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TSH Signaling Overcomes B-RafV600E–Induced Senescence in Papillary Thyroid Carcinogenesis through Regulation of DUSP6
- Source :
- Neoplasia: An International Journal for Oncology Research, Vol 16, Iss 12, Pp 1107-1120 (2014), Neoplasia (New York, N.Y.)
- Publication Year :
- 2014
- Publisher :
- Elsevier BV, 2014.
-
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.
- Subjects :
- Proto-Oncogene Proteins B-raf
Senescence
Cancer Research
endocrine system diseases
Thyrotropin
DUSP6
Enzyme-Linked Immunosorbent Assay
Real-Time Polymerase Chain Reaction
lcsh:RC254-282
Article
ROS, reactive oxygen species
Dual Specificity Phosphatase 6
GSK-3
DUSP, dual specific phosphatase
SOD, superoxide dismutase
Humans
Thyroid Neoplasms
Phosphorylation
GPx1, glutathione peroxidase-1
Protein kinase B
Cellular Senescence
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
biology
Kinase
Carcinoma
IP, immunoprecipitation
Sequence Analysis, DNA
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Carcinoma, Papillary
Up-Regulation
OIS, oncogene-induced senescence
Thyroid Cancer, Papillary
PTC, papillary thyroid carcinoma
TSHR, TSH receptor
Cancer research
biology.protein
RNA Interference
Signal transduction
Reactive Oxygen Species
Cell aging
Polymorphism, Restriction Fragment Length
TSH, thyroid-stimulating hormone
Plasmids
Signal Transduction
Subjects
Details
- ISSN :
- 14765586
- Volume :
- 16
- Issue :
- 12
- Database :
- OpenAIRE
- Journal :
- Neoplasia
- Accession number :
- edsair.doi.dedup.....b13b78048391460af79eb81114c4d33d
- Full Text :
- https://doi.org/10.1016/j.neo.2014.10.005