MCT1蛋白甲基化调节巨噬细胞极化促进结肠癌侵袭转移的研究

侵袭转移是影响结肠癌治疗疗效和预后的关键影响因素，M2型肿瘤相关巨噬细胞在结肠癌侵袭转移中发挥重要调控作用。研究表明，肿瘤细胞分泌的乳酸能够诱导巨噬细胞向M2型极化。本研究立足于前期研究提出科学假说：肿瘤细胞内乳酸转运蛋白MCT1能够发生甲基化，增强其乳酸转运功能，增加结肠癌中M2型巨噬细胞的富集，从而促进结肠癌的侵袭转移。本课题拟通过临床样本分析、体外细胞实验、模式动物研究等方法，重点阐述MCT1蛋白甲基化在其乳酸转运功能调控中的作用，明确介导MCT1蛋白甲基化的甲基转移酶，探索MCT1蛋白甲基化诱导结肠癌微环境中M2型巨噬细胞富集的分子机制，利用小分子短肽特异性抑制MCT1蛋白甲基化进而抑制结肠癌细胞乳酸释放，以减少结肠癌微环境中的M2型巨噬细胞富集，重塑结肠癌微环境，达到干预结肠癌侵袭转移的目的。研究可望丰富结肠癌侵袭转移的调控理论，为干预结肠癌侵袭转移提供靶点和策略。

Invasion and metastasis are the key influencing factors on the therapeutic effect and prognosis of colon cancer. M2 tumor-associated macrophages play an important regulatory role in colon cancer invasion and metastasis.Studies have shown that lactate secreted by tumor cells can induce macrophages to polarize to M2 type.Based on previous research, this study proposes a scientific hypothesis: MCT1, a lactate transporter in tumor cells, can undergo methylation and enhance its lactate transport function, thereby affecting the enrichment of M2-type tumor-associated macrophages in colon cancer and promoting the invasion and metastasis of colon cancer.This project intends to focus on the role of MCT1 protein methylation in the regulation of its lactate transporter function through clinical sample analysis, in vitro cell experiments and animal model research, identify methyl-transferase mediated MCT1 protein methylation, explore the molecular mechanism of enrichment of M2 macrophages in colon cancer microenvironment induced by methylation of MCT1 protein, and make use of specificity of small molecular peptides to inhibit the MCT1 protein methylation for the purpose of inhibiting colon cancer cell lactate release, thus reducing the M2 macrophages enrichment in colon cancer microenvironment, reshaping the colon cancer microenvironment, and achieving the goal of intervention in invasion and metastasis of colon cancer.The research is expected to enrich the regulation theory of colon cancer invasion and metastasis, and provide targets and strategies for intervention of colon cancer invasion and metastasis.