STAT3 negatively regulates thyroid tumorigenesis
- 13 August 2012
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 109 (35), E2361-70
- https://doi.org/10.1073/pnas.1201232109
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.This publication has 68 references indexed in Scilit:
- Cytoprotection by the modulation of mitochondrial electron transport chain: The emerging role of mitochondrial STAT3Mitochondrion, 2012
- Pyruvate Kinase M2 Regulates Gene Transcription by Acting as a Protein KinaseMolecular Cell, 2012
- Pyruvate Kinase M2 Is a PHD3-Stimulated Coactivator for Hypoxia-Inducible Factor 1Cell, 2011
- Thyrotrophin receptor signaling dependence of Braf-induced thyroid tumor initiation in miceProceedings of the National Academy of Sciences of the United States of America, 2011
- The JAK2 Inhibitor AZD1480 Potently Blocks Stat3 Signaling and Oncogenesis in Solid TumorsCancer Cell, 2009
- IL-6 and Stat3 Are Required for Survival of Intestinal Epithelial Cells and Development of Colitis-Associated CancerCancer Cell, 2009
- Molecular pathology of thyroid cancer: diagnostic and clinical implicationsBest Practice & Research Clinical Endocrinology & Metabolism, 2008
- Adaptation to hypoxia and acidosis in carcinogenesis and tumor progressionSeminars in Cancer Biology, 2008
- Cancer Cell Metabolism: Warburg and BeyondCell, 2008
- Oncogenic BRAF Induces Senescence and Apoptosis through Pathways Mediated by the Secreted Protein IGFBP7Cell, 2008