MARCH2调控内质网应激和自噬在结肠癌发生发展中的作用及机制

MARCH2 (Membrane-Associated RING-CH Protein 2) is a transmembrane protein with two transmembrane spans, mainly localized in endoplasmic reticulum. It participates in the transportation between the trans-Golgi network (TGN) and endosomes. Our study for the first time demonstrated that MARCH2 is a negative regulator of autophagy. On the one hand, this effect involves the activation of PIK3CA-AKT-MTOR signal pathway. On the other hand, it may be achieved through the interaction with CFTR to promote its functional inactivation. On the basis of previous work, we will explore the relationship between MARCH2-regulated ER stress and autophagy, or involved signal passways by gene transfection, CRISPR/Cas9-mediated genome editing and animal model.Furthermore,we will explore the role of MARCH2 in the occurrence and development of colon cancer. Finally, we will analysis the corelation between MARCH2 expression and clinicopathologic characteristics. This study is expected to make a breakthrough in the basic and applied research, and provide new ideas and methods for the prevention and treatment of ovarian cancer, which has important theoretical significance and application value.

MARCH2(Membrane-Associated RING-CH Protein 2，膜相关环指蛋白2)是定位于内质网的二次跨膜蛋白，参与高尔基体和内体之间的运输。我们首次发现了MARCH2是细胞自噬的负向调节分子，其效应的发挥一方面牵涉PIK3CA/AKT-MTOR信号通路的活化，另一方面可能是通过与CFTR相互作用，促进其功能失活而实现的。本课题在前期研究的基础上，利用基因转染、CRISPR/Cas9基因编辑技术以及动物模型，探讨MARCH2调控内质网应激与细胞自噬的关系，涉及的信号通路；进一步探讨MARCH2在结肠癌发生发展中的作用；分析MARCH2与结肠癌标本临床病理参数之间的相关性。该研究有望使MARCH2在基础与应用研究方面取得突破性的进展，同时为结肠癌的预防和治疗提供新的思路和途径，具有重要的理论意义和应用价值。

Membrane-associated RING-CH protein 2 (MARCH2)是MARCH家族成员之一，主要负责囊泡运输和自噬调节，本研究应用CRISPR/Cas9基因编辑技术构建了敲除MARCH2的HCT116细胞系，目的是为了研究MARCH2在体内、外对结肠癌的影响。沉默MARCH2可以抑制细胞增殖，促进自噬、凋亡和G2/M期细胞周期阻滞。这些效应与内质网应激的活化有关系，此外，沉默MARCH2可以增强HCT116细胞对化疗药物依托泊苷和顺铂的敏感性。而且，我们分析了MARCH2在100例人结肠癌组织中表达的临床意义，MARCH2高表达与恶性度更高的临床病理参数和不良预后密切相关。MARCH2表达与非折叠蛋白反应分子p-PERK呈负相关。总之，这些数据揭示了MARCH2与内质网应激和结肠癌之间的相关性，表明MARCH2在结肠癌的发生、发展中发挥重要作用。.本研究使MARCH2在基础与应用研究方面取得了较大进展，同时为结肠癌的预防和治疗提供新的思路和途径，具有重要的理论意义和应用价值。