Novel Regulatory Roles of Wnt1 in Infection-Associated Colorectal Cancer

Abstract

Salmonella infection is a major public health concern, and colonization in humans can be chronic and increases the risk of cancers. Wnt signaling is a key pathway for intestinal renewal and development, inflammation, and tumorigenesis. In the current study, we report a novel role of Wnt1 in infection and colon cancer using cell culture models, a Salmonella-colitis colon cancer model, and human samples. In contrast to the bacteria-induced increases in Wnt2 and Wnt11, Salmonella colonization significantly reduced the level of Wnt1 in intestinal epithelial cells in vivo and in vitro. The bacterial AvrA protein is known to activate the canonical Wnt pathway. Wnt1 expression level was downregulated by AvrA-expressing Salmonella but stabilized by AvrA-deficient Salmonella in the intestine of Salmonella-colitis mice. In a chronic Salmonella-infected cancer model, the Wnt1 protein level was decreased in the AvrA+ infected group. Thus, we further assessed the functional role of Wnt1 downregulation in the inflammatory response and colorectal cancer (CRC) progression. Moreover, downregulation of Wnt1 by the Crispr-Cas9 method promoted cancer cell invasion and migration. Interestingly, we found that Wnt1 was downregulated in human CRC tissue, and Wnt1 downregulation may be correlated with cancer progression. Our study provides insights into mechanisms by which enteric bacteria regulate Wnt1 expression and potentially contribute to infection-associated colon cancer.

Emerging Roles of Wnt Ligands in Human Colorectal Cancer

“…Moreover, the ectopic expression of microRNA (miR)-200b-3p and miR-185 could significantly inhibit the proliferation and induce the apoptosis of CRC cells by targeting the canonical Wnt1/β-catenin signaling ( 80 , 81 ). However, researches on the Wnt1 expression in human CRC tissues have yielded some conflicting results that the decrease or the increase of Wnt1 expression was detected in CRC tissues compared with normal colorectal mucosa ( 25 , 27 ), and a study even found that the expression level of Wnt1 was decreased in human CRC tissues and CRC mice, whereas Wnt1 knockdown could still dramatically decrease the cell migration and the invasion of human CRC cells, and β-catenin expression was also enhanced in the tumors, indicating that Wnt1 expression could be regulated by more complicated mechanisms during CRC tumorigenesis ( 82 ).…”

Wnt/β-Catenin Signaling as a Molecular Target by Pathogenic Bacteria

“…Wnt3, Wnt6, and Wnt9a, which are important ligands that modulate the activity of stem cell differentiation, were also upregulated in mouse intestinal epithelial cells (IECs) (13). Recently, another member of the Wnt family, Wnt1, was shown to be affected by S. enterica (32). Expression of Wnt1 was decreased by ubiquitination and degradation in the proteasome 26S.…”

In vivo Imaging of a Novel Strain of Bacteroides fragilis via Metabolic Labeling

“…( Deriu et al, 2013 ) Moreover, the ability of probiotics to colonize in intestine is considered to be a critical factor in immune regulation. ( Lebeer et al, 2010 ) Therefore, many in-vitro models have been established to examine the adhesion and colonization ability of bacteria in different tissues and cell lines including partial intestinal tissue resected from human, mucus isolated from feces, and ileostomy effluent and cells such as HT-29 and Caco-2 ( Ouwehand et al, 1995 ; Wang et al, 2018 ).…”