Association between hypothyroidism and hepatocellular carcinoma: A case-control study in the United States #

Hassan, Manal M.; Kaseb, Ahmed O.; Li, Donghui; Patt, Yehuda Z.; Vauthey, Jean‐Nicolas; Thomas, Melanie B.; Curley, Steven A.; Spitz, Margaret R.; Sherman, Steven I.; Abdalla, Eddie K.; Davila, Marta; Lozano, Richard D.; Hassan, D.; Chan, Wenyaw; Brown, Thomas; Abbruzzese, James L.

doi:10.1002/hep.22793

Cited by 151 publications

(135 citation statements)

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“…Clinical hypothyroidism seems to be a risk factor for several neoplasias such as liver cancer, thyroid malignancies, high-grade glioblastomas and human breast cancer (Reddi et al 2007, Polyzos et al 2008, Hassan et al 2009, Angelousi et al 2012. In contrast, increased TH levels have been associated with higher risk of esophageal, thyroid, breast and ovarian cancer development (Turkyilmaz et al 2005, Rasool et al 2014, Kunjumohamed et al 2015.…”

Section: Discussionmentioning

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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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%

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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“…34 A recent epidemiological study also suggested that long-term hypothyroidism is positively correlated with HCC incidence, independent of other risk factors. 35 However, the proposed tumor-suppressor role of TRs remains a subject of controversy. For example, an animal model of colorectal tumorigenesis revealed that TRα1 positively regulates several molecules downstream of the Wnt signal, consequently facilitating the expression of β-catenin/Tcf4 target genes and enhancing cell growth.…”

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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“…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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Association between hypothyroidism and hepatocellular carcinoma: A case-control study in the United States #

Cited by 151 publications

References 38 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

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

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

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