Epigenetic silencing of TFPI-2 in canine diffuse large B-cell lymphoma.

Epigenetic modifications are important early events during carcinogenesis. In particular, hypermethylation of CpG islands in the promoter region of tumor suppressor genes is a well-known mechanism of gene silencing that contributes to cancer development and progression. Tissue factor pathway inhibit...

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Autores principales:	Serena Ferraresso, Silvia Bresolin, Arianna Aricò, Stefano Comazzi, Maria Elena Gelain, Fulvio Riondato, Luca Bargelloni, Laura Marconato, Geertruy te Kronnie, Luca Aresu
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/7b0410274e524aa69afd23d7fc13b608
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spelling	oai:doaj.org-article:7b0410274e524aa69afd23d7fc13b6082021-11-18T08:25:20ZEpigenetic silencing of TFPI-2 in canine diffuse large B-cell lymphoma.1932-620310.1371/journal.pone.0092707https://doaj.org/article/7b0410274e524aa69afd23d7fc13b6082014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24695110/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Epigenetic modifications are important early events during carcinogenesis. In particular, hypermethylation of CpG islands in the promoter region of tumor suppressor genes is a well-known mechanism of gene silencing that contributes to cancer development and progression. Tissue factor pathway inhibitor 2 (TFPI-2) is a tumor suppressor involved in invasiveness inhibition. Although TFPI-2 transcriptional silencing, through promoter hypermethylation, has been widely reported in several human malignancies, it has never been explored in lymphoma. In the present study TFPI-2 methylation and gene expression have been investigated in canine Diffuse Large B-cell lymphomas (cDLBCL). The methylation level of 23 CpGs located within the TFPI-2 promoter was investigated by bisulfite-specific PCR and next generation amplicon deep sequencing (GS Junior 454, Roche) in 22 cDLBCLs and 9 controls. For the same specimens, TFPI-2 gene expression was assessed by means of Real-time RT-PCR. Sequence analysis clearly demonstrated that TFPI2 is frequently hypermethylated in cDLBCL. Hypermethylation of the TFPI-2 promoter was found in 77% of DLBCLs (17 out of 22) and in one normal lymph node. Globally, dogs with DLBCL showed a mean methylation level significantly increased compared to controls (p<0.01) and analysis of hypermethylation by site identified 19 loci out of 23 (82%) with mean methylation levels from 2- to 120-fold higher in cDLBCL. Gene expression analysis confirmed a significant down-regulation of TFPI-2 (p<0.05) in DLBCLs compared with normal lymph nodes, suggesting that TFPI-2 hypermethylation negatively regulates its transcription. In addition, a significant positive correlation (p<0.01) was found between TFPI-2 methylation levels and age providing the first indication of age-associated epigenetic modifications in canine DLBCL. To conclude, our findings demonstrated that epigenetic dysregulation of TFPI-2, leading to its reduced expression, is frequently detected in canine DLBCL. In the next future, the aberrant TFPI-2 promoter hypermethylation may be considered in association with prognosis and therapy.Serena FerraressoSilvia BresolinArianna AricòStefano ComazziMaria Elena GelainFulvio RiondatoLuca BargelloniLaura MarconatoGeertruy te KronnieLuca AresuPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 4, p e92707 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Serena Ferraresso Silvia Bresolin Arianna Aricò Stefano Comazzi Maria Elena Gelain Fulvio Riondato Luca Bargelloni Laura Marconato Geertruy te Kronnie Luca Aresu Epigenetic silencing of TFPI-2 in canine diffuse large B-cell lymphoma.
description	Epigenetic modifications are important early events during carcinogenesis. In particular, hypermethylation of CpG islands in the promoter region of tumor suppressor genes is a well-known mechanism of gene silencing that contributes to cancer development and progression. Tissue factor pathway inhibitor 2 (TFPI-2) is a tumor suppressor involved in invasiveness inhibition. Although TFPI-2 transcriptional silencing, through promoter hypermethylation, has been widely reported in several human malignancies, it has never been explored in lymphoma. In the present study TFPI-2 methylation and gene expression have been investigated in canine Diffuse Large B-cell lymphomas (cDLBCL). The methylation level of 23 CpGs located within the TFPI-2 promoter was investigated by bisulfite-specific PCR and next generation amplicon deep sequencing (GS Junior 454, Roche) in 22 cDLBCLs and 9 controls. For the same specimens, TFPI-2 gene expression was assessed by means of Real-time RT-PCR. Sequence analysis clearly demonstrated that TFPI2 is frequently hypermethylated in cDLBCL. Hypermethylation of the TFPI-2 promoter was found in 77% of DLBCLs (17 out of 22) and in one normal lymph node. Globally, dogs with DLBCL showed a mean methylation level significantly increased compared to controls (p<0.01) and analysis of hypermethylation by site identified 19 loci out of 23 (82%) with mean methylation levels from 2- to 120-fold higher in cDLBCL. Gene expression analysis confirmed a significant down-regulation of TFPI-2 (p<0.05) in DLBCLs compared with normal lymph nodes, suggesting that TFPI-2 hypermethylation negatively regulates its transcription. In addition, a significant positive correlation (p<0.01) was found between TFPI-2 methylation levels and age providing the first indication of age-associated epigenetic modifications in canine DLBCL. To conclude, our findings demonstrated that epigenetic dysregulation of TFPI-2, leading to its reduced expression, is frequently detected in canine DLBCL. In the next future, the aberrant TFPI-2 promoter hypermethylation may be considered in association with prognosis and therapy.
format	article
author	Serena Ferraresso Silvia Bresolin Arianna Aricò Stefano Comazzi Maria Elena Gelain Fulvio Riondato Luca Bargelloni Laura Marconato Geertruy te Kronnie Luca Aresu
author_facet	Serena Ferraresso Silvia Bresolin Arianna Aricò Stefano Comazzi Maria Elena Gelain Fulvio Riondato Luca Bargelloni Laura Marconato Geertruy te Kronnie Luca Aresu
author_sort	Serena Ferraresso
title	Epigenetic silencing of TFPI-2 in canine diffuse large B-cell lymphoma.
title_short	Epigenetic silencing of TFPI-2 in canine diffuse large B-cell lymphoma.
title_full	Epigenetic silencing of TFPI-2 in canine diffuse large B-cell lymphoma.
title_fullStr	Epigenetic silencing of TFPI-2 in canine diffuse large B-cell lymphoma.
title_full_unstemmed	Epigenetic silencing of TFPI-2 in canine diffuse large B-cell lymphoma.
title_sort	epigenetic silencing of tfpi-2 in canine diffuse large b-cell lymphoma.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/7b0410274e524aa69afd23d7fc13b608
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Epigenetic silencing of TFPI-2 in canine diffuse large B-cell lymphoma.

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