title: TSH signaling overcomes B-RafV600E-induced senescence in papillary thyroid carcinogenesis through regulation of DUSP6.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, Suwon, South Korea; Department of Biomedical Sciences, Graduate School, Ajou University, Suwon, South Korea.
authors.forename: Young Hwa
authors.initials: YH
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, Suwon, South Korea; Department of Biomedical Sciences, Graduate School, Ajou University, Suwon, South Korea.
authors.forename: Yong Won
authors.initials: YW
authors.lastname: Choi
authors.affiliation: Department of Pathology, Ajou University School of Medicine, Suwon, South Korea.
authors.forename: Jae Ho
authors.initials: JH
authors.lastname: Han
authors.affiliation: Department of Surgery, Ajou University School of Medicine, Suwon, South Korea.
authors.forename: Jeonghun
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Surgery, Ajou University School of Medicine, Suwon, South Korea.
authors.forename: Euy Young
authors.initials: EY
authors.lastname: Soh
authors.affiliation: Department of Pathology, Ajou University School of Medicine, Suwon, South Korea.
authors.forename: So Hyun
authors.initials: SH
authors.lastname: Park
authors.affiliation: Department of Pathology, Ajou University School of Medicine, Suwon, South Korea. Electronic address: drjhk@ajou.ac.kr.
authors.forename: Jang-Hee
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, Suwon, South Korea; Department of Biomedical Sciences, Graduate School, Ajou University, Suwon, South Korea. Electronic address: park64@ajou.ac.kr.
authors.forename: Tae Jun
authors.initials: TJ
authors.lastname: Park
mesh_terms: D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002291:Carcinoma, Papillary; D016922:Cellular Senescence / Q000235:genetics*; D054642:Dual Specificity Phosphatase 6 / Q000235:genetics* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D010957:Plasmids / Q000235:genetics; D012150:Polymorphism, Restriction Fragment Length; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000187:drug effects; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D013972:Thyrotropin / Q000097:blood / Q000494:pharmacology*; D015854:Up-Regulation
chemical_list: D017382:Reactive Oxygen Species; D013972:Thyrotropin; D048493:Proto-Oncogene Proteins B-raf; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C517035:DUSP6 protein, human; D054642:Dual Specificity Phosphatase 6