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Thyroid Hormone in Hepatocellular Carcinoma: Cancer Risk, Growth Regulation, and Anticancer Drug Resistance.

ABSTRACT: Thyroid hormone (TH) and its receptor (TR) are involved in differentiation, metabolic process, and growth regulation in hepatocellular carcinoma (HCC). The TH/TR complexes are ligand-dependent transcriptional factors, functioning through binding to thyroid hormone response elements (TREs) upstream of the target genes. To date, deciphering the biological effects of TH in cancer progression remains challenging. Several lines of evidence suggest a growth inhibitory effect of TH in liver cancer. Mutation and aberrant expression of TRs are highly correlated with several types of cancers including HCC. Several reports show that TH inhibits cell growth in liver cancer through regulation of cell-cycle-related genes and non-coding RNAs. A case-control study indicates that hypothyroidism is associated with an increased risk of HCC. Moreover, TH/TR suppresses hepatocarcinogenesis via selective autophagy. Conversely, other groups have indicated that TH promotes cancer cell proliferation. In vitro and in vivo experiments show that TH/TR enhances cancer cell migration and invasion, anticancer drug resistance, angiogenesis, and cancer stem cell self-renewal. Adding to the complexity of this issue, non-genomic effects of TH mediated by integrin receptor on cell surface can also modulate several biological functions. Accumulating evidence indicate that regulations by genomic and non-genomic effects of TH overlap. Taken together, these observations suggest that the functions of TH depend largely on cell context, and TH/TR plays a duel role in cancer progression. Therefore, understanding the maze of biological effects of TH has become a necessity when attempting to develop effective therapeutic and preventive strategies in liver cancer.

SUBMITTER: Lin YH

PROVIDER: S-EPMC7258858 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Thyroid Hormone in Hepatocellular Carcinoma: Cancer Risk, Growth Regulation, and Anticancer Drug Resistance.

Lin Yang-Hsiang YH Lin Kwang-Huei KH Yeh Chau-Ting CT

Frontiers in medicine 20200522

Thyroid hormone (TH) and its receptor (TR) are involved in differentiation, metabolic process, and growth regulation in hepatocellular carcinoma (HCC). The TH/TR complexes are ligand-dependent transcriptional factors, functioning through binding to thyroid hormone response elements (TREs) upstream of the target genes. To date, deciphering the biological effects of TH in cancer progression remains challenging. Several lines of evidence suggest a growth inhibitory effect of TH in liver cancer. Mut ...[more]

PMID: 32528965

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Project description:IntroductionHepatocellular carcinoma (HCC) is the most common type of primary liver cancers. It is an aggressive neoplasm with dismal outcome because most of the patients present with an advanced-stage disease, which precludes curative surgical options. Therefore, these patients require systemic therapies that typically induce small improvements in overall survival. Hence, it is crucial to identify new and promising therapeutic targets for HCC to improve the current outcome. The liver is a key organ in the signaling cascade triggered by the growth hormone receptor (GHR). Previous studies have shown that GHR signaling stimulates the proliferation and regeneration of liver cells and tissues; however, a definitive role of GHR signaling in HCC pathogenesis has not been identified.MethodsIn this study, we used a direct and specific approach to analyze the role of GHR in HCC development. This approach encompasses mice with global (Ghr-/- ) or liver-specific (LiGhr-/- ) disruption of GHR expression, and the injection of diethylnitrosamine (DEN) to develop HCC in these mice.ResultsOur data show that DEN induced HCC in a substantial majority of the Ghr+/+ (93.5%) and Ghr +/- (87.1%) mice but not in the Ghr-/- (5.6%) mice (P < 0.0001). Although 57.7% of LiGhr-/- mice developed HCC after injection of DEN, these mice had significantly fewer tumors than LiGhr+/+ (P < 0.001), which implies that the expression of GHR in the liver cells might increase tumor burden. Notably, the pathologic, histologic, and biochemical characteristics of DEN-induced HCC in mice resembled to a great extent human HCC, despite the fact that etiologically this model does not mimic this cancer in humans. Our data also show that the effects of DEN on mice livers were primarily related to its carcinogenic effects and ability to induce HCC, with minimal effects related to toxic effects.ConclusionCollectively, our data support an important role of GHR in HCC development, and suggest that exploiting GHR signaling may represent a promising approach to treat HCC.

Dataset Information

Thyroid Hormone in Hepatocellular Carcinoma: Cancer Risk, Growth Regulation, and Anticancer Drug Resistance.

Publications

Thyroid Hormone in Hepatocellular Carcinoma: Cancer Risk, Growth Regulation, and Anticancer Drug Resistance.

Similar Datasets

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