Linking inflammation and tumorigenesis in TPL2 deficient mice: COX-2 and the EP receptors

Skin cancer is the most prevalent form of cancer in the United States and inflammation is believed to be an important element for skin tumorigenesis. MAP3K8 (Tpl2 in mice) is a protein kinase in the MAPK inflammatory signaling pathway. Past studies have shown that mice lacking the Tpl2 gene (Tpl2-/- mice) have significantly higher tumor incidence and inflammation due to elevated levels of NF-kappaB. My thesis attempts to unveil a mechanism underlying increased inflammation and tumorigenesis as a result of higher NF-kappaB. COX-2, an enzyme necessary for prostaglandin production, shows altered expression in Tpl2-/- skin and squamous cell carcinomas, as does the PGE2 receptors, EP2 and EP4 in immunohistochemistry studies. Western blot analysis revealed differences in EP2 and EP4 expression between the C57Bl/6 wildtype and Tpl2-/- mouse primary keratinocytes. We also demonstrated through immunoassay that both PGE2 and cAMP, a downstream target of EP2 and EP4, levels were higher in Tpl2-/- skin. These experiments illustrate that COX-2 induction through NF-kappaB leads to an increase in PGE 2, EP2/EP4 and cAMP which turns on expression of COX-2 through CREB, thus creating a positive feedback loop and worsening inflammation, proliferation and angiogenesis.