小分子靶向UPF1激活免疫对抗转移性结直肠癌的作用机制研究

Although tumor immunotherapy achieved a great breakthrough, immunotherapy of metastatic colorectal cancer is still under a very severe situation. Our previous studies found that metastatic colorectal cancer cells could escape from NK cell-mediated killing by using themselves high activity of non-sense mediated mRNA decay (NMD), and highly expressed up-frameshift 1 (UPF1), a key factor of NMD pathway. Therefore, this study aims at UPF1 based on the characteristics of metastatic colorectal cancer cells and targets allosteric activation of UPF1 in order to inhibit NMD pathway, promote killing of metastatic colorectal cancer cells by immune cells such as NK cells, and build a new strategy for the immunotherapy of metastatic colorectal cancer. We aim to: 1) determine the high expression of UP1 in metastatic colorectal cancer cells and study the underlying mechanism; 2) identify key genes in NMD pathway and investigate the mechanism and effects of the NMD key genes on escaping immunosurveillance of metastatic colorectal cancer cells; 3) prove UPF1 as a drug target of anti-metastatic colorectal cancer therapy; 4) build up an activity analysis and drug screening system based on the allosteric activation of UPF1; 5) systematically investigate chemical biology characteristics and pharmacologic activity and mechanism of candidate compounds. Our study would lay the foundation for discovering new anti-metastatic colorectal cancer drugs.

肿瘤免疫疗法虽取得突破性进展，但针对转移性结直肠癌的免疫治疗仍面临严峻形势。我们的前期研究发现转移性结直肠癌细胞可利用自身高活力的无义介导的mRNA降解（NMD）信号逃避NK细胞的杀伤，并且高表达上游移码蛋白1（UPF1）—NMD信号的关键节点分子。为此，本项目基于前期发现的转移性结直肠癌的新特点，以高表达的UPF1为切入口，拟通过靶向UPF1的变构活化，抑制NMD信号，促进转移性结直肠癌细胞被NK等免疫细胞杀伤，进而建立转移性结直肠癌免疫治疗的新方法。包括：确证转移性结直肠癌细胞高表达UPF1，并探讨其高表达的分子机制；发现NMD的关键靶基因，并探讨其调控转移性结直肠癌细胞逃避免疫监视的机制；UPF1作为抗转移性结直肠癌的药物靶标属性的证实；建立基于UPF1变构活化的活性评价及药物筛选体系；系统探讨候选化合物的化学生物学特点及药理学活性与机制，为新型抗转移性结直肠癌药物的研制奠定基础。

肿瘤免疫疗法虽取得突破性进展，但针对转移性结直肠癌的免疫治疗仍具挑战。本项目围绕无义介导的mRNA降解（NMD）信号探究靶向UPF1激活免疫对抗转移性结直肠癌的作用及其机制。本研究首次发现并确证临床结肠癌转移灶中高表达UPF1蛋白，其机制为USP10通过去泛素化酶活性维持UPF1蛋白的稳定性；发现转移性结肠癌细胞通过增强NMD活性控制关键靶基因ICAM1以逃避NK细胞的杀伤作用；进一步建立了靶向UPF1抑制NMD的多层次活性评价体系，化合物9被筛选出可抑制NMD活力，小分子体内抑制NMD可降低结直肠癌转移灶的形成。本研究揭示了转移性结直肠癌通过劫持NMD信号逃避免疫监视的新病理机制，为转移性结直肠癌的治疗提供了新策略及新潜在药物。