Erbin介导MDM2调控p53泛素化降解在炎症相关结直肠癌发生中的新机制

Erbin is an important inflammatory regulatory factor, and is involved in the tumorigenesis of multiple cancers. We found that Erbin regulates EGFR signaling in colorectal cancer (J Pathol 2015) and participates in the development of hepatocellular carcinoma by ERa signaling (J Hepat 2017). However, the role of Erbin in the inflammation-related tumors, such as colitis-associated colorectal cancer, is unclear. Recently, we found that incidence rate of colitis-associated colorectal cancer was significantly reduced in Erbin gene deletion mice. At the same time, we observed that knockdown of Erbin causes upregulation of p53 expression and leads to cell mitosis G1 phase block, which may be related to Erbin regulate the ubiquitination of p53 protein through MDM2. Based on this, we suggest that Erbin promotes the tumorigenesis of colitis-associated colorectal cancer by mediating MDM2 to regulate promote ubiquitination of p53. In this study, we aimed mechanisms of Erbin in tumorigenesis of colitis-associated colorectal cancer by mediating MDM2 to promote ubiquitination of p53, using mice model of colitis-associated colorectal cancer, functional experiments in vitro and in vivo, protein interaction and ubiquitination experiments.

Erbin是一种重要的炎症调控因子，同时参与多种肿瘤的发生。前期我们发现，Erbin通过调控EGFR信号参与结肠癌（J Pathol 2015）、通过ERa信号参与肝细胞肝癌的发生（J Hepat 2017）。但它在炎症相关肿瘤如肠炎相关肠癌发生中的作用及机制不清。我们发现，Erbin基因缺失小鼠其炎症相关肠癌的发生明显下降；同时在细胞中我们观察到，Erbin敲降会引起p53表达上调并导致细胞有丝分裂G1期阻滞，这可能与Erbin通过MDM2调控p53蛋白的泛素化相关。基于此，我们提出，Erbin可通过介导MDM2调控p53泛素化降解促进炎症相关结直肠癌的发生。本研究拟通过Erbin基因修饰小鼠的肠炎相关肠癌模型，结合体内体外的功能试验、蛋白质相互作用及泛素化实验，进一步明确Erbin通过介导MDM2调控p53泛素化降解的效应及其机制，并明确其在炎症相关结直肠癌发生中的作用。

Erbin是一种重要的炎症调控因子，同时参与多种肿瘤的发生。但其在炎症相关肿瘤如肠炎相关肠癌发生中的作用及机制不清。通过Erbin基因缺失的小鼠炎症性肿瘤模型，我们证实Erbin缺失抑制炎症相关结直肠癌发生过程。同时，我们经细胞功能学研究证实Erbin介导MDM2调控p53抑制结直肠细胞凋亡。我们进一步通过CO-IP结合质谱分析，证实Erbin与E3泛素连接酶Trim21相互作用参与p53的调控。通过结直肠癌临床样品免疫组化检测、肿瘤功能学实验与Trim21基因敲除小鼠的炎症相关肠癌模型，我们明确了Trim21促进炎症相关肠癌的发生。稳定干扰Trim21能够抑制MDM2的表达，从而促进p53显著上调，进而活化p53下游凋亡靶基因BAX与PUMA，促进炎症诱导的细胞凋亡。我们的研究阐明了Erbin介导Trim21调控p53相关细胞凋亡在炎症相关肠癌进展中的作用。本研究进一步丰富了炎症相关性肠癌的分子机制，为进一步临床治疗提供有力的支撑。