β-Catenin Regulates Deiodinase Levels and Thyroid Hormone Signaling in Colon Cancer Cells

Dentice, Monica; Luongo, Cristina; Ambrosio, Raffaele; Sibilio, Annarita; Casillo, Antonella; Iaccarino, Antonino; Troncone, Giancarlo; Fenzi, Gianfranco; Larsen, P. Reed; Salvatore, Domenico

doi:10.1053/j.gastro.2012.06.042

Cited by 99 publications

(90 citation statements)

References 32 publications

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“…Additionally, experimental studies in BCC and in colon tumor cells have shown that the increase in the DIO3 levels accompanied of DIO2 reduction would be associated with the induction of cell proliferation, by overexpression of cyclin D1. Accordingly, DIO3 knockdown caused a five-fold reduction in the growth of xenograft tumor, while the T 3 addition promoted differentiation (Dentice et al 2007(Dentice et al , 2012. Nevertheless, the mechanisms underlying D3 and/or hypothyroidism induction of proliferation are still open to debate.…”

Section: Discussionmentioning

confidence: 99%

“…In BCC, the DIO3 induction occurs via activation of the SHH/GLI pathway and is associated with increased levels of cyclin D1 and keratinocyte proliferation (Dentice et al 2007). High levels of DIO3 mRNA also occur in human intestinal adenomas and carcinomas (Dentice et al 2012). Interestingly, the activating TH enzyme, D2, was downregulated by SHH and B-catenin activation.…”

Section: Introductionmentioning

confidence: 99%

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MAPK and SHH pathways modulate type 3 deiodinase expression in papillary thyroid carcinoma

Romitti¹,

Wajner²,

Ceolin³

et al. 2016

Endocrine-Related Cancer

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Type 3 deiodinase (DIO3, D3) is reactivated in human neoplasias. Increased D3 levels in papillary thyroid carcinoma (PTC) have been associated with tumor size and metast atic disease. The objective of this study is to investigate the signaling pathways involved in DIO3 upregulation in PTC. Experiments were performed in human PTC cell lines (K1 and TPC-1 cells) or tumor samples. DIO3 mRNA and activity were evaluated by real-time PCR and ion-exchange column chromatography respectively. Western blot analysis was used to determine the levels of D3 protein. DIO3 gene silencing was performed via siRNA transfection. DIO3 mRNA levels and activity were readily detected in K1 (BRAF V600E ) and, at lower levels, in TPC-1 (RET/PTC1) cells (P!0.007 and PZ0.02 respectively). Similarly, DIO3 mRNA levels were higher in PTC samples harboring the BRAF V600E mutation as compared with those with RET/PTC1 rearrangement or negative for these mutations (P!0.001). Specific inhibition of BRAF oncogene (PLX4032, 3 mM), MEK (U0126, 10-20 mM) or p38 (SB203580, 10-20 mM) signaling was associated with decreases in DIO3 expression in K1 and TPC-1 cells. Additionally, the blockage of the sonic hedgehog (SHH) pathway by cyclopamine (10 mM) resulted in markedly decreases in DIO3 mRNA levels. Interestingly, siRNA-mediated DIO3 silencing induced decreases on cyclin D1 expression and partial G1 phase cell cycle arrest, thereby downregulating cell proliferation. In conclusion, sustained activation of the MAPK and SHH pathways modulate the levels of DIO3 expression in PTC. Importantly, DIO3 silencing was associated with decreases in cell proliferation, thus suggesting a D3 role in tumor growth and aggressiveness.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

MAPK and SHH pathways modulate type 3 deiodinase expression in papillary thyroid carcinoma

Romitti¹,

Wajner²,

Ceolin³

et al. 2016

Endocrine-Related Cancer

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“…The relative quantification of gene expression was calculated in triplicate reactions using the comparative C t method (DDC t ). BLOCK-iT Lentiviral RNAi Expression System (Life Technologies, Ltd) was used to the expression of miRNA silencing D3 (iD3) or negative control miR (iCTRL) into dissociated sphere cells, as previously reported (12).…”

Section: Cr-csc Transductionmentioning

confidence: 99%

“…To assess the role of D3 in the modulation of intracellular T3 and its effect on tumorigenic potential, we infected CRCSCs with a lentivirus able to efficiently knockdown D3 (12). D3 knockdown in CR-CSCs cells dramatically reduced the in vitro clonogenicity and their invasive capability as well as tumor growth in immunocompromised mice (data not shown).…”

Section: T3 Treatment Alters the Clonogenic Capacity And Cell-cycle Kmentioning

confidence: 99%

“…The Wnt signal, which rigorously controls the sequential events that leads to the transition from normal colon mucosa to adenocarcinoma, is one of the major forces that maintain the stem cells' fate and capacity to self-renew as well as their ability to escape conventional chemotherapyinduced apoptosis (10,11). We recently demonstrated that the Wnt-b-catenin pathway drives an inverse, coordinated regulation of D2 and D3 in colon cancer cells (12).…”

Section: Introductionmentioning

confidence: 99%

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Activated Thyroid Hormone Promotes Differentiation and Chemotherapeutic Sensitization of Colorectal Cancer Stem Cells by Regulating Wnt and BMP4 Signaling

et al. 2016

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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 druginduced cell differentiation may represent a promising therapy for preventing CSC expansion and tumor progression. Cancer Res; 76(5); 1237-44. Ó2015 AACR.

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Association Between Thyroid Disorders and Colorectal Cancer Risk in Adult Patients in Taiwan

L'Heureux¹,

Wieland

Weng

et al. 2019

JAMA Netw Open

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Key Points Question Are thyroid disorders associated with colorectal cancer risk in an East Asian population? Findings In this case-control study that included 139 426 adults in Taiwan with or without a diagnosis of primary colorectal cancer, both hyperthyroidism and hypothyroidism appeared to be associated with a statistically significantly decreased risk of colorectal cancer diagnosis. Meaning Given these findings, it appears that biochemical in vivo research and epidemiologic studies are needed to further clarify the nature of the association found between thyroid disease and colorectal cancer and may potentially advance the therapies for colorectal cancer.

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β-Catenin Regulates Deiodinase Levels and Thyroid Hormone Signaling in Colon Cancer Cells

Cited by 99 publications

References 32 publications

MAPK and SHH pathways modulate type 3 deiodinase expression in papillary thyroid carcinoma

MAPK and SHH pathways modulate type 3 deiodinase expression in papillary thyroid carcinoma

Activated Thyroid Hormone Promotes Differentiation and Chemotherapeutic Sensitization of Colorectal Cancer Stem Cells by Regulating Wnt and BMP4 Signaling

Association Between Thyroid Disorders and Colorectal Cancer Risk in Adult Patients in Taiwan

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