Document details
STAT3 negatively regulates thyroid tumorigenesis(Article)(Open Access)
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- aDepartment of Cancer Biology, Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, 4200-465, Portugal
- bMedical Faculty of the University of Porto (FMUP), Porto, 4200-319, Portugal
- cDepartments of Medicine, Departments of Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, United States
- dInstitute of Biomedical Sciences Abel Salazar of the University of Porto, Porto, 4099-003, Portugal
- eDepartments of Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, United States
- fDepartment of Pathology, Hospital São João, Porto, 4200-465, Portugal
- gDepartments of Pediatrics and Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10021, United States
- hDepartments of Medicine, Weill Cornell Medical College, New York, NY 10021, United States
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Abstract
Although tyrosine-phosphorylated or activated STAT3 (pY-STAT3) is awell-described mediator of tumorigenesis, its role in thyroid cancer has not been investigated. We observed that 63 of 110 (57%) human primary papillary thyroid carcinoma (PTC) cases expressed nuclear pY-STAT3 in tumor cells, preferentially in associationwith the tumor stroma. An inverse relationship between pY-STAT3 expression with tumor size and the presence of distant metastases was observed. Using human thyroid cancer-derived cell lines [harboring rearranged during transfection (RET)/PTC, v-RAF murine sarcoma viral oncogene homolog B (BRAF), or rat sarcoma virus oncogene (RAS) alterations], we determined that IL-6/gp130/JAK signaling is responsible for STAT3 activation. STAT3 knockdown by shRNA in representative thyroid cancer cell lines that express high levels of pY-STAT3 had no effect on in vitro growth. However, xenografted short hairpin STAT3 cells generated larger tumors than control cells. Similarly, STAT3 deficiency in a murine model of BRAFV600E-induced PTC led to thyroid tumors thatweremore proliferative and larger than those tumors expressing STAT3wt. Genome expression analysis revealed that STAT3 knockdown resulted in the down-regulation of multiple transcripts, including the tumor suppressor insulin-like growth factor binding protein 7. Furthermore, STAT3 knockdown led to an increase in glucose consumption, lactate production, and expression of Hypoxia-inducible factor 1 (HIF1α) target genes, suggesting that STAT3 is a negative regulator of aerobic glycolysis. Our studies show that, in the context of thyroid cancer, STAT3 is paradoxically a negative regulator of tumor growth. These findings suggest that targeting STAT3 in these cancers could enhance tumor size and highlight the complexities of the role of STAT3 in tumorigenesis.
Indexed keywords
| EMTREE drug terms: | B Raf kinasebinding proteinglucose transporter 1glucose transporter 3glycoprotein gp 130hexokinasehypoxia inducible factor 1interleukin 6Janus kinaselactic acidprotein Retpyruvate dehydrogenase kinaseRas proteinshort hairpin RNASTAT3 proteintumor suppressor insulin like growth factor binding protein 7unclassified drugB Raf kinaseBraf protein, mouseglycoprotein gp 130IL6 protein, humaninsulin like growth factor binding protein related protein 1insulin-like growth factor binding protein-related protein 1interleukin 6Janus kinasesomatomedin binding proteinSTAT3 proteinSTAT3 protein, human |
|---|---|
| EMTREE medical terms: | aerobic glycolysisanimal modelanimal tissueArticlecancer sizecarcinogenesiscarcinogenicitycell proliferationcontrolled studydown regulationgene expressiongene silencinggenetic associationglucose intakeHEK293 cell linehumanhuman cellin vitro studyin vivo studynonhumanpriority journalprotein phosphorylationsignal transductionthyroid cancer cell linethyroid follicular cellthyroid tumortumor microenvironmentupregulationanimalarticlecancer transplantationcell divisiondisease modelgeneticsmetabolismmetastasismousepapillary carcinomapathologyphysiologysignal transductiontransgenic mousetumor cell linexenograft |
| MeSH: | AnimalsCarcinoma, PapillaryCell DivisionCell Line, TumorCytokine Receptor gp130Disease Models, AnimalGene Knockdown TechniquesHumansInsulin-Like Growth Factor Binding ProteinsInterleukin-6Janus KinasesMiceMice, TransgenicNeoplasm TransplantationProto-Oncogene Proteins B-rafSignal TransductionSTAT3 Transcription FactorThyroid NeoplasmsTransplantation, HeterologousTumor Microenvironment |
Chemicals and CAS Registry Numbers:
glucose transporter 1, 172077-08-6; glucose transporter 3, 174958-52-2; hexokinase, 9001-51-8; Janus kinase, 161384-16-3; lactic acid, 113-21-3, 50-21-5; protein Ret, 154251-46-4, 158709-11-6; pyruvate dehydrogenase kinase, 9074-01-5;
Braf protein, mouse, 2.7.11.1; Cytokine Receptor gp130, 133483-10-0; IL6 protein, human; Insulin-Like Growth Factor Binding Proteins; Interleukin-6; Janus Kinases, 2.7.10.2; Proto-Oncogene Proteins B-raf, 2.7.11.1; STAT3 Transcription Factor; STAT3 protein, human; insulin-like growth factor binding protein-related protein 1
Funding details
| Funding sponsor | Funding number | Acronym |
|---|---|---|
| Nicolaas Mulerius Foundation, University of Groningen See opportunities | ||
| SFRH/BD/40260/2007 | ||
| Fundação para a Ciência e a Tecnologia See opportunities | ||
| Hartwell Foundation | ||
| Stavros Niarchos Foundation | ||
| Baton Rouge Area Foundation | ||
| Mary Kay Foundation See opportunities | ||
| NCI-U54-CA143836 | ||
| American Hellenic Educational Progressive Association Foundation | ||
| Center for Outcomes Research and Evaluation, Yale School of Medicine | ||
| CA148967 | ||
| NCI-R01CA 098234-01 | ||
| Manning Educational Foundation | ||
| Children's Cancer and Blood Foundation |
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1
We thank V?tor Trovisco for the RET/PTC and BRAF expression vectors, Hugo Prazeres and Joana Nunes for their helpful comments, and the Molecular Cytology Core at Sloan-Kettering Institute, especially Alex Baldys and Afsar Barlas, for help with immunostainings. pIRE-Luc and pDM2-LacZ were provided by Dr. Robert Hofstra (University of Groningen, Groningen, The Netherlands). Astra Zeneca generously provided AZD1480. This study was supported in part by a Portuguese Foundation for Science and Technology (FCT) Project Grant. The Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP) is an Associate Laboratory of the Portuguese Ministry of Science, Technology, and Higher Education that is partially supported by the FCT. J.P.C. was supported by FCT Grant SFRH/BD/40260/2007. This project was supported by grants from the NIH-CA87637, U54: CA148967, Astra Zeneca, Sussman Family Fund, Marjorie and Charles Holloway Foundation and Lerner Awards (to J.F.B.). D.L. was supported by grants from the Children's Cancer and Blood Foundation, The Manning Foundation, The Hartwell Foundation, Pediatric Oncology Experimental Therapeutics Investigators Consortium, Stavros S. Niarchos Foundation, Champalimaud Foundation, The Nancy C. and Daniel P. Paduano Foundation, The Mary Kay Foundation, American Hellenic Educational Progressive Association 5th District, The Malcolm Hewitt Wiener Foundation, The George Best Costacos Foundation, NCI-R01CA 098234-01, NCI UO1 TMEN, Susan G. Komen for the Cure, and NCI-U54-CA143836 PSOC training grant. D.L. and J.F.B. were supported by The Beth C. Tortolani Foundation.
- ISSN: 00278424
- CODEN: PNASA
- Source Type: Journal
- Original language: English
- DOI: 10.1073/pnas.1201232109
- PubMed ID: 22891351
- Document Type: Article
- Publisher: National Academy of Sciences
© Copyright 2017 Elsevier B.V., All rights reserved.
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