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

• Published in: Endocrine-related cancer Vol. 23; no. 1; pp. 53 - 63
• Main Authors: Park, Jeong Won, Han, Cho Rong, Zhao, Li, Willingham, Mark C, Cheng, Sheue-yann
• Format: Journal Article
• Language: English
• Published: England Bioscientifica Ltd 01.01.2016
• Subjects: Aminosalicylic Acids - pharmacology; Animals; Benzenesulfonates - pharmacology; Carcinogenesis - drug effects; Cell Proliferation - drug effects; Cell Proliferation - genetics; Diet, High-Fat; Disease Models, Animal; Down-Regulation - drug effects; Epithelial-Mesenchymal Transition - drug effects; Epithelial-Mesenchymal Transition - genetics; Mice; Mice, Transgenic; Obesity - complications; Obesity - pathology; PTEN Phosphohydrolase - genetics; STAT3 Transcription Factor - antagonists & inhibitors; STAT3 Transcription Factor - metabolism; Thyroid Gland - drug effects; Thyroid Gland - pathology; Thyroid Hormone Receptors beta - genetics; Thyroid Neoplasms - etiology; Thyroid Neoplasms - genetics; Thyroid Neoplasms - mortality; Thyroid Neoplasms - pathology; thyroid hormone receptor β mutant; JAK2-STAT3 signaling; preclinical mouse model; thyroid cancer; STAT3 inhibitor; obesity; Pten-deficiency
• ISSN: 1351-0088; 1479-6821
• DOI: 10.1530/ERC-15-0417

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 (ThrbPV/PVPten+/− 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 ThrbPV/PVPten+/− 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 ThrbPV/PVPten+/− mice. Reduced occurrence of vascular invasion and blocking of anaplasia and lung metastasis in thyroid tumors of S3I-201-treated ThrbPV/PVPten+/− 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.