STAT3 negatively regulates thyroid tumorigenesis.
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.
Department of Cancer Biology,  Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), 4200-465 Porto,  Portugal.
Joana Pinto
JP
Couto
Laura
L
Daly
Ana
A
Almeida
Jeffrey A
JA
Knauf
James A
JA
Fagin
Manuel
M
Sobrinho-Simões
Jorge
J
Lima
Valdemar
V
Máximo
Paula
P
Soares
David
D
Lyden
Jacqueline F
JF
Bromberg
D000818:Animals; D002291:Carcinoma, Papillary / Q000378:metabolism* / Q000556:secondary; D002455:Cell Division / Q000502:physiology; D045744:Cell Line, Tumor; D050822:Cytokine Receptor gp130 / Q000378:metabolism; D004195:Disease Models, Animal; D055785:Gene Knockdown Techniques; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D053612:Janus Kinases / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013964:Thyroid Neoplasms / Q000378:metabolism* / Q000473:pathology; D014183:Transplantation, Heterologous; D059016:Tumor Microenvironment / Q000502:physiology
C508600:IL6 protein, human; D018969:Insulin-Like Growth Factor Binding Proteins; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C102529:insulin-like growth factor binding protein-related protein 1; D050822:Cytokine Receptor gp130; D053612:Janus Kinases; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf