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Inhibition of STAT3 activity delays obesity-induced thyroid carcinogenesis in a mouse model.

Abstract
Compelling epidemiologic studies indicate that obesity is a risk factor for many human cancers, including thyroid cancer. In recent decades, the incidence of thyroid cancer has dramatically increased along with a marked rise in obesity prevalence. We previously demonstrated that a high fat diet (HFD) effectively induced the obese phenotype in a mouse model of thyroid cancer (Thrb(PV/PV)Pten(+/-) mice). Moreover, HFD activates the STAT3 signal pathway to promote more aggressive tumor phenotypes. The aim of the present study was to evaluate the effect of S3I-201, a specific inhibitor of STAT3 activity, on HFD-induced aggressive cancer progression in the mouse model of thyroid cancer. WT and Thrb(PV/PV)Pten(+/-) mice were treated with HFD together with S3I-201 or vehicle-only as controls. We assessed the effects of S3I-201 on HFD-induced thyroid cancer progression, the leptin-JAK2-STAT3 signaling pathway, and key regulators of epithelial-mesenchymal transition (EMT). S3I-201 effectively inhibited HFD-induced aberrant activation of STAT3 and its downstream targets to markedly inhibit thyroid tumor growth and to prolong survival. Decreased protein levels of cyclins D1 and B1, cyclin dependent kinase 4 (CDK4), CDK6, and phosphorylated retinoblastoma protein led to the inhibition of tumor cell proliferation in S3I-201-treated Thrb(PV/PV)Pten(+/-) mice. Reduced occurrence of vascular invasion and blocking of anaplasia and lung metastasis in thyroid tumors of S3I-201-treated Thrb(PV/PV)Pten(+/-) mice were mediated via decreased expression of vimentin and matrix metalloproteinases, two key effectors of EMT. The present findings suggest that inhibition of the STAT3 activity would be a novel treatment strategy for obesity-induced thyroid cancer.
AuthorsJeong Won Park, Cho Rong Han, Li Zhao, Mark C Willingham, Sheue-yann Cheng
JournalEndocrine-related cancer (Endocr Relat Cancer) Vol. 23 Issue 1 Pg. 53-63 (Jan 2016) ISSN: 1479-6821 [Electronic] England
PMID26552408 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)
Copyright© 2016 Society for Endocrinology.
Chemical References
  • Aminosalicylic Acids
  • Benzenesulfonates
  • NSC 74859
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Thyroid Hormone Receptors beta
  • PTEN Phosphohydrolase
  • Pten protein, mouse
Topics
  • Aminosalicylic Acids (pharmacology)
  • Animals
  • Benzenesulfonates (pharmacology)
  • Carcinogenesis (drug effects)
  • Cell Proliferation (drug effects, genetics)
  • Diet, High-Fat
  • Disease Models, Animal
  • Down-Regulation (drug effects)
  • Epithelial-Mesenchymal Transition (drug effects, genetics)
  • Mice
  • Mice, Transgenic
  • Obesity (complications, pathology)
  • PTEN Phosphohydrolase (genetics)
  • STAT3 Transcription Factor (antagonists & inhibitors, metabolism)
  • Thyroid Gland (drug effects, pathology)
  • Thyroid Hormone Receptors beta (genetics)
  • Thyroid Neoplasms (etiology, genetics, mortality, pathology)

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