Compelling epidemiological evidence shows a strong positive correlation of obesity with thyroid cancer. In vivo studies have provided molecular evidence that high-fat-diet-induced obesity promotes thyroid cancer progression by aberrantly activating leptin-JAK2-STAT3 signaling in a mouse model of thyroid cancer (ThrbPV/PVPten+/- mice). The ThrbPV/PVPten+/- mouse expresses a dominantly negative thyroid hormone receptor beta (denoted as PV) and a deletion of one single allele of the Pten gene. The ThrbPV/PVPten+/- mouse spontaneously develops follicular thyroid cancer, which allows its use as a preclinical mouse model to test potential therapeutics. We recently showed that inhibition of STAT3 activity by a specific inhibitor markedly delays thyroid cancer progression in high-fat-diet-induced obese ThrbPV/PVPten+/- mice (HFD-ThrbPV/PVPten+/- mice). Further, metformin, a widely used antidiabetic drug, blocks invasion and metastasis, but not thyroid tumor growth in HFD-ThrbPV/PVPten+/- mice. To improve efficacy in reducing thyroid tumor growth, we treated HFD-ThrbPV/PVPten+/- with JQ1, a potent inhibitor of the activity of bromodomain and extraterminal domain (BET), and with metformin. We found that the combined treatment synergistically suppressed thyroid tumor growth by attenuating STAT3 and ERK signaling, resulting in decreased anti-apoptotic key regulators such as Mcl-1, Bcl-2, and sruvivin and increased pro-apoptotic regulators such as Bim, BAD and cleave caspase 3. Furthermore, combined treatment of JQ1 and metformin reduced cMYC protein levels to suppress vascular invasion, anaplasia, and lung metastasis. These findings indicate that combined treatment is more effective than metformin alone and suggest a novel treatment modality for obesity-activated thyroid cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC011191-10
Application #
9779825
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
10
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Kim, Won Gu; Cheng, Sheue-Yann (2018) Mechanisms Linking Obesity and Thyroid Cancer Development and Progression in Mouse Models. Horm Cancer 9:108-116
Park, Sunmi; Willingham, Mark C; Qi, Jun et al. (2018) Metformin and JQ1 synergistically inhibit obesity-activated thyroid cancer. Endocr Relat Cancer 25:865-877
Zhu, Xuguang; Cheng, Sheue-Yann (2018) Analysis of Thyroid Tumorigenesis in Xenograft Mouse Model. Methods Mol Biol 1801:207-223
Zhu, Xuguang; Cheng, Sheue Yann (2017) Epigenetic Modifications: Novel Therapeutic Approach for Thyroid Cancer. Endocrinol Metab (Seoul) 32:326-331
Park, Jeong Won; Zhao, Li; Willingham, Mark C et al. (2017) Inhibition of STAT3 signaling blocks obesity-induced mammary hyperplasia in a mouse model. Am J Cancer Res 7:727-739
Enomoto, Keisuke; Zhu, Xuguang; Park, Sunmi et al. (2017) Targeting MYC as a Therapeutic Intervention for Anaplastic Thyroid Cancer. J Clin Endocrinol Metab 102:2268-2280
Zhu, Xuguang; Enomoto, Keisuke; Zhao, Li et al. (2017) Bromodomain and Extraterminal Protein Inhibitor JQ1 Suppresses Thyroid Tumor Growth in a Mouse Model. Clin Cancer Res 23:430-440
Park, Jeongwon; Kim, Won Gu; Zhao, Li et al. (2016) Metformin blocks progression of obesity-activated thyroid cancer in a mouse model. Oncotarget :
Zhu, Xuguang; Kim, Dong Wook; Zhao, Li et al. (2016) SAHA-induced loss of tumor suppressor Pten gene promotes thyroid carcinogenesis in a mouse model. Endocr Relat Cancer 23:521-33
Park, Jeong Won; Zhao, Li; Willingham, Mark C et al. (2016) Loss of tyrosine phosphorylation at Y406 abrogates the tumor suppressor functions of the thyroid hormone receptor ?. Mol Carcinog :

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