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Activation of the RhoB Signaling Pathway by Thyroid Hormone Receptor β in Thyroid Cancer Cells

Thyroid hormone receptor (TR) mediates the crucial effects of the thyroid hormone (T3) on cellular growth, development, and differentiation. Decreased expression or inactivating somatic mutations of TRs have been found in human cancers of the liver, breast, lung, and thyroid. The mechanisms of TR-as...

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Autores principales: Ichijo, Sayaka, Furuya, Fumihiko, Shimura, Hiroki, Hayashi, Yoshitaka, Takahashi, Kazuya, Ohta, Kazuyasu, Kobayashi, Tetsuro, Kitamura, Kenichiro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4280201/
https://www.ncbi.nlm.nih.gov/pubmed/25548921
http://dx.doi.org/10.1371/journal.pone.0116252
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author Ichijo, Sayaka
Furuya, Fumihiko
Shimura, Hiroki
Hayashi, Yoshitaka
Takahashi, Kazuya
Ohta, Kazuyasu
Kobayashi, Tetsuro
Kitamura, Kenichiro
author_facet Ichijo, Sayaka
Furuya, Fumihiko
Shimura, Hiroki
Hayashi, Yoshitaka
Takahashi, Kazuya
Ohta, Kazuyasu
Kobayashi, Tetsuro
Kitamura, Kenichiro
author_sort Ichijo, Sayaka
collection PubMed
description Thyroid hormone receptor (TR) mediates the crucial effects of the thyroid hormone (T3) on cellular growth, development, and differentiation. Decreased expression or inactivating somatic mutations of TRs have been found in human cancers of the liver, breast, lung, and thyroid. The mechanisms of TR-associated carcinogenesis are still not clear. To establish the function of TRβ in thyroid cancer cell proliferation, we constructed a recombinant adenovirus vector, AdTRβ, which expresses human TRβ1 cDNA. Thyroid cancer cell lines in which TRβ protein levels were significantly decreased as compared to intact thyroid tissues were infected with AdTRβ and the function of TRβ on cell proliferation and migration was analyzed. Ligand-bound TRβ induced HDAC1 and HDAC3 dissociation from, and histone acetylation associated with the RhoB promoter and enhanced the expression of RhoB mRNA and protein. In AdTRβ-infected cells, T3 and farnesyl transferase inhibitor (FTI)-treatment induced the distribution of RhoB on the cell membrane and enhanced the abundance of active GTP-bound RhoB. This RhoB protein led to p21-associated cell-cycle arrest in the G0/G1 phase, following inhibition of cell proliferation and invasion. Conversely, lowering cellular RhoB by small interfering RNA knockdown in AdTRβ-infected cells led to downregulation of p21 and inhibited cell-cycle arrest. The growth of BHP18-21v tumor xenografts in vivo was significantly inhibited by AdTRβ injection with FTIs-treatment, as compared to control virus-injected tumors. This novel signaling pathway triggered by ligand-bound TRβ provides insight into possible mechanisms of proliferation and invasion of thyroid cancer and may provide new therapeutic targets for thyroid cancers.
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spelling pubmed-42802012015-01-07 Activation of the RhoB Signaling Pathway by Thyroid Hormone Receptor β in Thyroid Cancer Cells Ichijo, Sayaka Furuya, Fumihiko Shimura, Hiroki Hayashi, Yoshitaka Takahashi, Kazuya Ohta, Kazuyasu Kobayashi, Tetsuro Kitamura, Kenichiro PLoS One Research Article Thyroid hormone receptor (TR) mediates the crucial effects of the thyroid hormone (T3) on cellular growth, development, and differentiation. Decreased expression or inactivating somatic mutations of TRs have been found in human cancers of the liver, breast, lung, and thyroid. The mechanisms of TR-associated carcinogenesis are still not clear. To establish the function of TRβ in thyroid cancer cell proliferation, we constructed a recombinant adenovirus vector, AdTRβ, which expresses human TRβ1 cDNA. Thyroid cancer cell lines in which TRβ protein levels were significantly decreased as compared to intact thyroid tissues were infected with AdTRβ and the function of TRβ on cell proliferation and migration was analyzed. Ligand-bound TRβ induced HDAC1 and HDAC3 dissociation from, and histone acetylation associated with the RhoB promoter and enhanced the expression of RhoB mRNA and protein. In AdTRβ-infected cells, T3 and farnesyl transferase inhibitor (FTI)-treatment induced the distribution of RhoB on the cell membrane and enhanced the abundance of active GTP-bound RhoB. This RhoB protein led to p21-associated cell-cycle arrest in the G0/G1 phase, following inhibition of cell proliferation and invasion. Conversely, lowering cellular RhoB by small interfering RNA knockdown in AdTRβ-infected cells led to downregulation of p21 and inhibited cell-cycle arrest. The growth of BHP18-21v tumor xenografts in vivo was significantly inhibited by AdTRβ injection with FTIs-treatment, as compared to control virus-injected tumors. This novel signaling pathway triggered by ligand-bound TRβ provides insight into possible mechanisms of proliferation and invasion of thyroid cancer and may provide new therapeutic targets for thyroid cancers. Public Library of Science 2014-12-30 /pmc/articles/PMC4280201/ /pubmed/25548921 http://dx.doi.org/10.1371/journal.pone.0116252 Text en © 2014 Ichijo et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Ichijo, Sayaka
Furuya, Fumihiko
Shimura, Hiroki
Hayashi, Yoshitaka
Takahashi, Kazuya
Ohta, Kazuyasu
Kobayashi, Tetsuro
Kitamura, Kenichiro
Activation of the RhoB Signaling Pathway by Thyroid Hormone Receptor β in Thyroid Cancer Cells
title Activation of the RhoB Signaling Pathway by Thyroid Hormone Receptor β in Thyroid Cancer Cells
title_full Activation of the RhoB Signaling Pathway by Thyroid Hormone Receptor β in Thyroid Cancer Cells
title_fullStr Activation of the RhoB Signaling Pathway by Thyroid Hormone Receptor β in Thyroid Cancer Cells
title_full_unstemmed Activation of the RhoB Signaling Pathway by Thyroid Hormone Receptor β in Thyroid Cancer Cells
title_short Activation of the RhoB Signaling Pathway by Thyroid Hormone Receptor β in Thyroid Cancer Cells
title_sort activation of the rhob signaling pathway by thyroid hormone receptor β in thyroid cancer cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4280201/
https://www.ncbi.nlm.nih.gov/pubmed/25548921
http://dx.doi.org/10.1371/journal.pone.0116252
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