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

<p>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.</p>