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Using human thyroid cancer-derived cell lines [harboring rearranged during transfection (\n                    <jats:italic>RET<\/jats:italic>\n                    )\/PTC, v-RAF murine sarcoma viral oncogene homolog B (\n                    <jats:italic>BRAF<\/jats:italic>\n                    ), or rat sarcoma virus oncogene (\n                    <jats:italic>RAS<\/jats:italic>\n                    ) 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\n                    <jats:italic>BRAF<\/jats:italic>\n                    V600E-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\u03b1) 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.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1201232109","type":"journal-article","created":{"date-parts":[[2012,8,13]],"date-time":"2012-08-13T22:37:49Z","timestamp":1344897469000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":112,"title":["STAT3 negatively regulates thyroid tumorigenesis"],"prefix":"10.1073","volume":"109","author":[{"given":"Joana Pinto","family":"Couto","sequence":"first","affiliation":[{"name":"Department of Cancer Biology, Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), 4200-465 Porto, Portugal;"},{"name":"Medical Faculty of the University of Porto (FMUP), 4200-319 Porto, Portugal;"}]},{"given":"Laura","family":"Daly","sequence":"additional","affiliation":[{"name":"Departments of cMedicine and"}]},{"given":"Ana","family":"Almeida","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), 4200-465 Porto, Portugal;"},{"name":"Institute of Biomedical Sciences Abel Salazar of the University of Porto, 4099-003 Porto, Portugal;"}]},{"given":"Jeffrey A.","family":"Knauf","sequence":"additional","affiliation":[{"name":"Human Oncology and Pathogenesis Program, Memorial Sloan\u2013Kettering Cancer Center, New York, NY 10065;"}]},{"given":"James A.","family":"Fagin","sequence":"additional","affiliation":[{"name":"Departments of cMedicine and"},{"name":"Human Oncology and Pathogenesis Program, Memorial Sloan\u2013Kettering Cancer Center, New York, NY 10065;"}]},{"given":"Manuel","family":"Sobrinho-Sim\u00f5es","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), 4200-465 Porto, Portugal;"},{"name":"Medical Faculty of the University of Porto (FMUP), 4200-319 Porto, Portugal;"},{"name":"Department of Pathology, Hospital S\u00e3o Jo\u00e3o, 4200-465 Porto, Portugal; and"}]},{"given":"Jorge","family":"Lima","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), 4200-465 Porto, Portugal;"}]},{"given":"Valdemar","family":"M\u00e1ximo","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), 4200-465 Porto, Portugal;"},{"name":"Medical Faculty of the University of Porto (FMUP), 4200-319 Porto, Portugal;"}]},{"given":"Paula","family":"Soares","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), 4200-465 Porto, Portugal;"},{"name":"Medical Faculty of the University of Porto (FMUP), 4200-319 Porto, Portugal;"}]},{"given":"David","family":"Lyden","sequence":"additional","affiliation":[{"name":"Departments of gPediatrics and Cell and Developmental Biology and"}]},{"given":"Jacqueline F.","family":"Bromberg","sequence":"additional","affiliation":[{"name":"Departments of cMedicine and"},{"name":"Medicine, Weill Cornell Medical College, New York, NY 10021"}]}],"member":"341","published-online":{"date-parts":[[2012,8,13]]},"reference":[{"key":"e_1_1_2_17_11_1_2","doi-asserted-by":"publisher","DOI":"10.1186\/ar1916"},{"key":"e_1_1_2_17_11_2_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI31871"},{"key":"e_1_1_2_17_11_3_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1606508"},{"key":"e_1_1_2_17_11_4_2","doi-asserted-by":"publisher","DOI":"10.1210\/me.2002-0401"},{"key":"e_1_1_2_17_11_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2008.03.011"},{"key":"e_1_3_3_1_2","volume-title":"World Health Organization Classification of Tumours. 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