MiR-433 and miR-22 dysregulations induce HDAC6 overexpression and ciliary loss in cholangiocarcinoma

Publication Date:
2018-02-07
Publisher:
Wiley-Blackwell
Print ISSN:
0270-9139
Electronic ISSN:
1527-3350
Topics:
Medicine
Published by:
http://www.wiley.com/wiley-blackwell
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autor Adrian P. Mansini, Maria J. Lorenzo Pisarello, Kristen M. Thelen, Maetzin Cruz-Reyes, Estanislao Peixoto, Sujeong Jin, Brynn N. Howard, Christy E. Trussoni, Gabriella B. Gajdos, Nicholas F. La; Russo, Maria J. Perugorria, Jesus M. Banales, Sergio A. Gradilone
beschreibung ABSTRACT Cholangiocytes normally express primary cilia, a multisensory organelle that detects signals from the cellular environment. Cilia are significantly reduced in cholangiocarcinoma (CCA) by a mechanism involving overexpression of histone deacetylase 6 (HDAC6). Despite HDAC6 overexpression in CCA, we found no differences in its mRNA level, suggesting a post-transcriptional regulation, possibly involving miRNAs. Here we describe that at least two HDAC6-targeting miRNAs, miR-433 and miR-22, are downregulated in CCA both in vitro and in vivo . Experimental restoration of these miRNAs in CCA cells reduced HDAC6 expression, induced ciliary restoration, and decreased the malignant phenotype. Furthermore, in contrast to the mature forms, levels of precursor forms of these miRNAs were higher in CCA compared to normal cholangiocytes and accumulated in the nuclei, suggesting a defective nuclear export. We assessed the expression of Exportin-5, the protein responsible for transporting miRNA precursors out of the nucleus, and found it to be reduced by 50% in CCA compared to normal cholangiocytes. Experimental overexpression of Exportin-5 in CCA cells restored precursor and mature forms of these miRNAs to normal levels, inducing a decrease in the expression of HDAC6 and a decrease in the malignant phenotype. Conversely, shRNA depletion of Exportin-5 in normal cholangiocytes resulted in increased nuclear retention of precursor miRNAs, decreased mature miRNAs, increased cell proliferation, and shorter cilia. Conclusion: these data suggest that downregulated Exportin-5 impairs the nuclear export of miR-433 and miR-22 precursor forms, causing a decrease in levels of mature miR-433 and miR-22 forms, and leading to overexpression of HDAC6 and ciliary loss in CCA. This article is protected by copyright. All rights reserved.
citation_standardnr 6157405
datenlieferant ipn_articles
feed_copyright The American Association for the Study of Liver Diseases
feed_copyright_url http://www.aasld.org/
feed_id 2889
feed_publisher Wiley-Blackwell
feed_publisher_url http://www.wiley.com/wiley-blackwell
insertion_date 2018-02-07
journaleissn 1527-3350
journalissn 0270-9139
publikationsjahr_anzeige 2018
publikationsjahr_facette 2018
publikationsjahr_intervall 7984:2015-2019
publikationsjahr_sort 2018
publisher Wiley-Blackwell
quelle Hepatology
relation http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhep.29832
search_space articles
shingle_author_1 Adrian P. Mansini, Maria J. Lorenzo Pisarello, Kristen M. Thelen, Maetzin Cruz-Reyes, Estanislao Peixoto, Sujeong Jin, Brynn N. Howard, Christy E. Trussoni, Gabriella B. Gajdos, Nicholas F. La; Russo, Maria J. Perugorria, Jesus M. Banales, Sergio A. Gradilone
shingle_author_2 Adrian P. Mansini, Maria J. Lorenzo Pisarello, Kristen M. Thelen, Maetzin Cruz-Reyes, Estanislao Peixoto, Sujeong Jin, Brynn N. Howard, Christy E. Trussoni, Gabriella B. Gajdos, Nicholas F. La; Russo, Maria J. Perugorria, Jesus M. Banales, Sergio A. Gradilone
shingle_author_3 Adrian P. Mansini, Maria J. Lorenzo Pisarello, Kristen M. Thelen, Maetzin Cruz-Reyes, Estanislao Peixoto, Sujeong Jin, Brynn N. Howard, Christy E. Trussoni, Gabriella B. Gajdos, Nicholas F. La; Russo, Maria J. Perugorria, Jesus M. Banales, Sergio A. Gradilone
shingle_author_4 Adrian P. Mansini, Maria J. Lorenzo Pisarello, Kristen M. Thelen, Maetzin Cruz-Reyes, Estanislao Peixoto, Sujeong Jin, Brynn N. Howard, Christy E. Trussoni, Gabriella B. Gajdos, Nicholas F. La; Russo, Maria J. Perugorria, Jesus M. Banales, Sergio A. Gradilone
shingle_catch_all_1 MiR-433 and miR-22 dysregulations induce HDAC6 overexpression and ciliary loss in cholangiocarcinoma
ABSTRACT Cholangiocytes normally express primary cilia, a multisensory organelle that detects signals from the cellular environment. Cilia are significantly reduced in cholangiocarcinoma (CCA) by a mechanism involving overexpression of histone deacetylase 6 (HDAC6). Despite HDAC6 overexpression in CCA, we found no differences in its mRNA level, suggesting a post-transcriptional regulation, possibly involving miRNAs. Here we describe that at least two HDAC6-targeting miRNAs, miR-433 and miR-22, are downregulated in CCA both in vitro and in vivo . Experimental restoration of these miRNAs in CCA cells reduced HDAC6 expression, induced ciliary restoration, and decreased the malignant phenotype. Furthermore, in contrast to the mature forms, levels of precursor forms of these miRNAs were higher in CCA compared to normal cholangiocytes and accumulated in the nuclei, suggesting a defective nuclear export. We assessed the expression of Exportin-5, the protein responsible for transporting miRNA precursors out of the nucleus, and found it to be reduced by 50% in CCA compared to normal cholangiocytes. Experimental overexpression of Exportin-5 in CCA cells restored precursor and mature forms of these miRNAs to normal levels, inducing a decrease in the expression of HDAC6 and a decrease in the malignant phenotype. Conversely, shRNA depletion of Exportin-5 in normal cholangiocytes resulted in increased nuclear retention of precursor miRNAs, decreased mature miRNAs, increased cell proliferation, and shorter cilia. Conclusion: these data suggest that downregulated Exportin-5 impairs the nuclear export of miR-433 and miR-22 precursor forms, causing a decrease in levels of mature miR-433 and miR-22 forms, and leading to overexpression of HDAC6 and ciliary loss in CCA. This article is protected by copyright. All rights reserved.
Adrian P. Mansini, Maria J. Lorenzo Pisarello, Kristen M. Thelen, Maetzin Cruz-Reyes, Estanislao Peixoto, Sujeong Jin, Brynn N. Howard, Christy E. Trussoni, Gabriella B. Gajdos, Nicholas F. La; Russo, Maria J. Perugorria, Jesus M. Banales, Sergio A. Gradilone
Wiley-Blackwell
0270-9139
02709139
1527-3350
15273350
shingle_catch_all_2 MiR-433 and miR-22 dysregulations induce HDAC6 overexpression and ciliary loss in cholangiocarcinoma
ABSTRACT Cholangiocytes normally express primary cilia, a multisensory organelle that detects signals from the cellular environment. Cilia are significantly reduced in cholangiocarcinoma (CCA) by a mechanism involving overexpression of histone deacetylase 6 (HDAC6). Despite HDAC6 overexpression in CCA, we found no differences in its mRNA level, suggesting a post-transcriptional regulation, possibly involving miRNAs. Here we describe that at least two HDAC6-targeting miRNAs, miR-433 and miR-22, are downregulated in CCA both in vitro and in vivo . Experimental restoration of these miRNAs in CCA cells reduced HDAC6 expression, induced ciliary restoration, and decreased the malignant phenotype. Furthermore, in contrast to the mature forms, levels of precursor forms of these miRNAs were higher in CCA compared to normal cholangiocytes and accumulated in the nuclei, suggesting a defective nuclear export. We assessed the expression of Exportin-5, the protein responsible for transporting miRNA precursors out of the nucleus, and found it to be reduced by 50% in CCA compared to normal cholangiocytes. Experimental overexpression of Exportin-5 in CCA cells restored precursor and mature forms of these miRNAs to normal levels, inducing a decrease in the expression of HDAC6 and a decrease in the malignant phenotype. Conversely, shRNA depletion of Exportin-5 in normal cholangiocytes resulted in increased nuclear retention of precursor miRNAs, decreased mature miRNAs, increased cell proliferation, and shorter cilia. Conclusion: these data suggest that downregulated Exportin-5 impairs the nuclear export of miR-433 and miR-22 precursor forms, causing a decrease in levels of mature miR-433 and miR-22 forms, and leading to overexpression of HDAC6 and ciliary loss in CCA. This article is protected by copyright. All rights reserved.
Adrian P. Mansini, Maria J. Lorenzo Pisarello, Kristen M. Thelen, Maetzin Cruz-Reyes, Estanislao Peixoto, Sujeong Jin, Brynn N. Howard, Christy E. Trussoni, Gabriella B. Gajdos, Nicholas F. La; Russo, Maria J. Perugorria, Jesus M. Banales, Sergio A. Gradilone
Wiley-Blackwell
0270-9139
02709139
1527-3350
15273350
shingle_catch_all_3 MiR-433 and miR-22 dysregulations induce HDAC6 overexpression and ciliary loss in cholangiocarcinoma
ABSTRACT Cholangiocytes normally express primary cilia, a multisensory organelle that detects signals from the cellular environment. Cilia are significantly reduced in cholangiocarcinoma (CCA) by a mechanism involving overexpression of histone deacetylase 6 (HDAC6). Despite HDAC6 overexpression in CCA, we found no differences in its mRNA level, suggesting a post-transcriptional regulation, possibly involving miRNAs. Here we describe that at least two HDAC6-targeting miRNAs, miR-433 and miR-22, are downregulated in CCA both in vitro and in vivo . Experimental restoration of these miRNAs in CCA cells reduced HDAC6 expression, induced ciliary restoration, and decreased the malignant phenotype. Furthermore, in contrast to the mature forms, levels of precursor forms of these miRNAs were higher in CCA compared to normal cholangiocytes and accumulated in the nuclei, suggesting a defective nuclear export. We assessed the expression of Exportin-5, the protein responsible for transporting miRNA precursors out of the nucleus, and found it to be reduced by 50% in CCA compared to normal cholangiocytes. Experimental overexpression of Exportin-5 in CCA cells restored precursor and mature forms of these miRNAs to normal levels, inducing a decrease in the expression of HDAC6 and a decrease in the malignant phenotype. Conversely, shRNA depletion of Exportin-5 in normal cholangiocytes resulted in increased nuclear retention of precursor miRNAs, decreased mature miRNAs, increased cell proliferation, and shorter cilia. Conclusion: these data suggest that downregulated Exportin-5 impairs the nuclear export of miR-433 and miR-22 precursor forms, causing a decrease in levels of mature miR-433 and miR-22 forms, and leading to overexpression of HDAC6 and ciliary loss in CCA. This article is protected by copyright. All rights reserved.
Adrian P. Mansini, Maria J. Lorenzo Pisarello, Kristen M. Thelen, Maetzin Cruz-Reyes, Estanislao Peixoto, Sujeong Jin, Brynn N. Howard, Christy E. Trussoni, Gabriella B. Gajdos, Nicholas F. La; Russo, Maria J. Perugorria, Jesus M. Banales, Sergio A. Gradilone
Wiley-Blackwell
0270-9139
02709139
1527-3350
15273350
shingle_catch_all_4 MiR-433 and miR-22 dysregulations induce HDAC6 overexpression and ciliary loss in cholangiocarcinoma
ABSTRACT Cholangiocytes normally express primary cilia, a multisensory organelle that detects signals from the cellular environment. Cilia are significantly reduced in cholangiocarcinoma (CCA) by a mechanism involving overexpression of histone deacetylase 6 (HDAC6). Despite HDAC6 overexpression in CCA, we found no differences in its mRNA level, suggesting a post-transcriptional regulation, possibly involving miRNAs. Here we describe that at least two HDAC6-targeting miRNAs, miR-433 and miR-22, are downregulated in CCA both in vitro and in vivo . Experimental restoration of these miRNAs in CCA cells reduced HDAC6 expression, induced ciliary restoration, and decreased the malignant phenotype. Furthermore, in contrast to the mature forms, levels of precursor forms of these miRNAs were higher in CCA compared to normal cholangiocytes and accumulated in the nuclei, suggesting a defective nuclear export. We assessed the expression of Exportin-5, the protein responsible for transporting miRNA precursors out of the nucleus, and found it to be reduced by 50% in CCA compared to normal cholangiocytes. Experimental overexpression of Exportin-5 in CCA cells restored precursor and mature forms of these miRNAs to normal levels, inducing a decrease in the expression of HDAC6 and a decrease in the malignant phenotype. Conversely, shRNA depletion of Exportin-5 in normal cholangiocytes resulted in increased nuclear retention of precursor miRNAs, decreased mature miRNAs, increased cell proliferation, and shorter cilia. Conclusion: these data suggest that downregulated Exportin-5 impairs the nuclear export of miR-433 and miR-22 precursor forms, causing a decrease in levels of mature miR-433 and miR-22 forms, and leading to overexpression of HDAC6 and ciliary loss in CCA. This article is protected by copyright. All rights reserved.
Adrian P. Mansini, Maria J. Lorenzo Pisarello, Kristen M. Thelen, Maetzin Cruz-Reyes, Estanislao Peixoto, Sujeong Jin, Brynn N. Howard, Christy E. Trussoni, Gabriella B. Gajdos, Nicholas F. La; Russo, Maria J. Perugorria, Jesus M. Banales, Sergio A. Gradilone
Wiley-Blackwell
0270-9139
02709139
1527-3350
15273350
shingle_title_1 MiR-433 and miR-22 dysregulations induce HDAC6 overexpression and ciliary loss in cholangiocarcinoma
shingle_title_2 MiR-433 and miR-22 dysregulations induce HDAC6 overexpression and ciliary loss in cholangiocarcinoma
shingle_title_3 MiR-433 and miR-22 dysregulations induce HDAC6 overexpression and ciliary loss in cholangiocarcinoma
shingle_title_4 MiR-433 and miR-22 dysregulations induce HDAC6 overexpression and ciliary loss in cholangiocarcinoma
timestamp 2025-06-30T23:32:32.014Z
titel MiR-433 and miR-22 dysregulations induce HDAC6 overexpression and ciliary loss in cholangiocarcinoma
titel_suche MiR-433 and miR-22 dysregulations induce HDAC6 overexpression and ciliary loss in cholangiocarcinoma
topic WW-YZ
uid ipn_articles_6157405