The TPL2 kinase is a suppressor of lung carcinogenesis

Aristides Eliopoulos ¹ Katerina Gkirtzimanaki ¹ Kalliopi Gkouskou ¹ George Nikolaidis ² Michalis Liontos ³ Vassiliki Pelekanou ⁴ Dimitris Kanellis ¹ Efstathios Stathopoulos ⁴ John Field ² Philip Tsichlis ⁵ Vassilis Gorgoulis ³ Triantafillos Liloglou ²

¹Molecular & Cellular Biology Laboratory, University of Crete Medical School, Heraklion
²Department of Molecular & Clinical Cancer Medicine, University of Liverpool, Liverpool
³Department of Histology and Embryology, National & Kaposidtrian University of Athens Medical School, Athens
⁴Department of Pathology, University of Crete Medical School, Heraklion
⁵Molecular Oncology Research Institute, Tufts Medical Center, Boston

TPL2 is a MAP3 kinase widely recognized for its prominent role in inflammatory signal transduction but its function in malignancy remains enigmatic. Here we report that TPL2 expression is suppressed in human lung cancer as a result of diverse genetic and epigenetic aberrations, including allelic imbalance at the TPL2 locus, upregulation of miR-370 which targets TPL2 transcripts and activated RAS signaling. Low TPL2 levels correlate with reduced lung cancer patient survival and ablation of the TPL2 gene in mice accelerates the onset and multiplicity of urethane-induced lung tumorigenesis. Mechanistically, TPL2 was found to antagonize oncogene-induced cell transformation and survival through a pathway involving p53 downstream of JNK and to be required for optimal p53 response to genotoxic stress. These results identify multiple oncogenic pathways leading to TPL2 deregulation and highlight its major tumor-suppressing function in the lung.