Regulation of AKR1B1 by thyroid hormone and its receptors

Liao, Chen Shin; Tai, Pei Ju; Huang, Yeou‐Lih; Chen, Ruey Nan; Wu, Sheng; Kuo, Lu Wei; Yeh, Chau Ting; Tsai, Ming Chieh; Chen, Wei Jan; Lin, Kwang Huei

doi:10.1016/j.mce.2009.04.013

“…Recently, oligonucleotide microarrays were carried out to identify more TR-target genes. Some of the results have been published including the identification of FURIN (Chen et al, 2008a), SPON2 , MATA1A (Wu et al, 2010), SULT2A1 (Huang et al, 2006) and AKR1B1 (Liao et al, 2009). Supplementary Table S1 lists several cancer-related genes, including those encoding cathepsin proteases positively regulated by T 3 .…”

Section: Resultsmentioning

confidence: 99%

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

Wu

¹

,

Huang

²

,

Yeh

³

et al. 2011

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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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“…Subsequent procedures were performed as described previously. 48 Rabbit anti-human antibodies against Bim and active caspase-3 were purchased from Epitomics (Burlingame, CA, USA). The rabbit anti-GFP antibody was obtained from GeneTex (Irvine, CA, USA).…”

Section: Methodsmentioning

confidence: 99%

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

Cheng

¹

,

Chen

²

,

Cheng

³

et al. 2016

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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.

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“…Subsequent procedures were performed as described previously. 48 Rabbit antihuman antibodies against Bim and active caspase-3 were purchased from Epitomics (Burlingame, CA, USA). The rabbit anti-GFP antibody was obtained from GeneTex (Irvine, CA, USA).…”

Section: Real-time Pcr (Qrt-pcr)mentioning

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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Regulation of AKR1B1 by thyroid hormone and its receptors

Cited by 19 publications

References 30 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

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

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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