Loss of tumor progression locus 2 (tpl2) enhances tumorigenesis and inflammation in two-stage skin carcinogenesis

K. L. Decicco-Skinner, E. L. Trovato, J. K. Simmons, P. K. Lepage, J. S. Wiest

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

Tumor progression locus 2 (Tpl2) is a serine/threonine kinase in the mitogen-activated protein kinase signal transduction cascade known to regulate inflammatory pathways. Previously identified as an oncogene, its mutation or overexpression is reported in a variety of human cancers. To address its role in skin carcinogenesis, Tpl2-/- or wild-type (WT) C57BL/6 mice were subjected to a two-stage dimethylbenzanthracene/12-O-tetradecanoylphorbol-13- acetate (TPA) mouse skin carcinogenesis model. Tpl2-/- mice developed a significantly higher incidence of tumors (80%) than WT mice (17%), as well as a reduced tumor latency and a significantly higher number of total tumors (113 vs 6). Moreover, Tpl2-/- mice treated with TPA experienced significantly higher nuclear factor kappaB (NF-B) activation, edema, infiltrating neutrophils and production of proinflammatory cytokines than did WT mice. We investigated the role of the p38, JNK, MEK and NF-B signaling pathways both in vitro and in vivo in WT and Tpl2-/- mice by using inhibitors for each of these pathways. We confirmed that the proinflammatory effect in Tpl2-/- mice was due to heightened activity of the NF-B pathway. These studies indicate that Tpl2 may serve more as a tumor suppressor than as an oncogene in chemically induced skin carcinogenesis, with its absence contributing to both tumorigenesis and inflammation.

Original languageEnglish (US)
Pages (from-to)389-397
Number of pages9
JournalOncogene
Volume30
Issue number4
DOIs
StatePublished - Jan 27 2011
Externally publishedYes

Keywords

  • MAP3K8
  • NF-κB
  • Tpl2
  • inflammation
  • skin cancer

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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