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Loss of miR-514a-3p regulation of PEG3 activates the NF-kappa B pathway in human testicular germ cell tumors

Deregulation of microRNAs (miRNAs) contributes to the development and progression of many cancer types; however, their functions in the pathogenesis of testicular germ cell tumor (TGCT) remain unclear. Here, we determined miRNA expression profiles of TGCTs and normal testes using small RNA sequencin...

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Autores principales: Özata, Deniz Mahmut, Li, Xidan, Lee, Linkiat, Liu, Jikai, Warsito, Dudi, Hajeri, Praveensingh, Hultman, Isabell, Fotouhi, Omid, Marklund, Stefan, Ährlund-Richter, Lars, Juhlin, Carl Christofer, Larsson, Catharina, Lui, Weng-Onn
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5520681/
https://www.ncbi.nlm.nih.gov/pubmed/28471449
http://dx.doi.org/10.1038/cddis.2016.464
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author Özata, Deniz Mahmut
Li, Xidan
Lee, Linkiat
Liu, Jikai
Warsito, Dudi
Hajeri, Praveensingh
Hultman, Isabell
Fotouhi, Omid
Marklund, Stefan
Ährlund-Richter, Lars
Juhlin, Carl Christofer
Larsson, Catharina
Lui, Weng-Onn
author_facet Özata, Deniz Mahmut
Li, Xidan
Lee, Linkiat
Liu, Jikai
Warsito, Dudi
Hajeri, Praveensingh
Hultman, Isabell
Fotouhi, Omid
Marklund, Stefan
Ährlund-Richter, Lars
Juhlin, Carl Christofer
Larsson, Catharina
Lui, Weng-Onn
author_sort Özata, Deniz Mahmut
collection PubMed
description Deregulation of microRNAs (miRNAs) contributes to the development and progression of many cancer types; however, their functions in the pathogenesis of testicular germ cell tumor (TGCT) remain unclear. Here, we determined miRNA expression profiles of TGCTs and normal testes using small RNA sequencing, and identified several deregulated miRNAs in TGCTs, including the miR-506~514 cluster. In functional studies in vitro we demonstrated that miR-514a-3p induced apoptosis through direct regulation of the paternally expressed gene 3 (PEG3), and ectopically expressed PEG3 could rescue the apoptotic effect of miR-514a-3p overexpression. Silencing of PEG3 or miR-514a-3p overexpression reduced nuclear accumulation of p50 and NF-κB reporter activity. Furthermore, PEG3 was co-immunoprecipitated with tumor necrosis factor receptor-associated factor 2 (TRAF2) in TGCT cell lysates. We propose a model of PEG3-mediated activation of NF-κB in TGCT. Loss of miR-514a-3p expression in TGCT increases PEG3 expression that recruits TRAF2 and activates the NF-kappa B pathway, which protects germ cells from apoptosis. Importantly, we observed strong expression of PEG3 and nuclear p50 in the majority of TGCTs (83% and 78%, respectively). In conclusion, our study describes a novel function for miR-514a-3p in TGCT and highlights an unrecognized mechanism of PEG3 regulation and NF-κB activation in TGCT.
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spelling pubmed-55206812017-07-27 Loss of miR-514a-3p regulation of PEG3 activates the NF-kappa B pathway in human testicular germ cell tumors Özata, Deniz Mahmut Li, Xidan Lee, Linkiat Liu, Jikai Warsito, Dudi Hajeri, Praveensingh Hultman, Isabell Fotouhi, Omid Marklund, Stefan Ährlund-Richter, Lars Juhlin, Carl Christofer Larsson, Catharina Lui, Weng-Onn Cell Death Dis Original Article Deregulation of microRNAs (miRNAs) contributes to the development and progression of many cancer types; however, their functions in the pathogenesis of testicular germ cell tumor (TGCT) remain unclear. Here, we determined miRNA expression profiles of TGCTs and normal testes using small RNA sequencing, and identified several deregulated miRNAs in TGCTs, including the miR-506~514 cluster. In functional studies in vitro we demonstrated that miR-514a-3p induced apoptosis through direct regulation of the paternally expressed gene 3 (PEG3), and ectopically expressed PEG3 could rescue the apoptotic effect of miR-514a-3p overexpression. Silencing of PEG3 or miR-514a-3p overexpression reduced nuclear accumulation of p50 and NF-κB reporter activity. Furthermore, PEG3 was co-immunoprecipitated with tumor necrosis factor receptor-associated factor 2 (TRAF2) in TGCT cell lysates. We propose a model of PEG3-mediated activation of NF-κB in TGCT. Loss of miR-514a-3p expression in TGCT increases PEG3 expression that recruits TRAF2 and activates the NF-kappa B pathway, which protects germ cells from apoptosis. Importantly, we observed strong expression of PEG3 and nuclear p50 in the majority of TGCTs (83% and 78%, respectively). In conclusion, our study describes a novel function for miR-514a-3p in TGCT and highlights an unrecognized mechanism of PEG3 regulation and NF-κB activation in TGCT. Nature Publishing Group 2017-05-04 /pmc/articles/PMC5520681/ /pubmed/28471449 http://dx.doi.org/10.1038/cddis.2016.464 Text en Copyright © 2017 The Author(s) http://creativecommons.org/licenses/by/4.0/ Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Original Article
Özata, Deniz Mahmut
Li, Xidan
Lee, Linkiat
Liu, Jikai
Warsito, Dudi
Hajeri, Praveensingh
Hultman, Isabell
Fotouhi, Omid
Marklund, Stefan
Ährlund-Richter, Lars
Juhlin, Carl Christofer
Larsson, Catharina
Lui, Weng-Onn
Loss of miR-514a-3p regulation of PEG3 activates the NF-kappa B pathway in human testicular germ cell tumors
title Loss of miR-514a-3p regulation of PEG3 activates the NF-kappa B pathway in human testicular germ cell tumors
title_full Loss of miR-514a-3p regulation of PEG3 activates the NF-kappa B pathway in human testicular germ cell tumors
title_fullStr Loss of miR-514a-3p regulation of PEG3 activates the NF-kappa B pathway in human testicular germ cell tumors
title_full_unstemmed Loss of miR-514a-3p regulation of PEG3 activates the NF-kappa B pathway in human testicular germ cell tumors
title_short Loss of miR-514a-3p regulation of PEG3 activates the NF-kappa B pathway in human testicular germ cell tumors
title_sort loss of mir-514a-3p regulation of peg3 activates the nf-kappa b pathway in human testicular germ cell tumors
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5520681/
https://www.ncbi.nlm.nih.gov/pubmed/28471449
http://dx.doi.org/10.1038/cddis.2016.464
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