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Published on: August 23, 2019
Thyroid hormone suppresses cell proliferation through endoglin-mediated promotion of p21 stability
1Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan, Taiwan, Republic of China.
Abstract:
Hypothyroidism has been associated with significantly elevated risk for hepatocellular carcinoma (HCC), although the precise underlying mechanisms remain unknown at present. Thyroid hormone (T3) and its receptor (TR) are involved in metabolism and growth. Endoglin is a T3/TR candidate target gene identified from our previous studies. Here, we demonstrated that T3 positively regulates endoglin mRNA and protein levels, both in vitro and in vivo. The thyroid hormone response elements of endoglin were identified at positions -2114/-2004 and -2032/-1973 of the promoter region using the electrophoretic mobility shift assay and chromatin immunoprecipitation assay. Endoglin was downregulated in the subgroups of HCC patients and significantly associated with histology grade (negative association, P=0.001), and this expression level was significantly associated with TRα1 in these HCC patients. Our results clearly indicate that p21 is involved in T3-mediated suppression of cell proliferation. Knock down of endoglin expression in HCC cells facilitated p21 polyubiquitination and promoted cell proliferation in the presence of T3. The data collectively suggest that T3/TR signaling suppresses cell proliferation by upregulating endoglin, in turn, affecting p21 stability. The results indicate that endoglin has a suppressor role to inhibit cell proliferation in HCC cell lines.
Insights
Thyroid hormone (T3) signaling suppresses hepatocellular carcinoma (HCC) cell proliferation by upregulating endoglin. This mechanism involves T3/TR signaling influencing p21 stability, with endoglin acting as a tumor suppressor in HCC.
Area of Science:
- Endocrinology
- Oncology
- Molecular Biology
Background:
- Hypothyroidism is linked to increased hepatocellular carcinoma (HCC) risk, but mechanisms are unclear.
- Thyroid hormone (T3) and its receptor (TR) regulate metabolism and growth.
- Endoglin is a potential T3/TR target gene implicated in T3 regulation.
Purpose of the Study:
- To investigate the role of T3/TR signaling in HCC.
- To elucidate the function of endoglin in T3-mediated regulation of HCC cell proliferation.
Main Methods:
- In vitro and in vivo experiments to assess T3 regulation of endoglin.
- Electrophoretic mobility shift and chromatin immunoprecipitation assays to identify thyroid hormone response elements in the endoglin promoter.
- Analysis of endoglin expression in HCC patient subgroups and correlation with histology and TRα1.
- Experiments involving endoglin knockdown in HCC cells to assess proliferation and p21 polyubiquitination.
Main Results:
- T3 positively regulates endoglin mRNA and protein levels.
- Endoglin promoter contains T3/TR binding sites.
- Endoglin is downregulated in HCC and associated with histology grade and TRα1 expression.
- T3-mediated suppression of HCC cell proliferation involves p21.
- Endoglin knockdown promotes HCC cell proliferation by affecting p21 stability.
Conclusions:
- T3/TR signaling suppresses HCC cell proliferation via endoglin upregulation.
- Endoglin influences p21 stability, contributing to its tumor suppressor role in HCC.
- Endoglin acts as an inhibitor of cell proliferation in HCC cell lines.
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