Abstract
Lung cancer is a heterogeneous disease at both clinical and molecular levels, posing conceptual and practical bottlenecks in defining key pathways affecting its initiation and progression. Molecules with a central role in lung carcinogenesis are likely to be targeted by multiple deregulated pathways and may have prognostic, predictive, and/or therapeutic value. Here, we report that Tumor Progression Locus 2 (TPL2), a kinase implicated in the regulation of innate and adaptive immune responses, fulfils a role as a suppressor of lung carcinogenesis and is subject to diverse genetic and epigenetic aberrations in lung cancer patients. We show that allelic imbalance at the TPL2 locus, up-regulation of microRNA-370, which targets TPL2 transcripts, and activated RAS (rat sarcoma) signaling may result in down-regulation of TPL2 expression. Low TPL2 levels correlate with reduced lung cancer patient survival and accelerated onset and multiplicity of urethane-induced lung tumors in mice. Mechanistically, TPL2 was found to antagonize oncogene-induced cell transformation and survival through a pathway involving p53 downstream of cJun N-terminal kinase (JNK) and 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.
Original language | English |
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Pages (from-to) | E1470-9 |
Journal | Proceedings of the National Academy of Sciences of the United States of America |
Volume | 110 |
Issue number | 16 |
DOIs | |
Publication status | Published - 16 Apr 2013 |
Keywords
- Animals
- Base Sequence
- Cell Transformation, Neoplastic/genetics
- DNA Methylation
- DNA Mutational Analysis
- DNA Primers/genetics
- Flow Cytometry
- Gene Expression Regulation, Neoplastic/immunology
- Humans
- Immunoblotting
- Lung Neoplasms/immunology
- MAP Kinase Kinase Kinases/genetics
- Mice
- MicroRNAs/metabolism
- Molecular Sequence Data
- Polymerase Chain Reaction
- Proto-Oncogene Proteins/genetics
- Sequence Analysis, DNA
- ras Proteins/metabolism