title: Diet-induced obesity increases tumor growth and promotes anaplastic change in thyroid cancer in a mouse model.
abstract: Recent epidemiological studies provide strong evidence suggesting obesity is a risk factor in several cancers, including thyroid cancer. However, the molecular mechanisms by which obesity increases the risk of thyroid cancer are poorly understood. In this study, we evaluated the effect of diet-induced obesity on thyroid carcinogenesis in a mouse model that spontaneously develops thyroid cancer (Thrb(PV/PV)Pten(+/-) mice). These mice harbor a mutated thyroid hormone receptor-β (denoted as PV) and haplodeficiency of the Pten gene. A high-fat diet (HFD) efficiently induced the obese phenotype in Thrb(PV/PV)Pten(+/-) mice after 15 weeks. Thyroid tumor growth was markedly greater and survival was significantly lower in Thrb(PV/PV)Pten(+/-) mice fed an HFD than in controls fed a low-fat diet (LFD). The HFD increased thyroid tumor cell proliferation by increasing the protein levels of cyclin D1 and phosphorylated retinoblastoma protein to propel cell cycle progression. Histopathological analysis showed that the frequency of anaplasia of thyroid cancer was significantly greater (2.6-fold) in the HFD group than the LFD group. The HFD treatment led to an increase in parametrial/epididymal fat pad and elevated serum leptin levels in Thrb(PV/PV)Pten(+/-) mice. Further molecular analyses indicated that the HFD induced more aggressive pathological changes that were mediated by increased activation of the Janus kinase 2-signaling transducer and activator of transcription 3 (STAT3) signaling pathway and induction of STAT3 target gene expression. Our findings demonstrate that diet-induced obesity exacerbates thyroid cancer progression in Thrb(PV/PV)Pten(+/-) mice and suggest that the STAT3 signaling pathway could be tested as a potential target for the treatment of thyroid cancer.
authors.affiliation: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892-4264, USA.
authors.forename: Won Gu
authors.initials: WG
authors.lastname: Kim
authors.forename: Jeong Won
authors.initials: JW
authors.lastname: Park
authors.forename: Mark C
authors.initials: MC
authors.lastname: Willingham
authors.forename: Sheue-yann
authors.initials: SY
authors.lastname: Cheng
mesh_terms: D000818:Animals; D002453:Cell Cycle; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects*; D004195:Disease Models, Animal; D005260:Female; D006579:Heterozygote; D053614:Janus Kinase 2 / Q000378:metabolism; D020738:Leptin / Q000097:blood; D008297:Male; D051379:Mice; D009154:Mutation; D009765:Obesity / Q000209:etiology / Q000503:physiopathology*; D051059:PTEN Phosphohydrolase / Q000235:genetics; D010766:Phosphorylation; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D013961:Thyroid Gland / Q000378:metabolism / Q000473:pathology*; D037042:Thyroid Hormone Receptors beta / Q000235:genetics; D013964:Thyroid Neoplasms / Q000235:genetics / Q000473:pathology*; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C494812:Bcl2l1 protein, mouse; D020738:Leptin; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D016160:Retinoblastoma Protein; D050796:STAT3 Transcription Factor; D037042:Thyroid Hormone Receptors beta; D051020:bcl-X Protein; D019938:Cyclin D1; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D051059:PTEN Phosphohydrolase