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

Abstract

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...

Molecular functions and clinical impact of thyroid hormone-triggered autophagy in liver-related diseases

“…For instance, administration of TH not only reduces the size of preneoplastic lesions in the livers of rats suffering with HCC, but suppresses the aberrant cellular growth via control the expression of cell cycle regulators, such as CDK2, Cyclin E, UHRF1, STMN1 mir-214 and BC200 lncRNA [7,[171][172][173][174]. Our recent studies further support the preventive effect of TH on hepatocarcinogenesis via activating autophagy [16,17], whereas TH/THR is reported to promote metastasis and chemoresistance through control the expressions of BSSP4, TRAIL, BCL2L11, LCN2, mir-21, and mir-130b [7,173,[175][176][177][178][179][180]. This characteristic of THs supports the double-edged sword effect of autophagy in cancer progression.…”

Global DNA methylation analysis reveals miR-214-3p contributes to cisplatin resistance in pediatric intracranial nongerminomatous malignant germ cell tumors

“…37 The pro-apoptotic protein BCL2L11 (BIM) is associated with cisplatin resistance in several cancers, including ovarian cancer 38 and hepatocarcinoma. 39 Furthermore, better prognosis correlates with higher BCL2L11 expression in nasopharyngeal carcinomas. 29 Dysregulated miRNA expression is well known in cancers and can contribute to chemotherapy resistance through the binding and transcription regulation of downstream targets.…”

Screening of Hub Genes in Hepatocellular Carcinoma Based on Network Analysis and Machine Learning

“…Hepatocellular carcinoma is a sex-specific cancer, and in general, men are two to four times more likely to develop HCC than women [86], which predicts that some hormonal changes may contribute to this difference, among which progesterone receptor expression can affect the proliferation of hepatocellular carcinoma [87]. Enriched pathway, in which the FOXO transcription factor family plays an important role in tumor proliferation and apoptosis [88], FOXO1 was shown to play a repressive role in hepatocellular carcinoma [89], and other FOXO transcription factors have been shown to be associated with hepatocellular carcinoma [90,91]. These evidences suggest that the genes we screened affect the progression of hepatocellular carcinoma by influencing the metabolic, immune, and other pathways.…”