Vitamin D3 Upregulated Protein 1 Deficiency Promotes Azoxymethane/Dextran Sulfate Sodium-Induced Colorectal Carcinogenesis in Mice

TL;DR

This study shows that a deficiency in the VDUP1 protein worsens colon cancer development in mice with inflammatory bowel disease.

Contribution

The study reveals that VDUP1 acts as a tumor suppressor in colitis-associated colorectal cancer in mice.

Findings

VDUP1 deficiency increases colitis severity and tumor burden in a mouse model of colorectal cancer.

Loss of VDUP1 promotes cell proliferation and reduces apoptosis in tumor tissues.

VDUP1 deficiency elevates pro-inflammatory signaling pathways in colon tumors.

Abstract

Inflammatory bowel disease (IBD) increases the risk of developing colitis-associated colorectal cancer (CAC) compared to the general population. The specific genetic alterations associated with the onset of CAC are largely unknown. In this study, we investigated the role of vitamin D3 upregulated protein 1 (VDUP1) in a CAC mouse model. VDUP1 knockout (KO) increased the severity of colitis and CAC development. Our data suggest that VDUP1 may be explored as a potential therapeutic approach for CAC prevention.

VDUP1 acts as a tumor suppressor gene in various cancers. VDUP1 is expressed at low levels in sporadic and ulcerative-colitis-associated colorectal cancer. However, the effects of VDUP1 deficiency on CAC remain unclear. In this study, we found that VDUP1 deficiency promoted CAC development in mice. Wild-type (WT) and VDUP1 KO mice were used to investigate the role of VDUP1 in the development of azoxymethane (AOM)- and dextran sulfate sodium (DSS)-induced CAC. VDUP1 levels significantly decreased in the colonic tumor and adjacent nontumoral tissues of WT mice after AOM/DSS treatment. Moreover, AOM/DSS-treated VDUP1 KO mice exhibited a worse survival rate, disease activity index, and tumor burden than WT mice. VDUP1 deficiency significantly induced cell proliferation and anti-apoptosis in tumor tissues of VDUP1 KO mice compared to WT littermates. Additionally, mRNA levels of interleukin-6 and tumor necrosis factor-alpha and active forms of signal transducer and activator of transcription 3 and nuclear factor-kappa B p65 were significantly increased in the tumor tissues of VDUP1 KO mice. Overall, this study demonstrated that the loss of VDUP1 promoted AOM/DSS-induced colon tumorigenesis in mice, highlighting the potential of VDUP1-targeting strategies for colon cancer prevention and treatment.

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