TRIM21 Is Decreased in Colitis-associated Cancer and Negatively Regulates Epithelial Carcinogenesis

Abstract

Abstract 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-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. 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.