Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 109, Issue 35, Pages E2361-E2370Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1201232109
Keywords
cytokine; tumor microenvironment; metabolic reprogramming
Categories
Funding
- Portuguese Foundation for Science and Technology (FCT) Project Grant
- FCT [SFRH/BD/40260/2007]
- NIH [CA87637, U54: CA148967]
- Astra Zeneca
- Sussman Family Fund
- Marjorie and Charles Holloway Foundation
- Lerner Awards
- Children's Cancer and Blood Foundation
- Manning Foundation
- Hartwell Foundation
- Pediatric Oncology Experimental Therapeutics Investigators Consortium
- Stavros S. Niarchos Foundation
- Champalimaud Foundation
- Nancy C. and Daniel P. Paduano Foundation
- Mary Kay Foundation
- American Hellenic Educational Progressive Association 5th District
- Malcolm Hewitt Wiener Foundation
- George Best Costacos Foundation
- NCI UO1 TMEN
- Susan G. Komen for the Cure
- PSOC training grant [NCI-U54-CA143836]
- Beth C. Tortolani Foundation
- [NCI-R01CA 098234-01]
- Fundação para a Ciência e a Tecnologia [SFRH/BD/40260/2007] Funding Source: FCT
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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 association with 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 that were more 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 (HIF1 alpha) 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.
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