞水平实验发现DGKα可诱导巨噬细胞迁移及M2型极化，该效应不是通过其产生的PA直接作用于巨噬细胞。我们以往发现DGKα可部分依赖其产生PA激活ESCC细胞中FAK。目前已知：FAK可介导癌细胞募集巨噬细胞并诱导其M2型极化。综上，我们提出如下假设：ESCC中DGKα可通过激活FAK促进相关细胞因子表达分泌，进而募集巨噬细胞并诱导其M2型极化，促进ESCC恶性进展。此外，我们首次提出DGKα一个新的生物学功能：不依赖PA产生，直接与FAK的FERM结构域相互结合以释放其自磷酸化抑制。本研究有望为临床从炎性微环境角度研发靶向DGKα抗ESCC恶性进展的治疗策略提供实验依据。

中国是食管鳞癌（ESCC）发病率和死亡率较高的国家之一。ESCC同其他实体瘤一样，恶性进展能力极强。近年来采取以手术为主的多学科综合治疗，新的化疗药物和局部治疗方法不断涌现，但对ESCC总体疗效却不尽人意。深入研究ESCC恶性进展的分子机制、寻找有效的干预靶点是提高ESCC总体疗效的关键。.. 项目负责人一直专注于ESCC领域的分子肿瘤学实验研究。在本项目实施过程中，我们严格按照制定的研究计划，围绕关键癌分子DGKα及NOX5调控肿瘤细胞/微环境互作，进而促进ESCC恶性进展的研究假设，进行了系统和创新研究，在科研产出等方面取得了较好的成果。.. 本项目主要研究内容为：发现癌分子DGKα及NOX5作为分子靶点，调控肿瘤细胞/微环境互作，进而促进ESCC恶性进展。.. 本项目的重要结果、关键数据：.1.DGKα/FAK轴作为重要分子靶点调控ESCC恶性进展；.2.NOX5调控ESCC恶性进展及癌/微环境互作。.. 本项目的科学意义：.本研究深入研究DGKα/FAK轴及NOX5通过调控癌/微环境互作，进而促进ESCC恶性进展，并探讨了DGKα/FAK轴作为治疗靶点的可行性。本项目为研究重要癌分子调控ESCC恶性进展的机制及其作为分子靶点的可行性提供了实验依据。