The BRAFV600E Oncogene Induces Transforming Growth Factor β Secretion Leading to Sodium Iodide Symporter Repression and Increased Malignancy in Thyroid Cancer

Autor: Garcilaso Riesco-Eizaguirre, Pilar Santisteban, Irene Rodríguez, Antonio De la Vieja, Nancy Carrasco, Eugenia Costamagna, Manuel Nistal
Rok vydání: 2009
Předmět:
Adult
Male
Proto-Oncogene Proteins B-raf
MAPK/ERK pathway
Sodium-iodide symporter
Cancer Research
medicine.medical_specialty
endocrine system diseases
Blotting
Western
Down-Regulation
Fluorescent Antibody Technique
Enzyme-Linked Immunosorbent Assay
Smad2 Protein
SMAD
Immunoenzyme Techniques
Transforming Growth Factor beta
Internal medicine
Tumor Cells
Cultured
medicine
Humans
Neoplasm Invasiveness
RNA
Messenger
Thyroid Neoplasms
Extracellular Signal-Regulated MAP Kinases
Luciferases
Autocrine signalling
Mitogen-Activated Protein Kinase Kinases
Symporters
Oncogene
Reverse Transcriptase Polymerase Chain Reaction
business.industry
Iodides
Carcinoma
Papillary
Gene Expression Regulation
Neoplastic
Autocrine Communication
Endocrinology
Oncology
Mutation
Symporter
Cancer research
Female
Mitogen-Activated Protein Kinases
business
Receptors
Transforming Growth Factor beta
V600E
Transforming growth factor
Zdroj: Digital.CSIC. Repositorio Institucional del CSIC
instname
ISSN: 1538-7445
0008-5472
2007-6061
Popis: The activating mutation BRAFV600E is a frequent genetic event in papillary thyroid carcinomas (PTC) that predicts a poor prognosis, leading to loss of sodium/iodide symporter (NIS) expression and subsequent radioiodide-refractory metastatic disease. The molecular basis of such an aggressive behavior induced by BRAF remains unclear. Here, we show a mechanism through which BRAF induces NIS repression and promotes epithelial to mesenchimal transition and invasion based on the operation of an autocrine transforming growth factor (TGF)β loop. BRAF induces secretion of functional TGFβ and blocking TGFβ/Smad signaling at multiple levels rescues BRAF-induced NIS repression. Although this mechanism is MAP/extracellular signal-regulated kinase (ERK) kinase (MEK)-ERK independent, secreted TGFβ cooperates with MEK-ERK signaling in BRAF-induced cell migration, Matrigel invasion, and EMT. Consistent with this process, TGFβ and other key components of TGFβ signaling, such as TβRII and pSmad2, are overexpressed in human PTC, suggesting a widespread activation of this pathway by locally released TGFβ. Moreover, this high TGFβ/Smad activity is associated with PTCinvasion, nodal metastasis, and BRAF status. Interestingly, TGFβ is overexpressed in the invasive front, whereas NIS is preferentially expressed in the central regions of the tumors, suggesting that this negative correlation between TGFβ and NIS occurs locally inside the tumor. Our study describes a novel mechanism of NIS repression in thyroid cancer and provides evidence that TGFβ may play a key role in promoting radioiodide resistance and tumor invasion during PTC progression. ©2009 American Association for Cancer Research.
Grant support: Spanish Ministry of Science and Innovation: SAF2007-60614, RD06/0020/0060, and Acción Transversal del Cáncer (FIS, Instituto de Salud Carlos III; P. Santisteban), by FIS ISCIII PI06-1231 (A. De la Vieja), and by NIH grants DK-41544 and CA-098390 (N. Carrasco). G. Riesco-Eizaguirre was supported in part by FIS-CM03 from Instituto de Salud Carlos III.
Databáze: OpenAIRE
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