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Thyroid hormone suppresses cell proliferation through endoglin-mediated promotion of p21 stability

Oncogene volume 32, pages 3904–3914 (2013)Cite this article

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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.

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Acknowledgements

This work was supported by Grants from Chang-Gung University, Taoyuan, Taiwan (CMRPD 34013, NMRP 140511) and from the National Science Council of the Republic of China (NSC 94-2320-B-182-052).

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Authors and Affiliations

  1. Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan, Taiwan, Republic of China,

    Y-H Lin, M-H Wu, S-M Wu, H-C Chi, C-J Liao, C-Y Chen, Y-H Tseng, C-Y Tsai & K-H Lin

  2. Liver Research Center, Chang Gung Memorial Hospital, Linko, Taiwan, Republic of China,

    Y-H Huang

  3. Department of Nursing, Chang-Gung University of Science and Technology, Taoyuan, Taiwan, Republic of China,

    M-M Tsai

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  1. Y-H Lin
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Lin, YH., Huang, YH., Wu, MH. et al. Thyroid hormone suppresses cell proliferation through endoglin-mediated promotion of p21 stability. Oncogene 32, 3904–3914 (2013). https://doi.org/10.1038/onc.2013.5

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