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.