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Supplementary Figures 1 through 9 from Activated Thyroid Hormone Promotes Differentiation and Chemotherapeutic Sensitization of Colorectal Cancer Stem Cells by Regulating Wnt and BMP4 Signaling

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posted on 2023-03-30, 23:44 authored by Veronica Catalano, Monica Dentice, Raffaele Ambrosio, Cristina Luongo, Rosachiara Carollo, Antonina Benfante, Matilde Todaro, Giorgio Stassi, Domenico Salvatore

Supplemental Material. Fig. S1: Summary of TRα and β, MCT8 and MCT10 expressions in the cell lines used in this study. Fig. S2: E-Cadherin and sucrose isomaltase expressions. Fig. S3: Flow cytometry profiles on freshly purified CRC cells. Fig. S4: Functional promoter studies in HEK293 cells treated or not with 30nM T3 in the presence of an empty vector or TRα expressing plasmid. Fig. S5: FACS analysis of cell cycle distribution of CR-CSCs untreated and treated with T3, FBS or FBS plus rT3. Fig. S6: p21 and p27 protein expression levels measured by western blot analysis in CR- CRC cells under different conditions. Fig. S7: Hes-1 expressions in cells knocked down for D3 (iD3). Fig. S8: Clustergrams of up and down-regulated Wnt Targets- and Pathways-related genes in CR-CSCs treated cells.Fig. S9: Representative H&E, CK20, Ki67, CD133 immunohistochemical analysis of cells treated with different THs.

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Associazione Italiana per la Ricerca sul Cancro (AIRC)

the financial support of the Italian Ministry of University and Research

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ARTICLE 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.

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