具有抗凋亡特性的N-RAS活化促进了炎症相关结肠癌的发生

Colon cancer is the third most common form of cancer and develops as a result of accumulation of genetic and epigenetic alterations. Individuals suffering from chronic gastrointestinal inflammation (e.g. Inflammatory bowel disease, IBD) are at high risk for developing colon cancer. Interestingly, different mechanisms are suggested for sporadic colon cancer and inflammation associated colon cancer. The pathogenesis of inflammation associated colon cancer has been poorly described as compared to sporadic colon cancer . ..N-RAS is one member of a family of onco-proteins that are commonly mutated in cancer. Activating mutations in N-RAS occur in a subset of colorectal cancers, but little is known about how the mutant protein contributes to onset and progression of the disease. We have found in our preliminary studies that NRAS activated mutation correlates with a less favorable clinical outcome for colon cancer patients. Frequency of N-RAS Mutation is higher in IBD and IBD associated colon cancer. our studies of genetically engineered mice indicated that N-RasG12D enhanced colon cancer development in the context of chronic inflammation. In addition, the pro-tumorigenic nature of mutant N-RAS is related to its anti-apoptotic function in vivo and in vitro. Above data demonstrate the important role that N-RAS plays in inflammation associated colon cancer. Presently, it is unclear if/how the anti-apoptotic phenotype associated with mutationally activated N-RAS contributes to the initiation and progression of inflammation associated colon cancer...Based on our preliminary studies of N-RAS function in mouse models and human cell lines, our driving hypothesis is that N-RAS is activated by Toll-like receptor agonist and activated N-RAS suppress apoptosis and promote proliferation, which ultimately results in tumorigenesis in the context of chronic inflammation...The ultimate goals of this study are (1) to understand how N-RAS is activated by TLR agonist and characterize cells harbored activated N-RAS including proliferation, clone formation, invasion and xenograft; (2) to decipher the complex network of downstream signals that mediate its anti-apoptotic and proliferation phenotype, and (3) to establish a connection between N-Ras, apoptosis, and inflammation-induced colon cancer using a mouse model of the disease...A better understanding of activated N-RAS will provide novel insights into the mechanisms of inflammation associated colon cancer pathogenesis and in the end may serve to shift paradigms relating to Ras signaling and tumorigenesis.

慢性感染是结肠癌发生的重要危险因素。感染性肠炎患者结肠癌的发病率是普通人群的10-40倍，死亡率高于其它类型结肠癌。与自发性结肠癌相比，炎症相关结肠癌研究甚少，机制不明。我们在前期研究中发现感染性肠病和炎症相关结肠癌中患者N-RAS变异频率高于自发性肿瘤；在体内外N-RAS活化可以抵抗细胞凋亡并促进炎症诱发结肠癌小鼠模型中肿瘤的发生。以上结果提示活化的N-RAS在炎症诱发结肠癌中起着重要作用。本课题拟证实N-RAS可以被肠道炎症中 TLR激动剂活化；通过体外培养RAS活化结肠上皮细胞，探索N-RAS促细胞增殖的信号传导通路；通过复制慢性肠炎小鼠模型，进一步明确N-RAS活化变异在肿瘤发生发展中的作用和机制。课题的研究结果将首次在分子水平阐明N-RAS促炎症相关肿瘤发生和发展中的作用机制，为该类型结肠癌提供早期诊断依据和药物作用的新靶点，也为炎症与原癌基因之间相互作用提供了新的依据。

慢性感染是结肠癌发生的重要危险因素。感染性肠炎患者结肠癌的发病率是普通人群的10-40倍，死亡率高于其它类型结肠癌。与自发性结肠癌相比，炎症相关结肠癌研究甚少，机制不明。我们在研究中发现感染性肠病和炎症相关结肠癌中患者N-RAS变异频率高于自发性肿瘤。在结直肠癌细胞中过表达活化的N-RAS可以活化MEK-ERK和IL-6-STAT3信号通路，并抑制抑制凋亡蛋白(IAP), 从而抵抗细胞凋亡。通过转基因技术在肠上皮细胞高表达活化N-RAS，在慢性肠炎小鼠模型中研究发现活化的N-Ras在抑制上皮细胞凋亡的同时，还能够上调免疫反应的负性调节蛋白PD-L1和PD-L2，从而在肿瘤局部造成免疫抑制的微环境。上述结果进一步明确N-RAS活化变异在肿瘤发生发展中的作用和机制。本课题的完成首次在分子水平阐明N-RAS促炎症相关肿瘤发生和发展中的作用机制，为该类型结肠癌提供早期诊断依据和药物作用的新靶点，也为炎症与原癌基因之间相互作用提供了新的依据。