Premium
Emerging regulatory roles of Wnt1 in host‐pathogen interactions in inflammation and colon cancer
Author(s) -
Liu Xingyin,
Chen Hongshan,
Zhang Yongguo,
Lu Rong,
Liu Qisha,
Sun Jun
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1019.1
Subject(s) - wnt signaling pathway , salmonella , secretion , biology , inflammation , cancer , microbiology and biotechnology , cancer research , immunology , signal transduction , bacteria , biochemistry , genetics
Salmonella infection is a major public health concern and colonization in humans can be chronic as carrier state. The Wnt signaling plays an essential role in gastrointestinal epithelial proliferation. Our previous studies have demonstrated that both Wnt2 and Wnt1 protein secretion in epithelial cells were elevated after bacterial infection (Liu et al., 2011 and 2012). Bacteria modulate the host by injecting bacterial effectors to the host cells. AvrA is a Salmonella protein that is transported into intestinal epithelial cells by a type 3 secretion system. Our own studies, as well as those of other investigators, have demonstrated that AvrA influences eukaryotic cell pathways by altering ubiquitination and acetylation of target proteins to modulate inflammation, epithelial apoptosis and proliferation. Deubiquitination properties of AvrA leads to upregulation of the Wnt/beta‐catenin signaling pathway, which is critical in initiation of colon cancer. In the current study, we report that Wnt1 plays a role in infection and colon cancer. Different from the bacteria‐induced increase of Wnt2 and Wnt11, pathogenic Salmonella colonization significantly reduces the level of Wnt1 in intestinal epithelial cells in vivo and in vitro . We observed that Wnt1 expression level were down‐regulated by Salmonella infection, but stabilized under AvrA‐deficient Salmonella iin the intestine of Salmonella ‐colitis mice. In a chronic Salmonella infected cancer model, the wnt1 protein level is decreased in AvrA+ infected group, consistent with our observation in the Salmonella ‐colitis animal model. Furthermore, we assess the functional role of down‐regulation of Wnt1 in the inflammatory response and colon cancer progression. We found that Wnt1 is involved in the regulation of inflammatory pathway in Salmonella ‐epithelia cell interaction. Moreover, down‐regulation Wnt1 promotes cancer cell invasion and migration. Interestingly, we found the Wnt1 is down‐regulated in colon cancer patients, which is correlated with colon cancer progression. The results suggest Salmonella effector AvrA and Wnt1 may functionally interrelate in the development of colon cancer. Growing interest and accumulating data on human microbiota implicate that host‐microbe interplay has an important role in the development of colon cancer. A recent study reported that antibody against Salmonella flagellin was higher in colorectal cancer and pre‐cancer cases than controls in two distinct populations in US and the Netherlands and that dietary intake is the one of the mediating factors, suggesting a potential link of Salmonella to colorectal cancer. Our study provides novel insights into mechanisms by which the bacteria effector regulates Wnt1 expression and potential contributes to infectious‐associated colon cancer. Support or Funding Information Starting package of Nanjing Medical University to Xingyin Liu and NIH R01 to Jun Sun