title: Inhibition of tumorigenesis by the thyroid hormone receptor β in xenograft models.
abstract: BACKGROUND
  Previous studies showed a close association between several types of human cancers and somatic mutations of thyroid hormone receptor β (TRβ) and reduced expression of TRβ due to epigenetic inactivation and/or deletion of the THRB gene. These observations suggest that TRβ could act as a tumor suppressor in carcinogenesis. However, the mechanisms by which TRβ could function to inhibit tumorigenesis are less well understood.
  
  
  METHODS
  We used the human follicular thyroid cancer cell lines (FTC-133 and FTC-236 cells) to elucidate how functional expression of the THRB gene could affect tumorigenesis. We stably expressed the THRB gene in FTC cells and evaluated the effects of the expressed TRβ on cancer cell proliferation, migration, and tumor growth in cell-based studies and xenograft models.
  
  
  RESULTS
  Expression of TRβ in FTC-133 cells, as compared with control FTC cells without TRβ, reduced cancer cell proliferation and impeded migration of tumor cells through inhibition of the AKT-mTOR-p70 S6K pathway. TRβ expression in FTC-133 and FTC-236 led to less tumor growth in xenograft models. Importantly, new vessel formation was significantly suppressed in tumors induced by FTC cells expressing TRβ compared with control FTC cells without TRβ. The decrease in vessel formation was mediated by the downregulation of vascular endothelial growth factor in FTC cells expressing TRβ.
  
  
  CONCLUSIONS
  These findings indicate that TRβ acts as a tumor suppressor through downregulation of the AKT-mTOR-p70 S6K pathway and decreased vascular endothelial growth factor expression in FTC cells. The present results raise the possibility that TRβ could be considered as a potential therapeutic target for thyroid cancer.
authors.affiliation: Laboratory of Molecular Biology, Center for Cancer Research , National Cancer Institute, Bethesda, Maryland.
authors.forename: Won Gu
authors.initials: WG
authors.lastname: Kim
authors.forename: Li
authors.initials: L
authors.lastname: Zhao
authors.forename: Dong Wook
authors.initials: DW
authors.lastname: Kim
authors.forename: Mark C
authors.initials: MC
authors.lastname: Willingham
authors.forename: Sheue-yann
authors.initials: SY
authors.lastname: Cheng
mesh_terms: D018263:Adenocarcinoma, Follicular / Q000473:pathology; D020533:Angiogenesis Inhibitors / Q000502:physiology; D000818:Animals; D045744:Cell Line, Tumor; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D058570:TOR Serine-Threonine Kinases; D037042:Thyroid Hormone Receptors beta / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D013964:Thyroid Neoplasms / Q000473:pathology; D014284:Triiodothyronine / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000096:biosynthesis
chemical_list: D020533:Angiogenesis Inhibitors; D037042:Thyroid Hormone Receptors beta; D025521:Tumor Suppressor Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D014284:Triiodothyronine; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases