Although tyrosine-phosphorylated or activated STAT3 (pY-STAT3) is a 
well-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 (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.