Epigenetic regulation of thyroid hormone receptor beta in renal cancer.

Thyroid hormone receptor beta (THRB) gene is commonly deregulated in cancers and, as strengthened by animal models, postulated to play a tumor-suppressive role. Our previous studies revealed downregulation of THRB in clear cell renal cell carcinoma (ccRCC), but the culpable mechanisms have not been...

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Autores principales:	Anna Wojcicka, Agnieszka Piekielko-Witkowska, Hanna Kedzierska, Beata Rybicka, Piotr Poplawski, Joanna Boguslawska, Adam Master, Alicja Nauman
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/b4bc2b432cf4431f9f593115fbc66c2f
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spelling	oai:doaj.org-article:b4bc2b432cf4431f9f593115fbc66c2f2021-11-18T08:18:22ZEpigenetic regulation of thyroid hormone receptor beta in renal cancer.1932-620310.1371/journal.pone.0097624https://doaj.org/article/b4bc2b432cf4431f9f593115fbc66c2f2014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24849932/?tool=EBIhttps://doaj.org/toc/1932-6203Thyroid hormone receptor beta (THRB) gene is commonly deregulated in cancers and, as strengthened by animal models, postulated to play a tumor-suppressive role. Our previous studies revealed downregulation of THRB in clear cell renal cell carcinoma (ccRCC), but the culpable mechanisms have not been fully elucidated. Since epigenetic regulation is a common mechanism influencing the expression of tumor suppressors, we hypothesized that downregulation of THRB in renal cancer results from epigenetic aberrances, including CpG methylation and microRNA-dependent silencing. Our study revealed that ccRCC tumors exhibited a 56% decrease in THRB and a 37% increase in DNA methyltransferase 1 (DNMT1) expression when compared with paired non-neoplastic control samples. However, THRB CpG methylation analysis performed using BSP, SNaPshot and MSP-PCR consistently revealed no changes in methylation patterns between matched tumor and control samples. In silico analysis resulted in identification of four microRNAs (miR-155, miR-425, miR-592, and miR-599) as potentially targeting THRB transcript. Luciferase assay showed direct binding of miR-155 and miR-425 to 3'UTR of THRB, and subsequent in vivo analyses revealed that transfection of UOK171 cell line with synthetic miR-155 or miR-425 resulted in decreased expression of endogenous TRHB by 22% and 64%, respectively. Finally, real-time PCR analysis showed significant upregulation of miR-155 (354%) and miR-425 (162%) in ccRCC when compared with matched controls. Moreover, microRNA levels were negatively correlated with the amount of THRB transcript in tissue samples. We conclude that CpG methylation is not the major mechanism contributing to decreased THRB expression in ccRCC. In contrast, THRB is targeted by microRNAs miR-155 and miR-425, whose increased expression may be responsible for downregulation of THRB in ccRCC tumors.Anna WojcickaAgnieszka Piekielko-WitkowskaHanna KedzierskaBeata RybickaPiotr PoplawskiJoanna BoguslawskaAdam MasterAlicja NaumanPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 5, p e97624 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Anna Wojcicka Agnieszka Piekielko-Witkowska Hanna Kedzierska Beata Rybicka Piotr Poplawski Joanna Boguslawska Adam Master Alicja Nauman Epigenetic regulation of thyroid hormone receptor beta in renal cancer.
description	Thyroid hormone receptor beta (THRB) gene is commonly deregulated in cancers and, as strengthened by animal models, postulated to play a tumor-suppressive role. Our previous studies revealed downregulation of THRB in clear cell renal cell carcinoma (ccRCC), but the culpable mechanisms have not been fully elucidated. Since epigenetic regulation is a common mechanism influencing the expression of tumor suppressors, we hypothesized that downregulation of THRB in renal cancer results from epigenetic aberrances, including CpG methylation and microRNA-dependent silencing. Our study revealed that ccRCC tumors exhibited a 56% decrease in THRB and a 37% increase in DNA methyltransferase 1 (DNMT1) expression when compared with paired non-neoplastic control samples. However, THRB CpG methylation analysis performed using BSP, SNaPshot and MSP-PCR consistently revealed no changes in methylation patterns between matched tumor and control samples. In silico analysis resulted in identification of four microRNAs (miR-155, miR-425, miR-592, and miR-599) as potentially targeting THRB transcript. Luciferase assay showed direct binding of miR-155 and miR-425 to 3'UTR of THRB, and subsequent in vivo analyses revealed that transfection of UOK171 cell line with synthetic miR-155 or miR-425 resulted in decreased expression of endogenous TRHB by 22% and 64%, respectively. Finally, real-time PCR analysis showed significant upregulation of miR-155 (354%) and miR-425 (162%) in ccRCC when compared with matched controls. Moreover, microRNA levels were negatively correlated with the amount of THRB transcript in tissue samples. We conclude that CpG methylation is not the major mechanism contributing to decreased THRB expression in ccRCC. In contrast, THRB is targeted by microRNAs miR-155 and miR-425, whose increased expression may be responsible for downregulation of THRB in ccRCC tumors.
format	article
author	Anna Wojcicka Agnieszka Piekielko-Witkowska Hanna Kedzierska Beata Rybicka Piotr Poplawski Joanna Boguslawska Adam Master Alicja Nauman
author_facet	Anna Wojcicka Agnieszka Piekielko-Witkowska Hanna Kedzierska Beata Rybicka Piotr Poplawski Joanna Boguslawska Adam Master Alicja Nauman
author_sort	Anna Wojcicka
title	Epigenetic regulation of thyroid hormone receptor beta in renal cancer.
title_short	Epigenetic regulation of thyroid hormone receptor beta in renal cancer.
title_full	Epigenetic regulation of thyroid hormone receptor beta in renal cancer.
title_fullStr	Epigenetic regulation of thyroid hormone receptor beta in renal cancer.
title_full_unstemmed	Epigenetic regulation of thyroid hormone receptor beta in renal cancer.
title_sort	epigenetic regulation of thyroid hormone receptor beta in renal cancer.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/b4bc2b432cf4431f9f593115fbc66c2f
work_keys_str_mv	AT annawojcicka epigeneticregulationofthyroidhormonereceptorbetainrenalcancer AT agnieszkapiekielkowitkowska epigeneticregulationofthyroidhormonereceptorbetainrenalcancer AT hannakedzierska epigeneticregulationofthyroidhormonereceptorbetainrenalcancer AT beatarybicka epigeneticregulationofthyroidhormonereceptorbetainrenalcancer AT piotrpoplawski epigeneticregulationofthyroidhormonereceptorbetainrenalcancer AT joannaboguslawska epigeneticregulationofthyroidhormonereceptorbetainrenalcancer AT adammaster epigeneticregulationofthyroidhormonereceptorbetainrenalcancer AT alicjanauman epigeneticregulationofthyroidhormonereceptorbetainrenalcancer
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Epigenetic regulation of thyroid hormone receptor beta in renal cancer.

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