Zhou Guangxi, Wu Huili, Lin Jian, Lin Ritian, Feng Baisui, Liu Zhanju
Department of Gastroenterology, The Shanghai Tenth People's Hospital of Tongji University, Shanghai, China.
Department of Gastroenterology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, China.
Inflamm Bowel Dis. 2021 Mar 15;27(4):458-468. doi: 10.1093/ibd/izaa229.
Tripartite motif-containing (TRIM)21 is reported to be associated with the regulation of immune response in gut mucosa. Here we studied the underlying mechanisms of TRIM21 in the pathogenesis of colitis-associated cancer (CAC).
We analyzed TRIM21 expression in tumor tissues from patients with colorectal cancer (CRC) and ulcerative colitis (UC)-associated cancer by immunohistochemistry and real-time polymerase chain reaction and established a CAC model in TRIM21-∕- and wild type mice by azoxymethane (AOM) and dextran sodium sulfate (DSS). Associated gene expression of tumor cell proliferation, adhesion, tissue remodeling and angiogenesis, and inflammatory cytokines were examined in normal colon and CAC by immunohistochemistry and real-time polymerase chain reaction.
Expression of TRIM21 was found to be decreased in tumor tissues from patients with CRC and UC-associated cancer than that in controls, and TRIM21-∕- deficiency promoted AOM/DSS-induced CAC, characterized by more weight loss and multiple, large colon tumors in TRIM21-∕- mice. Moreover, associated gene expression of tumor cell proliferation (eg, Ki67), tissue remodeling and angiogenesis (eg, MMP10, HIF1-α, COX2, Ang4), and pro-inflammatory cytokines (eg, IL-6, TNF-α, IL-1β) markedly upregulated, whereas associated gene expression of tumor cell adhesion (E-cadherin) and inflammatory cytokines (eg, IL-10, TGF-β, Foxp3, IFN-γ) downregulated in tumor tissues from TRIM21-/- mice compared with controls.
TRIM21 is decreased in colitis-associated cancer and negatively regulates intestinal epithelial carcinogenesis by modulating epithelial cell proliferation, adhesion, tissue remodeling and angiogenesis, and pro-inflammatory responses. Therefore, TRIM21 may serve as a novel therapeutic target for CAC therapy.
据报道，含三联基序蛋白（TRIM）21与肠道黏膜免疫反应的调节有关。在此，我们研究了TRIM21在结肠炎相关癌（CAC）发病机制中的潜在机制。
我们通过免疫组织化学和实时聚合酶链反应分析了结直肠癌（CRC）和溃疡性结肠炎（UC）相关癌患者肿瘤组织中TRIM21的表达，并通过氧化偶氮甲烷（AOM）和葡聚糖硫酸钠（DSS）在TRIM21基因敲除小鼠和野生型小鼠中建立了CAC模型。通过免疫组织化学和实时聚合酶链反应检测正常结肠和CAC中肿瘤细胞增殖、黏附、组织重塑和血管生成以及炎性细胞因子的相关基因表达。
发现CRC和UC相关癌患者肿瘤组织中TRIM21的表达低于对照组，TRIM21基因敲除促进了AOM/DSS诱导的CAC，其特征为TRIM21基因敲除小鼠体重减轻更多且出现多个大的结肠肿瘤。此外，与肿瘤细胞增殖（如Ki67）、组织重塑和血管生成（如基质金属蛋白酶10、缺氧诱导因子1-α、环氧化酶2、血管生成素4）以及促炎细胞因子（如白细胞介素-6、肿瘤坏死因子-α、白细胞介素-1β）相关的基因表达明显上调，而与肿瘤细胞黏附（E-钙黏蛋白）和炎性细胞因子（如白细胞介素-10、转化生长因子-β、叉头框蛋白3、干扰素-γ）相关的基因表达在TRIM21基因敲除小鼠的肿瘤组织中与对照组相比下调。
TRIM21在结肠炎相关癌中表达降低，并通过调节上皮细胞增殖、黏附、组织重塑和血管生成以及促炎反应对肠道上皮癌变起负向调节作用。因此，TRIM21可能成为CAC治疗的新靶点。
