Abstract
Thyroid carcinomas that harbor RET/PTC oncogenes are well differentiated, relatively benign neoplasms compared with those expressing oncogenic RAS or BRAF mutations despite signaling through shared transforming pathways. A distinction, however, is that RET/PTCs induce immunostimulatory programs, suggesting that, in the case of this tumor type, the additional pro-inflammatory pathway reduces aggressiveness. Here, we demonstrate that pro-inflammatory programs are selectively activated by TRAF2 and TRAF6 association with RET/PTC oncoproteins. Eliminating this mechanism reduces pro-inflammatory cytokine production without decreasing transformation efficiency. Conversely, ablating MEK/ERK or PI3K/AKT signaling eliminates transformation but not pro-inflammatory cytokine secretion. Functional uncoupling of the two pathways demonstrates that intrinsic pro-inflammatory pathways are not required for cellular transformation and suggests a need for further investigation into the role inflammation plays in thyroid tumor progression.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Line, Tumor
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Humans
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Inflammation / genetics
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Inflammation / metabolism
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Inflammation / pathology
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MAP Kinase Signaling System*
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Mice
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Mitogen-Activated Protein Kinase Kinases / genetics
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Mitogen-Activated Protein Kinase Kinases / metabolism
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NIH 3T3 Cells
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Oncogene Proteins, Fusion / genetics
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Oncogene Proteins, Fusion / metabolism*
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / metabolism*
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Protein-Tyrosine Kinases / genetics
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Protein-Tyrosine Kinases / metabolism*
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Rats
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TNF Receptor-Associated Factor 2 / genetics
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TNF Receptor-Associated Factor 2 / metabolism*
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TNF Receptor-Associated Factor 3 / genetics
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TNF Receptor-Associated Factor 3 / metabolism*
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Thyroid Neoplasms / genetics
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Thyroid Neoplasms / metabolism*
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Thyroid Neoplasms / pathology
Substances
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Oncogene Proteins, Fusion
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TNF Receptor-Associated Factor 2
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TNF Receptor-Associated Factor 3
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Phosphatidylinositol 3-Kinases
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Protein-Tyrosine Kinases
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RET-PTC oncoprotein, rat
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ret-PTC fusion oncoproteins, human
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Mitogen-Activated Protein Kinase Kinases