Altered Prostanoid Signaling Contributes to Increased Skin Tumorigenesis in Tpl2 Knockout Mice

Kathleen L. DeCicco-Skinner, Sabrina J. Nolan, Monika M. Deshpande, Erika L. Trovato, Taylor A. Dempsey, Jonathan S. Wiest

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


Squamous cell carcinoma is the second most common form of skin cancer with the incidence expected to double over the next 20 years. Inflammation is believed to be a critical component in skin cancer progression. Therefore, understanding genes involved in the regulation of inflammatory pathways is vital to the design of targeted therapies. Numerous studies show cyclooxygenases (COXs) play an essential role in inflammation-associated cancers. Tpl2 (MAP3K8) is a protein kinase in the MAP Kinase signal transduction cascade. Previous research using a two-stage skin carcinogenesis model revealed that Tpl2-/- mice have significantly higher tumor incidence and inflammatory response than wild-type (WT) controls. The current study investigates whether cyclooxygenase-2 (COX-2) and COX-2- regulated prostaglandins and prostaglandin receptors drive the highly tumorigenic state of Tpl2-/- mice by investigating the relationship between Tpl2 and COX-2. Keratinocytes from newborn WT or Tpl2-/- mice were treated with 12-O-tetradecanoylphorbol-13-acetate (TPA) for various times over 24 hours. Western analysis revealed significant differences in COX-2 and COX-2 dependent prostanoids and prostanoid receptors. Additionally, in vivo experiments confirmed that COX-2 and COX-2 downstream factors were elevated in TPA-treated Tpl2-/- skin, as well as in papillomas from Tpl2-/- mice. Use of the selective COX-2 inhibitor Celecoxib showed the increased tumorigenesis in the Tpl2-/- mice to primarily be mediated through COX-2. These experiments illustrate COX-2 induction in the absence of Tpl2 may be responsible for the increased tumorigenesis found in Tpl2-/- mice. Defining the relationship between Tpl2 and COX-2 may lead to new ways to downregulate COX-2 through the modulation of Tpl2.

Original languageEnglish (US)
Article numbere56212
JournalPloS one
Issue number2
StatePublished - Feb 15 2013
Externally publishedYes

ASJC Scopus subject areas

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