The DOI matches its Crossref record; 37 of the 37 references it cites were found in a registry or an index.
The BRAFV600E Oncogene Induces Transforming Growth Factor β Secretion Leading to Sodium Iodide Symporter Repression and Increased Malignancy in Thyroid Cancer
Abstract
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 PTC invasion, 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. [Cancer Res 2009;69(21):8317–25]
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“PTC patients with RET/PTC rearrangements [30–32] or the BRAFV600E mutation [33, 34] exhibit cell dedifferentiation.”
From Restoration of p53 using the novel MDM2-p53 antagonist APG115 suppresses dedifferentiated papillary thyroid cancer cells (2017) · cites this paper as [33]
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Cites
2 retracted
Melillo, R. M., Castellone, M. D., Guarino, V., Falco, V. D., Cirafici, A. M., Salvatore, G., Caiazzo, F., Basolo, F., Giannini, R., Kruhøffer, M., et al. (2016) · Journal of Clinical Investigation · doi:10.1172/jci87345 · Cited by 305
RetractedMelillo, R. M., Castellone, M. D., Guarino, V., Falco, V. D., Cirafici, A. M., Salvatore, G., Caiazzo, F., Basolo, F., Giannini, R., Kruhøffer, M., et al. (2005) · Journal of Clinical Investigation · doi:10.1172/jci22758 · Cited by 298
RetractedMutations of the BRAF gene in human cancer
Davies, H., Bignell, G. R., Cox, C., Stephens, P., Edkins, S., Clegg, S., Teague, J., Woffendin, H., Garnett, M. J., Bottomley, W., et al. (2002) · Nature · doi:10.1038/nature00766 · Cited by 10,674
Identification of Smad7, a TGFβ-inducible antagonist of TGF-β signalling
Nakao, A., Afrakhte, M., Morn, A., Nakayama, T., Christian, J. L., Heuchel, R. L., Itoh, S., Kawabata, M., Heldin, N., Heldin, C., et al. (1997) · Nature · doi:10.1038/39369 · Cited by 1,796
Kimura, E. T., Nikiforova, M. N., Zhu, Z., Knauf, J. A., Nikiforov, Y. E., & Fagin, J. A. (2003) · PubMed · Cited by 1,510
BRAF mutation predicts sensitivity to MEK inhibition
Solit, D. B., Garraway, L. A., Pratilas, C. A., Sawai, A., Getz, G. A., Basso, A., Ye, Q., Lobo, J. M., She, Y., Osman, I., et al. (2005) · Nature · doi:10.1038/nature04304 · Cited by 1,326
The RAF proteins take centre stage
Wellbrock, C., Karasarides, M., & Marais, R. (2004) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1498 · Cited by 1,223
Cloning and characterization of the thyroid iodide transporter
Dai, G., Levy, O., & Carrasco, N. (1996) · Nature · doi:10.1038/379458a0 · Cited by 1,109
Self-citationTargeting the mitogen-activated protein kinase cascade to treat cancer
Sebolt, J. S., & Herrera, R. (2004) · Nature reviews. Cancer · doi:10.1038/nrc1503 · Cited by 1,103
Nikiforova, M. N., Kimura, E. T., Gandhi, M., Biddinger, P. W., Knauf, J. A., Basolo, F., Zhu, Z., Giannini, R., Salvatore, G., Fusco, A., et al. (2003) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2003-030838 · Cited by 1,036
Cited by
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Molecular pathogenesis and mechanisms of thyroid cancer
Xing, M. (2013) · Nature reviews. Cancer · doi:10.1038/nrc3431 · Cited by 1,452
Chakravarty, D., Santos, E. B., Ryder, M. M., Knauf, J. A., Liao, X.-H., West, B. L., Bollag, G. E., Kolesnick, R. N., Thin, T. H., Rosen, N. X., et al. (2011) · Journal of Clinical Investigation · doi:10.1172/jci46382 · Cited by 399
Rothenberg, S. M., McFadden, D. G., Palmer, E. L., Daniels, G. H., & Wirth, L. J. (2014) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-2915 · Cited by 384
Thyroid hormone biosynthesis and release
Carvalho, D. P., & Dupuy, C. (2017) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2017.01.038 · Cited by 346
Raf kinases in cancer–roles and therapeutic opportunities
Maurer, G., Tarkowski, B., & Baccarini, M. (2011) · Oncogene · doi:10.1038/onc.2011.160 · Cited by 311
Metadata
- Authors
- Riesco-Eizaguirre, G., Rodríguez, I., De la Vieja, A., Costamagna, E., Carrasco, N., Nistal, M., & Santisteban, P.
- Affiliations
- 1Instituto de Investigaciones Biomédicas “Alberto Sols” Consejo Superior de Investigaciones Científicas y Universidad Autónoma de Madrid; 2Servicio de Endocrinología y Nutrición and 3Departamento de Anatomía Patológica, Hospital Universitario La Paz; and 4Área de Biología Celular y Desarrollo, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Madrid, Spain; and 5Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York
- Albert Einstein College of Medicine (US)
- Venue
- Cancer Research
- Published
- 2009-10-28
- Volume
- 69
- Issue
- 21
- Pages
- 8317-8325
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2139518879
- Cited by
- 265
- References
- 37
- Citations by year
- 2026: 10 · 2025: 11 · 2024: 7 · 2023: 13 · 2022: 12 · 2021: 22 · 2020: 11 · 2019: 19 · 2018: 18 · 2017: 13 · 2016: 15 · 2015: 24 · 2014: 23 · 2013: 18 · 2012: 14
- FWCI
- 11.86
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- Funders
- Instituto de Salud Carlos III
- National Cancer Institute (R01CA098390, CA098390)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Cancer Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Keywords
- BRAF V600E mutation, papillary thyroid carcinoma, TGF-beta, sodium iodide symporter, epithelial-mesenchymal transition, tumor invasion, lymph node metastasis, MEK/ERK signaling, Smad2, TGFBR2, cell migration
- MeSH terms
- Sodium-Iodide Symporters, Adult, Carcinoma, Papillary, Enzyme-Linked Immunosorbent Assay, Female, Fluorescent Antibody Technique, Humans, Immunoenzyme Techniques, Iodides, Luciferases, Male, Mutation, Neoplasm Invasiveness, RNA, Messenger, Thyroid Neoplasms, Tumor Cells, Cultured, Blotting, Western, Down-Regulation, Gene Expression Regulation, Neoplastic, Transforming Growth Factor beta, Receptors, Transforming Growth Factor beta, Autocrine Communication, Reverse Transcriptase Polymerase Chain Reaction, Mitogen-Activated Protein Kinases, Mitogen-Activated Protein Kinase Kinases, Symporters, Extracellular Signal-Regulated MAP Kinases, Proto-Oncogene Proteins B-raf, Smad2 Protein
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