Obesity-induced tumor growth, invasion, and metastasis are blocked by an inhibitor of leptin-JAK-STAT3 signaling in a mouse model of thyroid cancer

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Authors

• JW Park
• CR Han
• L Zhao
• MC Willingham
• SY Cheng

Abstract

Compelling epidemiologic studies indicate that obesity is a risk factor for many human cancers, including thyroid cancer. However, the molecular mechanisms by which obesity could contribute to thyroid cancer remain unclear. We have developed a mutant mouse that expresses a mutated thyroid hormone receptor beta (denoted as PV) with haplodeficiency of the Pten gene (ThrbPV/PVPten+/- mice). This mouse spontaneously develops follicular thyroid cancer similar to human thyroid cancer. In line with epidemiologic findings in human cancer, treatment of ThrbPV/PVPten+/- mice with a high fat diet (HFD) effectively induced the obese phenotype. Moreover, HFD activates the STAT3 signal pathway to promote more aggressive tumor phenotypes. Thus, diet-induced obesity exacerbated thyroid cancer progression, suggesting that STAT3 could be a potential therapeutic target for obesity-induced thyroid cancer. To test this possibility, we treated HFD-ThrbPV/PVPten+/- mice with S3I-201, a specific inhibitor of STAT3. S3I-201 effectively inhibited HFD-induced aberrant activation of STAT3 and its downstream targets to markedly inhibit tumor growth and prolong survival. The abundance of several key cell cycle regulators such as cyclins D1, B1, and phosphorylated retinoblastoma protein was decreased by S3I-201 treatment. Histological analysis showed that S3I-201 prevented the occurrence of anaplasia and lung metastasis in HFD-treated mice by inhibiting key regulators of the epithelial-mesenchymal transition, such as vimentin and MMP2. Taken together, the present findings not only elucidate how obesity could contribute to thyroid cancer progress at the molecular level, but also, importantly, suggest that inhibition of the STAT3 activity could be a novel treatment strategy for obesity-induced thyroid cancer.

Scientific Focus Area: Cancer Biology

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