STAT3 negatively regulates thyroid tumorigenesis

• Type: Article in International Scientific Journal
• Date: 2012

Authors

Joana Pinto Couto (Author) Other; Laura Daly (Author) Other; Ana Almeida (Author) Other; Jeffrey A Knauf (Author) Other; James A Fagin (Author) Other; Manuel Sobrinho Simoes (Author) FMUP; Jorge Lima (Author) FMUP; Valdemar Maximo (Author) FMUP; Paula Soares (Author) FMUP; David Lyden (Author) Other; Jacqueline F Bromberg (Author) Other

Journal

Title: Proceedings of the National Academy of Sciences of the United States of America

Vol. 109

Pages: E2361-E2370

ISSN: 0027-8424

Publisher: National Academy of Sciences

Indexing

ISI Web of Knowledge - 105 Citations

Scopus - 110 Citations

Other information

Authenticus ID: P-002-6TS

DOI: 10.1073/pnas.1201232109

Abstract (EN): 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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 10