TRIM21 Is Decreased in Colitis-associated Cancer and Negatively Regulates Epithelial Carcinogenesis
TRIM21 Is Decreased in Colitis-associated Cancer and Negatively Regulates Epithelial Carcinogenesis
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TRIM21 在结肠炎相关癌症中减少并负向调节上皮癌发生
DOI：
10.1093/ibd/izaa229
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发表时间：
2021-03-15
影响因子：
4.9
通讯作者：
Liu, Zhanju
中科院分区：
文献类型：
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作者：
Zhou, Guangxi;Wu, Huili;Liu, Zhanju
背景 据报道，含三联基序 (TRIM)21 与肠粘膜免疫反应的调节有关。在这里，我们研究了 TRIM21 在结肠炎相关癌症 (CAC) 发病机制中的潜在机制。方法通过免疫组织化学和实时聚合酶链反应分析结直肠癌（CRC）和溃疡性结肠炎（UC）相关癌症患者肿瘤组织中TRIM21的表达，并通过氧化偶氮甲烷（AOM）和葡聚糖硫酸钠（DSS）在TRIM21-/-和野生型小鼠中建立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、粘附、组织重塑和血管生成以及炎症细胞因子的相关基因表达。结果发现，与对照组相比，CRC 和 UC 相关癌症患者的肿瘤组织中 TRIM21 的表达降低，TRIM21-/- 缺陷促进了 AOM/DSS 诱导的 CAC，其特征是 TRIM21-/- 小鼠体重减轻更多和多发大结肠肿瘤。此外，肿瘤细胞增殖（例如Ki67）、组织重塑和血管生成（例如MMP10、HIF1-α、COX2、Ang4）和促炎细胞因子（例如IL-6、TNF-α、IL-1β）的相关基因表达显着上调，而肿瘤细胞粘附（E-钙粘蛋白）和炎性细胞因子（例如IL-10、TGF-β、Foxp3、与对照组相比，TRIM21(-/-)小鼠的肿瘤组织中IFN-gamma)下调。结论 TRIM21 在结肠炎相关癌症中减少，并通过调节上皮细胞增殖、粘附、组织重塑和血管生成以及促炎反应来负向调节肠上皮癌发生。因此，TRIM21可能作为CAC治疗的新治疗靶点。
Background 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). Methods 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. Results 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-alpha, COX2, Ang4), and pro-inflammatory cytokines (eg, IL-6, TNF-alpha, IL-1 beta) markedly upregulated, whereas associated gene expression of tumor cell adhesion (E-cadherin) and inflammatory cytokines (eg, IL-10, TGF-beta, Foxp3, IFN-gamma) downregulated in tumor tissues from TRIM21(-/-) mice compared with controls. Conclusions 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.