模式识别受体MDA5调节结直肠癌的作用及机制研究

炎症是结直肠癌(CRC)发病的公认危险因子，模式识别受体(PRRs)对炎症发生和调节至关重要。MDA5是识别RNA的PRRs，在抗病毒感染中很重要，最近发现其也可调控癌症的发生，可能与MDA5-MAVS-TBK1-IRF3/7信号通路激活I型干扰素有关，但具体机制不清，特别是MDA5在CRC中的作用还未知。我们的预数据发现MDA5的表达在人和小鼠CRC组织中显著性下降，且MDA5缺陷小鼠对结肠炎易感，提示其可能抑制炎症相关性CRC的发生。我们将研究MDA5表达和CRC患者肿瘤病理分级的相关性及其临床意义，过表达和干扰MDA5及相关信号通路分子研究其对肠癌细胞增殖、迁移、侵袭和凋亡的影响，使用MDA5缺陷小鼠研究MDA5对炎症相关性CRC的抑制作用，并探讨抑制作用与I型干扰素及其信号通路的关系。研究MDA5在CRC中的作用对寻找新的、可靠的CRC诊断和治疗靶标具有重要意义。

Inflammation is well recognized as a risk factor for colorectal cancer (CRC) and pattern recognition receptors (PRRs) are critical for inflammation initiation and regulation. MDA5 are one of RNA-sensing PRRs, and is critical for host defense against viral infection. Recent evidences suggest that MDA5 can control tumor development possibly through the activation of Type I interferons by MDA5-MAVS-TBK1-IRF3/7 signaling pathway, but the specific mechanism is not clear. Furthermore, the role of MDA5 in CRC is unknown. Our preliminary experiments found that the expression of MDA5 was significantly reduced in human and mouse CRC tissues, and MDA5 deficient mice were susceptible to colitis, suggesting that it may inhibit colitis-associated CRC. In this project we will study the relationship between the MDA5 expression of CRC and tumor pathological classification and its clinical significance; the effect of overexpression and silence of MDA5 and its downstream molecules on the proliferation, migration, invasion, and apoptosis of CRC cells. Furthermore, we will confirm the in vivo inhibitory effect of MDA5 on CRC and investigate the relationship between this inhibitory effect and Type I interferons and related signaling pathway. This study is of great significance in the search for a new and reliable diagnostic and therapeutic target for the treatment of CRC.