Cooperation Between the Thyroid Hormone Receptor TRα1 and the WNT Pathway in the Induction of Intestinal Tumorigenesis

Kress, Elsa; Skah, Seham; Sirakov, M; Nadjar, Julien; Gadot, Nicolas; Scoazec, Jean‐Yves; Samarut, Jacques; Plateroti, Michelina

doi:10.1053/j.gastro.2010.01.041

Cited by 73 publications

(97 citation statements)

References 36 publications

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“…Recent report showed that hypothyroidism was associated with a high risk of HCC in women (Hassan et al, 2009) (Kress et al, 2010). However, TRa1 when specifically overexpressed in the intestinal epithelium is unable to induce cancer development.…”

Section: Discussionmentioning

confidence: 99%

Cathepsin H regulated by the thyroid hormone receptors associate with tumor invasion in human hepatoma cells

Huang

Yeh

et al. 2011

Oncogene

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Thyroid hormone, 3, 3 0 , 5-triiodo-L-thyronine (T 3 ), mediates cell growth, development and differentiation by binding to its nuclear receptors (TRs). The role of TRs in cancer is still undefined. Notably, hyperthyroxinemia has been reported to influence the rate of colon cancer in an experimental model of carcinogenesis in rats. Previous microarray analysis revealed that cathepsin H (CTSH) is upregulated by T 3 in HepG2-TR cells. We verified that mRNA and protein expression of CTSH are induced by T 3 in HepG2-TR cells and in thyroidectomized rats following administration of T 3 . The possible thyroid hormone-responsive elements of the CTSH promoter localized to the nucleotides -2038 to -1966 and -1565 to -1501 regions. An in vitro functional assay showed that CTSH can increase metastasis. J7 cells overexpressing CTSH were inoculated into severe combined immunedeficient mice and these J7-CTSH mice displayed a greater metastatic potential than did J7-control mice. The clinicopathologic significance of CTSH expression in hepatocellular carcinoma (HCC) was also investigated. The CTSH overexpressing in HCC was associated with the presence of microvascular invasion (P ¼ 0.037). The microvascular invasion characteristic is closely related to our in vitro characterization of CTSH function. Our results show that T 3 -mediated upregulation of CTSH led to matrix metallopeptidase or extracellular signal-regulated kinase activation and increased cell migration. This study demonstrated that CTSH overexpression in a subset hepatoma may be TR dependent and suggests that this overexpression has an important role in hepatoma progression.

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Section: Discussionmentioning

confidence: 99%

Cathepsin H regulated by the thyroid hormone receptors associate with tumor invasion in human hepatoma cells

Huang

Yeh

et al. 2011

Oncogene

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“…6), which are key cellular transduction pathways in normal functional cells and important regulators of cellular growth, metabolism, and survival. Recent evidence, however, recognizes INSRA and THRA as being overexpressed in several tumors including colonic adenomas 24 and CRC. 25 The PI3K and MAPK signaling pathways converge on MKNK2, as does several pathways of a range of inflammation-associated cytokine receptors (e.g., interleukin 1 and tumor necrosis factor alpha; Fig.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Analysis of Left-sided Colitis, Pancolitis, and Ulcerative Colitis-associated Dysplasia

Bjerrum

Nielsen

Riis

et al. 2014

Inflammatory Bowel Diseases

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“…Intriguingly, in a strain of Wntactivated Apc + / 1638N mice, TRα overexpression in the intestinal epithelium did not induce cancer formation but rather accelerated tumorigenesis. 36 Recently, another group reported that TRs act as potent suppressors of tumor metastasis in breast cancer cell lines. 37 The investigators further showed that mice with double knockout of TRα and TRβ are vulnerable to epithelial tumors and that TR deficiency suppresses the number of benign tumors but enhances malignant tumor formation during carcinogenesis.…”

Section: Discussionmentioning

confidence: 99%

Chemotherapy resistance and metastasis-promoting effects of thyroid hormone in hepatocarcinoma cells are mediated by suppression of FoxO1 and Bim pathway

Chi¹,

Lin²

2016

EJEA

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Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide, and systemic chemotherapy is the major treatment strategy for late-stage HCC patients. Poor prognosis following chemotherapy is the general outcome owing to recurrent resistance. Recent studies have suggested that in addition to cytotoxic effects on tumor cells, chemotherapy can induce an alternative cascade that supports tumor growth and metastasis. In the present investigation, we showed that thyroid hormone (TH), a potent hormone-mediating cellular differentiation and metabolism, acts as an antiapoptosis factor upon challenge of thyroid hormone receptor (TR)-expressing HCC cells with cancer therapy drugs, including cisplatin, doxorubicin and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). TH/TR signaling promoted chemotherapy resistance through negatively regulating the pro-apoptotic protein, Bim, resulting in doxorubicin-induced metastasis of chemotherapy-resistant HCC cells. Ectopic expression of Bim in hepatoma cells challenged with chemotherapeutic drugs abolished TH/TR-triggered apoptosis resistance and metastasis. Furthermore, Bim expression was directly transactivated by Forkhead box protein O1 (FoxO1), which was negatively regulated by TH/TR. TH/TR suppressed FoxO1 activity through both transcriptional downregulation and nuclear exclusion of FoxO1 triggered by Akt-mediated phosphorylation. Ectopic expression of the constitutively active FoxO1 mutant, FoxO1-AAA, but not FoxO1-wt, diminished the suppressive effect of TH/TR on Bim. Our findings collectively suggest that expression of Bim is mediated by FoxO1 and indirectly downregulated by TH/TR, leading to chemotherapy resistance and doxorubicin-promoted metastasis of hepatoma cells. Cell Death and Disease (2016) 7, e2324; doi:10.1038/cddis.2016.227; published online 4 August 2016Hormones are molecules produced by glands in the body that enter the bloodstream and influence the behavior of another group of cells located distally. Aberrant hormone levels are implicated in the formation of several cancers. For instance, excessive estrogen or progesterone is reported to promote cellular growth of breast and prostate tumors, with antiestrogen and progesterone currently used as the main treatment strategies for these cancer types.1,2 Thyroid hormones (TH), mainly 3,3′-5-tri-iodo-L-thyronine (T 3 ), are potent mediators of multiple physiological activities, including cellular differentiation, metabolic rate, digestive functions and lipid metabolism.3,4 The actions of T 3 are executed via binding to thyroid hormone receptor (TR) located in the nucleus. TRs are ligand-dependent transcription factors encoded by two genes, TRα and TRβ. Upon binding of T 3 , TRs release associated co-repressors and recruit transcriptional co-activators to initiate target gene transcription.5 Liver is one of the major target organs of T 3 , and body TH levels are closely correlated with multiple liver-associated diseases, such as hepatocellular carcinoma (HCC). 6-9In the die...

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Cooperation Between the Thyroid Hormone Receptor TRα1 and the WNT Pathway in the Induction of Intestinal Tumorigenesis

Cited by 73 publications

References 36 publications

Cathepsin H regulated by the thyroid hormone receptors associate with tumor invasion in human hepatoma cells

Cathepsin H regulated by the thyroid hormone receptors associate with tumor invasion in human hepatoma cells

Transcriptional Analysis of Left-sided Colitis, Pancolitis, and Ulcerative Colitis-associated Dysplasia

Chemotherapy resistance and metastasis-promoting effects of thyroid hormone in hepatocarcinoma cells are mediated by suppression of FoxO1 and Bim pathway

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