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TSH signaling overcomes B-RafV600E-induced senescence in papillary thyroid carcinogenesis through regulation of DUSP6.

Authors
Kim, YH; Choi, YW; Han, JH; Lee, J; Soh, EY; Park, SH; Kim, JH; Park, TJ
Citation
Neoplasia (New York, N.Y.), 16(12):1107-1120, 2014
Journal Title
Neoplasia (New York, N.Y.)
ISSN
1522-80021476-5586
Abstract
B-RafV600E oncogene mutation occurs most commonly in papillary thyroid carcinoma (PTC) and is associated with tumor initiation. However, a genetic modification by B-RafV600E in thyrocytes results in oncogene-induced senescence (OIS). In the present study, we explored the factors involved in the senescence overcome program in PTC. First of all, we observed down-regulation of p-extracellular signal-regulated kinases 1/2 and up-regulation of dual specific phosphatase 6 (DUSP6) in the PTC with B-RafV600E mutation. DUSP6 overexpression in vitro induced extracellular signal-regulated kinases 1/2 dephosphorylation and inhibited B-RafV600E-induced senescence in thyrocytes. Although DUSP6 protein was degraded by B-RafV600E-induced reactive oxygen species (ROS), thyroid-stimulating hormone (TSH) stabilized DUSP6 protein by increasing Mn superoxide dismutase expression and inhibited B-RafV600E-induced senescence. Although serum TSH was not increased, its receptor was markedly upregulated in PTC with B-RafV600E. Furthermore, TSH together with DUSP6 reactivated Ras signaling, resulted in activation of Ras/AKT/glycogen synthase kinase 3β, and stabilized c-Myc protein by inhibiting its degradation. These observations led us to conclude that increased TSH signaling overcomes OIS and is essential for B-RafV600E-induced papillary thyroid carcinogenesis.
MeSH terms
Carcinoma/geneticsCarcinoma/metabolismCarcinoma/pathologyCell Aging/geneticsDual Specificity Phosphatase 6/geneticsDual Specificity Phosphatase 6/metabolismEnzyme-Linked Immunosorbent AssayHumansMitogen-Activated Protein Kinase 1/metabolismMitogen-Activated Protein Kinase 3/metabolismPhosphorylationPlasmids/geneticsPolymorphism, Restriction Fragment LengthProto-Oncogene Proteins B-raf/genetics*Proto-Oncogene Proteins B-raf/metabolismRNA InterferenceReactive Oxygen Species/metabolismReal-Time Polymerase Chain ReactionSequence Analysis, DNASignal Transduction/drug effectsThyroid Neoplasms/geneticsThyroid Neoplasms/metabolismThyroid Neoplasms/pathologyThyrotropin/bloodThyrotropin/pharmacologyUp-Regulation
DOI
10.1016/j.neo.2014.10.005
PMID
25499223
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Pathology
Journal Papers > School of Medicine / Graduate School of Medicine > Surgery
Journal Papers > School of Medicine / Graduate School of Medicine > Biochemistry & Molecular Biology
AJOU Authors
한, 재호이, 정훈소, 의영김, 장희박, 태준
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