MCPIP1通过NF-κB途径对结直肠癌发生发展的影响及其分子机制

Colorectal cancer (CRC) is one of the most common cancers worldwide. Abnormal activation of the NF-κB signaling pathway is a pivotal reason for inflammation to malignant transformation, CRC development and progression. The MCPIP1 protein acts as a pro-apoptosis transcriptional activator as well as negatively modulates inflammatory responses. Up to date, MCPIP1 has been reported to be associated with several human cancers. In our previous study, down-expression of MCPIP1 is found in CRC tissues and predicts poor prognosis of CRC patients. Over-expression of MCPIP1 inhibits proliferation and migration of CRC cells, down-regulation of MCPIP1 behaves on the contrary, probably through K63-deubiquitination of TRAF6, leading to suppression of the NF-κB signaling pathway. However, the underlying mechanism of MCPIP1 function in CRC is not fully understood. In this study, we tent to investigate the mechanism and clinical significance of MCPIP1 down-expression, providing reference for using MCPIP1 as a diagnosis and prognosis prediction biomarker in CRC. Also, with molecular, cellular and animal model studies, we tent to unravel the effect of MCPIP1 on CRC development and progression and its underlying mechanism through NF-κB-dependent pathway, providing theoretical basis for inflammation modulation and translational research of inflammation to malignant transformation.

结直肠癌（Colorectal Cancer，CRC）是世界范围内最常见的肿瘤之一，NF-κB信号通路的异常活化是炎-癌转化及CRC发生发展的重要诱因。MCPIP1是一种促凋亡转录因子且具有抑制炎症反应的功能，已被发现与多种肿瘤关系密切。本项目前期研究发现MCPIP1在CRC组织中表达降低且与预后不良相关，过表达MCPIP1可抑制CRC细胞克隆形成和迁移的能力，敲降MCPIP1则表现相反，这可能是通过负调控TRAF6泛素化水平抑制NF-κB信号通路来实现的。但是MCPIP1在CRC中的作用其机制尚未完全阐明。本项目拟研究CRC中MCPIP1下调表达的机制及临床意义，为将MCPIP1作为CRC诊断和预后判断的标志物提供理论依据；拟从分子、细胞及动物模型上揭示MCPIP1通过NF-κB途径对CRC发生发展的影响及其机制，为炎症调控及炎-癌转化研究提供理论基础。

结直肠癌（Colorectal Cancer，CRC）是世界范围内最常见的肿瘤之一，本项目前期研究发现MCPIP1在CRC组织和细胞中可能扮演“抑癌”角色，但MCPIP1在CRC中的作用机制尚未完全阐明。本项目发现MCPIP1在CRC因为基因启动子普遍高度甲基化造成表达量降低，且为CRC病人不良预后因子。将MCPIP1作为CRC诊断和预后判断的标志物对于在临床决策中筛选复发、转移高危的患者，提前采用综合治疗有重要的临床实践指导意义。体外实验证实MCPIP1抑制CRC细胞克隆形成、增殖、迁移和侵袭，促进凋亡，并且能够抑制CRC细胞在体内的成瘤能力。具体来讲，MCPIP1是通过抑制NF-κB通路活性，阻碍下游基因转录启动，从而影响CRC细胞的增殖和迁移能力，而这种抑制是通过解除TRAF6的K63型泛素化而实现的，以上发现为今后临床肿瘤治疗提供了新的切入点。