The
glutathione peroxidases, a family of
selenocysteine-containing redox
enzymes, play pivotal roles in balancing the signaling, immunomodulatory, and deleterious effects of
reactive oxygen species (ROS). The
glutathione peroxidase GPX3 is the only extracellular member of this family, suggesting it may defend cells against ROS in the extracellular environment. Notably, GPX3 hypermethylation and underexpression occur commonly in prostate, gastric, cervical, thyroid, and
colon cancers. We took a reverse genetics approach to investigate whether GPX3 would augment inflammatory colonic
tumorigenesis, a process characterized by oxidative stress and
inflammation, comparing Gpx3(-/-) mice in an established two-stage model of inflammatory colon
carcinogenesis. Gpx3-deficient mice exhibited an increased
tumor number, though not size, along with a higher degree of dysplasia. In addition, they exhibited increased
inflammation with redistribution toward protumorigenic M2 macrophage subsets, increased proliferation, hyperactive WNT signaling, and increased DNA damage. To determine the impact of acute gene loss in an established
colon cancer line, we silenced GPX3 in human Caco2 cells, resulting in increased ROS production, DNA damage and apoptosis in response to oxidative stress, combined with decreased contact-independent growth. Taken together, our results suggested an immunomodulatory role for GPX3 that limits the development of
colitis-associated
carcinoma.