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LIN28A facilitates the transformation of human neural stem cells and promotes glioblastoma tumorigenesis through a pro-invasive genetic program

The cellular reprogramming factor LIN28A promotes tumorigenicity in cancers arising outside the central nervous system, but its role in brain tumors is unknown. We detected LIN28A protein in a subset of human gliomas observed higher expression in glioblastoma (GBM) than in lower grade tumors. Knockd...

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Autores principales: Mao, Xing-gang, Hütt-Cabezas, Marianne, Orr, Brent A., Weingart, Melanie, Taylor, Isabella, Rajan, Anand K.D., Odia, Yazmin, Kahlert, Ulf, Maciaczyk, Jarek, Nikkhah, Guido, Eberhart, Charles G., Raabe, Eric H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3759665/
https://www.ncbi.nlm.nih.gov/pubmed/23846349
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author Mao, Xing-gang
Hütt-Cabezas, Marianne
Orr, Brent A.
Weingart, Melanie
Taylor, Isabella
Rajan, Anand K.D.
Odia, Yazmin
Kahlert, Ulf
Maciaczyk, Jarek
Nikkhah, Guido
Eberhart, Charles G.
Raabe, Eric H.
author_facet Mao, Xing-gang
Hütt-Cabezas, Marianne
Orr, Brent A.
Weingart, Melanie
Taylor, Isabella
Rajan, Anand K.D.
Odia, Yazmin
Kahlert, Ulf
Maciaczyk, Jarek
Nikkhah, Guido
Eberhart, Charles G.
Raabe, Eric H.
author_sort Mao, Xing-gang
collection PubMed
description The cellular reprogramming factor LIN28A promotes tumorigenicity in cancers arising outside the central nervous system, but its role in brain tumors is unknown. We detected LIN28A protein in a subset of human gliomas observed higher expression in glioblastoma (GBM) than in lower grade tumors. Knockdown of LIN28A using lentiviral shRNA in GBM cell lines inhibited their invasion, growth and clonogenicity. Expression of LIN28A in GBM cell lines increased the number and size of orthotopic xenograft tumors. LIN28A expression also enhanced the invasiveness of GBM cells in vitro and in vivo. Increasing LIN28A was associated with down-regulation of tumor suppressing microRNAs let-7b and let-7g and up-regulation of the chromatin modifying protein HMGA2. The increase in tumor cell aggressiveness in vivo and in vitro was accompanied by an upregulation of pro-invasive gene expression, including SNAI1. To further investigate the oncogenic potential of LIN28A, we infected hNSC with lentiviruses encoding LIN28A together with dominant negative R248W-TP53, constitutively active KRAS and hTERT. Resulting subclones proliferated at an increased rate and formed invasive GBM-like tumors in orthotopic xenografts in immunodeficient mice. Similar to LIN28A-transduced GBM neurosphere lines, hNSC-derived tumor cells showed increased expression of HMGA2. Taken together, these data suggest a role for LIN28A in high grade gliomas and illustrate an HMGA2-associated, pro-invasive program that can be activated in GBM by LIN28A-mediated suppression of let-7 microRNAs.
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spelling pubmed-37596652013-09-10 LIN28A facilitates the transformation of human neural stem cells and promotes glioblastoma tumorigenesis through a pro-invasive genetic program Mao, Xing-gang Hütt-Cabezas, Marianne Orr, Brent A. Weingart, Melanie Taylor, Isabella Rajan, Anand K.D. Odia, Yazmin Kahlert, Ulf Maciaczyk, Jarek Nikkhah, Guido Eberhart, Charles G. Raabe, Eric H. Oncotarget Research Papers The cellular reprogramming factor LIN28A promotes tumorigenicity in cancers arising outside the central nervous system, but its role in brain tumors is unknown. We detected LIN28A protein in a subset of human gliomas observed higher expression in glioblastoma (GBM) than in lower grade tumors. Knockdown of LIN28A using lentiviral shRNA in GBM cell lines inhibited their invasion, growth and clonogenicity. Expression of LIN28A in GBM cell lines increased the number and size of orthotopic xenograft tumors. LIN28A expression also enhanced the invasiveness of GBM cells in vitro and in vivo. Increasing LIN28A was associated with down-regulation of tumor suppressing microRNAs let-7b and let-7g and up-regulation of the chromatin modifying protein HMGA2. The increase in tumor cell aggressiveness in vivo and in vitro was accompanied by an upregulation of pro-invasive gene expression, including SNAI1. To further investigate the oncogenic potential of LIN28A, we infected hNSC with lentiviruses encoding LIN28A together with dominant negative R248W-TP53, constitutively active KRAS and hTERT. Resulting subclones proliferated at an increased rate and formed invasive GBM-like tumors in orthotopic xenografts in immunodeficient mice. Similar to LIN28A-transduced GBM neurosphere lines, hNSC-derived tumor cells showed increased expression of HMGA2. Taken together, these data suggest a role for LIN28A in high grade gliomas and illustrate an HMGA2-associated, pro-invasive program that can be activated in GBM by LIN28A-mediated suppression of let-7 microRNAs. Impact Journals LLC 2013-07-06 /pmc/articles/PMC3759665/ /pubmed/23846349 Text en Copyright: © 2013 Mao et al. http://creativecommons.org/licenses/by/2.5/ 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 credited
spellingShingle Research Papers
Mao, Xing-gang
Hütt-Cabezas, Marianne
Orr, Brent A.
Weingart, Melanie
Taylor, Isabella
Rajan, Anand K.D.
Odia, Yazmin
Kahlert, Ulf
Maciaczyk, Jarek
Nikkhah, Guido
Eberhart, Charles G.
Raabe, Eric H.
LIN28A facilitates the transformation of human neural stem cells and promotes glioblastoma tumorigenesis through a pro-invasive genetic program
title LIN28A facilitates the transformation of human neural stem cells and promotes glioblastoma tumorigenesis through a pro-invasive genetic program
title_full LIN28A facilitates the transformation of human neural stem cells and promotes glioblastoma tumorigenesis through a pro-invasive genetic program
title_fullStr LIN28A facilitates the transformation of human neural stem cells and promotes glioblastoma tumorigenesis through a pro-invasive genetic program
title_full_unstemmed LIN28A facilitates the transformation of human neural stem cells and promotes glioblastoma tumorigenesis through a pro-invasive genetic program
title_short LIN28A facilitates the transformation of human neural stem cells and promotes glioblastoma tumorigenesis through a pro-invasive genetic program
title_sort lin28a facilitates the transformation of human neural stem cells and promotes glioblastoma tumorigenesis through a pro-invasive genetic program
topic Research Papers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3759665/
https://www.ncbi.nlm.nih.gov/pubmed/23846349
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