期刊
ONCOGENE
卷 22, 期 29, 页码 4569-4577出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.onc.1206759
关键词
autoimmunity; inflammation; inflammatory cytokines; oncogene; RET/PTC; tumor antigen
资金
- NCI NIH HHS [CA-76259, T32-CA09678] Funding Source: Medline
Differentiated thyroid carcinomas are the most frequent endocrine neoplasms, but account for few cancer-related deaths. Although the indolent growth of these cancers correlates well with longevity, the biological basis for this good prognosis is not known. In contrast, two of the most frequent autoimmune diseases involve the thyroid suggesting a high propensity for this organ to invoke destructive immunity. Unfortunately, the mechanism linking malignancy and autoimmunity is not clear, although the expression of the oncogenic fusion protein RET/PTC3 (RP3) in both of these disorders may provide a clue. Interestingly, the signaling caused by activated RET kinase involves overlapping pathways and some common to the inflammatory response. Accordingly, we analyzed the function of RP3 and a mutant RP3 molecule to induce proinflammatory pathways in thyroid epithelial cells. Indeed, we find that RP3 alone causes increases in nuclear NF-kappaB activity and secretion of MCP-1 and GM-CSF. Finally, transfer of RP3-expressing thyrocytes into mice in vivo attracted dense macrophage infiltrates, which lead to rapid thyroid cell death. Further, cytokine synthesis and inflammation was largely abrogated by mutation of RP3 Tyr(588); an important protein-binding site for downstream signaling. Together, these studies implicate oncogene-induced cytokine-signaling pathways in a new mechanism linking inflammation with cancer.
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