title: 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.
authors.affiliation: Laboratory of Molecular BiologyCenter for Cancer Research, National Cancer Institute, National Institutes of Health, 37 Convent Dr, Room 5128, Bethesda, Maryland 20892-6264, USA.
authors.forename: Jeong Won
authors.initials: JW
authors.lastname: Park
authors.affiliation: Laboratory of Molecular BiologyCenter for Cancer Research, National Cancer Institute, National Institutes of Health, 37 Convent Dr, Room 5128, Bethesda, Maryland 20892-6264, USA.
authors.forename: Cho Rong
authors.initials: CR
authors.lastname: Han
authors.affiliation: Laboratory of Molecular BiologyCenter for Cancer Research, National Cancer Institute, National Institutes of Health, 37 Convent Dr, Room 5128, Bethesda, Maryland 20892-6264, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Laboratory of Molecular BiologyCenter for Cancer Research, National Cancer Institute, National Institutes of Health, 37 Convent Dr, Room 5128, Bethesda, Maryland 20892-6264, USA.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Willingham
authors.affiliation: Laboratory of Molecular BiologyCenter for Cancer Research, National Cancer Institute, National Institutes of Health, 37 Convent Dr, Room 5128, Bethesda, Maryland 20892-6264, USA chengs@mail.nih.gov.
authors.forename: Sheue-yann
authors.initials: SY
authors.lastname: Cheng
mesh_terms: D000636:Aminosalicylic Acids / Q000494:pharmacology; D000818:Animals; D001557:Benzenesulfonates / Q000494:pharmacology*; D063646:Carcinogenesis / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009765:Obesity / Q000150:complications* / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013961:Thyroid Gland / Q000187:drug effects / Q000473:pathology; D037042:Thyroid Hormone Receptors beta / Q000235:genetics; D013964:Thyroid Neoplasms / Q000209:etiology* / Q000235:genetics / Q000401:mortality / Q000473:pathology*
chemical_list: D000636:Aminosalicylic Acids; D001557:Benzenesulfonates; C520337:NSC 74859; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D037042:Thyroid Hormone Receptors beta; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse
keywords: JAK2-STAT3 signaling; Pten-deficiency; STAT3 inhibitor; obesity; preclinical mouse model; thyroid cancer; thyroid hormone receptor β mutant