Novel tumor suppressor function of glucocorticoid-induced TNF receptor GITR in multiple myeloma.
Glucocorticoid-induced TNF receptor (GITR) plays a crucial role in modulating immune response and inflammation, however the role of GITR in human cancers is poorly understood. In this study, we demonstrated that GITR is inactivated during tumor progression in Multiple Myeloma (MM) through promoter C...
Main Authors: | , , , , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Public Library of Science (PLoS)
2013-01-01
|
Series: | PLoS ONE |
Online Access: | http://europepmc.org/articles/PMC3681775?pdf=render |
id |
doaj-83cc26c8a93d4097a69e4061555199c6 |
---|---|
record_format |
Article |
spelling |
doaj-83cc26c8a93d4097a69e4061555199c62020-11-25T01:47:07ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-0186e6698210.1371/journal.pone.0066982Novel tumor suppressor function of glucocorticoid-induced TNF receptor GITR in multiple myeloma.Yang LiuPhong QuangEsteban BraggioHai NgoGayane Badalian-VeryLudmila FloresYong ZhangAntonio SaccoPatricia MaisoAbdel Kareem AzabFeda AzabRuben CarrascoBarrett J RollinsAldo M RoccaroIrene M GhobrialGlucocorticoid-induced TNF receptor (GITR) plays a crucial role in modulating immune response and inflammation, however the role of GITR in human cancers is poorly understood. In this study, we demonstrated that GITR is inactivated during tumor progression in Multiple Myeloma (MM) through promoter CpG island methylation, mediating gene silencing in primary MM plasma cells and MM cell lines. Restoration of GITR expression in GITR deficient MM cells led to inhibition of MM proliferation in vitro and in vivo and induction of apoptosis. These findings were supported by the presence of induction of p21 and PUMA, two direct downstream targets of p53, together with modulation of NF-κB in GITR-overexpressing MM cells. Moreover, the unbalanced expression of GITR in clonal plasma cells correlated with MM disease progression, poor prognosis and survival. These findings provide novel insights into the pivotal role of GITR in MM pathogenesis and disease progression.http://europepmc.org/articles/PMC3681775?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Yang Liu Phong Quang Esteban Braggio Hai Ngo Gayane Badalian-Very Ludmila Flores Yong Zhang Antonio Sacco Patricia Maiso Abdel Kareem Azab Feda Azab Ruben Carrasco Barrett J Rollins Aldo M Roccaro Irene M Ghobrial |
spellingShingle |
Yang Liu Phong Quang Esteban Braggio Hai Ngo Gayane Badalian-Very Ludmila Flores Yong Zhang Antonio Sacco Patricia Maiso Abdel Kareem Azab Feda Azab Ruben Carrasco Barrett J Rollins Aldo M Roccaro Irene M Ghobrial Novel tumor suppressor function of glucocorticoid-induced TNF receptor GITR in multiple myeloma. PLoS ONE |
author_facet |
Yang Liu Phong Quang Esteban Braggio Hai Ngo Gayane Badalian-Very Ludmila Flores Yong Zhang Antonio Sacco Patricia Maiso Abdel Kareem Azab Feda Azab Ruben Carrasco Barrett J Rollins Aldo M Roccaro Irene M Ghobrial |
author_sort |
Yang Liu |
title |
Novel tumor suppressor function of glucocorticoid-induced TNF receptor GITR in multiple myeloma. |
title_short |
Novel tumor suppressor function of glucocorticoid-induced TNF receptor GITR in multiple myeloma. |
title_full |
Novel tumor suppressor function of glucocorticoid-induced TNF receptor GITR in multiple myeloma. |
title_fullStr |
Novel tumor suppressor function of glucocorticoid-induced TNF receptor GITR in multiple myeloma. |
title_full_unstemmed |
Novel tumor suppressor function of glucocorticoid-induced TNF receptor GITR in multiple myeloma. |
title_sort |
novel tumor suppressor function of glucocorticoid-induced tnf receptor gitr in multiple myeloma. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2013-01-01 |
description |
Glucocorticoid-induced TNF receptor (GITR) plays a crucial role in modulating immune response and inflammation, however the role of GITR in human cancers is poorly understood. In this study, we demonstrated that GITR is inactivated during tumor progression in Multiple Myeloma (MM) through promoter CpG island methylation, mediating gene silencing in primary MM plasma cells and MM cell lines. Restoration of GITR expression in GITR deficient MM cells led to inhibition of MM proliferation in vitro and in vivo and induction of apoptosis. These findings were supported by the presence of induction of p21 and PUMA, two direct downstream targets of p53, together with modulation of NF-κB in GITR-overexpressing MM cells. Moreover, the unbalanced expression of GITR in clonal plasma cells correlated with MM disease progression, poor prognosis and survival. These findings provide novel insights into the pivotal role of GITR in MM pathogenesis and disease progression. |
url |
http://europepmc.org/articles/PMC3681775?pdf=render |
work_keys_str_mv |
AT yangliu noveltumorsuppressorfunctionofglucocorticoidinducedtnfreceptorgitrinmultiplemyeloma AT phongquang noveltumorsuppressorfunctionofglucocorticoidinducedtnfreceptorgitrinmultiplemyeloma AT estebanbraggio noveltumorsuppressorfunctionofglucocorticoidinducedtnfreceptorgitrinmultiplemyeloma AT haingo noveltumorsuppressorfunctionofglucocorticoidinducedtnfreceptorgitrinmultiplemyeloma AT gayanebadalianvery noveltumorsuppressorfunctionofglucocorticoidinducedtnfreceptorgitrinmultiplemyeloma AT ludmilaflores noveltumorsuppressorfunctionofglucocorticoidinducedtnfreceptorgitrinmultiplemyeloma AT yongzhang noveltumorsuppressorfunctionofglucocorticoidinducedtnfreceptorgitrinmultiplemyeloma AT antoniosacco noveltumorsuppressorfunctionofglucocorticoidinducedtnfreceptorgitrinmultiplemyeloma AT patriciamaiso noveltumorsuppressorfunctionofglucocorticoidinducedtnfreceptorgitrinmultiplemyeloma AT abdelkareemazab noveltumorsuppressorfunctionofglucocorticoidinducedtnfreceptorgitrinmultiplemyeloma AT fedaazab noveltumorsuppressorfunctionofglucocorticoidinducedtnfreceptorgitrinmultiplemyeloma AT rubencarrasco noveltumorsuppressorfunctionofglucocorticoidinducedtnfreceptorgitrinmultiplemyeloma AT barrettjrollins noveltumorsuppressorfunctionofglucocorticoidinducedtnfreceptorgitrinmultiplemyeloma AT aldomroccaro noveltumorsuppressorfunctionofglucocorticoidinducedtnfreceptorgitrinmultiplemyeloma AT irenemghobrial noveltumorsuppressorfunctionofglucocorticoidinducedtnfreceptorgitrinmultiplemyeloma |
_version_ |
1725016116335476736 |