Tumor Necrosis Factor Ligand-Related Molecule 1A Regulates the Occurrence of Colitis-Associated Colorectal Cancer

Background: Tumor necrosis factor ligand-related molecule 1 A (TLlA) is closely related to the occurrence and development of inflammatory bowel disease.

Aims: We aimed to explore whether TLlA was involved in the occurrence of colitis-associated colorectal Cancer (CAC).

Methods: Firstly, azoxymethane (AOM) and dextran sulfate sodium (DSS) were used to construct the CAC mice model in wild-type (WT) and TL1A transgenic (Tg) mice with TL1A high expression. The histopathological analysis was used for the evaluation of inflammation level, and the immunohistochemistry staining analysis was used to test the expression and location of proliferating cell nuclear antigen (PCNA) and β-catenin. Secondly, the HCT116 and HT29 cell lines were used for knockdown of TL1A gene for further assay including cell viability, cell clone, cell Apoptosis and matrigel invasion. Western blot were used for quantitative protein expression of β-catenin and downstream oncogenes including c-Myc and Cyclin D1 after knockdown of TL1A gene.

Results: The evaluation of inflammation level showed that the disease activity index score and tumor formation rate were significantly higher in AOM + DSS/Tg group than that in AOM + DSS/WT group. The expression of PCNA, β-catenin, c-Myc, and Cyclin D1 in AOM + DSS/Tg group was significantly higher than that in AOM + DSS/WT group. The cell experiment showed that TL1A knockdown inhibited the cell proliferation, invasion, and migration. Moreover, the expression of c-Myc and Cyclin D1 was significantly decreased after TL1A knockdown.

Conclusions: TL1A can induce tumor cell proliferation and promote the occurrence of CAC by activating Wnt/β-catenin pathway.