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RESEARCH PRODUCT
Activated Thyroid Hormone Promotes Differentiation and Chemotherapeutic Sensitization of Colorectal Cancer Stem Cells by Regulating Wnt and BMP4 Signaling
Raffaele AmbrosioCristina LuongoMatilde TodaroDomenico SalvatoreR. CarolloAntonina BenfanteGiorgio StassiVeronica CatalanoMonica Denticesubject
Male0301 basic medicineThyroid Hormonesendocrine systemCancer Researchmedicine.medical_specialtyendocrine system diseasesCellular differentiationDeiodinaseBone Morphogenetic Protein 4Colorectal NeoplasmMice03 medical and health sciencesCancer stem cellCell Line TumorInternal medicinemedicineAnimalsHumansThyroid HormoneWnt Signaling PathwayHormone activityThyroid hormone receptorbiologyAnimalThyroidWnt signaling pathwayCell DifferentiationMiddle Aged030104 developmental biologyEndocrinologymedicine.anatomical_structureOncologyNeoplastic Stem CellsCancer researchbiology.proteinNeoplastic Stem CellColorectal NeoplasmsHumanSignal TransductionHormonedescription
Abstract Thyroid hormone is a pleiotropic factor that controls many cellular processes in multiple cell types such as cancer stem cells (CSC). Thyroid hormone concentrations in the blood are stable, but the action of the deiodinases (D2–D3) provides cell-specific regulation of thyroid hormone activity. Deregulation of deiodinase function and thyroid hormone status has been implicated in tumorigenesis. Therefore, we investigated the role of thyroid hormone metabolism and signaling in colorectal CSCs (CR-CSC), where deiodinases control cell division and chemosensitivity. We found that increased intracellular thyroid hormone concentration through D3 depletion induced cell differentiation and sharply mitigated tumor formation. Upregulated BMP4 expression and concomitantly attenuated Wnt signaling accompanied these effects. Furthermore, we demonstrate that BMP4 is a direct thyroid hormone target and is involved in a positive autoregulatory feedback loop that modulates thyroid hormone signaling. Collectively, our findings highlight a cell-autonomous metabolic mechanism by which CR-CSCs exploit thyroid hormone signaling to facilitate their self-renewal potential and suggest that drug-induced cell differentiation may represent a promising therapy for preventing CSC expansion and tumor progression. Cancer Res; 76(5); 1237–44. ©2015 AACR.
year | journal | country | edition | language |
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2016-01-01 | Cancer Research |