STAT3 negatively regulates thyroid tumorigenesis Journal Article
| Authors: | Couto, J. P.; Daly, L.; Almeida, A.; Knauf, J. A.; Fagin, J. A.; Sobrinho-Simões, M.; Lima, J.; Maximo, V.; Soares, P.; Lyden, D.; Bromberg, J. F. |
| Article Title: | STAT3 negatively regulates thyroid tumorigenesis |
| Abstract: | 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. |
| Keywords: | signal transduction; genetics; mouse; animal; metabolism; animals; mice; cell division; stat3 protein; metastasis; carcinoma, papillary; pathology; cell line, tumor; physiology; transgenic mouse; mice, transgenic; disease model; xenograft; janus kinase; tumor cell line; transplantation, heterologous; interleukin 6; interleukin-6; cytokine receptor gp130; stat3 transcription factor; thyroid neoplasms; gene silencing; neoplasm transplantation; papillary carcinoma; disease models, animal; b raf kinase; thyroid tumor; stat3 protein, human; gene knockdown techniques; proto-oncogene proteins b-raf; somatomedin binding protein; braf protein, mouse; cancer transplantation; tumor microenvironment; glycoprotein gp 130; insulin-like growth factor binding proteins; janus kinases; il6 protein, human; insulin like growth factor binding protein related protein 1; insulin-like growth factor binding protein-related protein 1 |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 109 |
| Issue: | 35 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2012-08-28 |
| Start Page: | E2361 |
| End Page: | E2370 |
| Language: | English |
| PUBMED: | 22891351 |
| PROVIDER: | scopus |
| PMCID: | PMC3435219 |
| DOI: | 10.1073/pnas.1201232109 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 4 February 2013" - "Source: Scopus" |
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