Oncotarget

Research Papers:

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

Xing-gang Mao, Marianne Hütt-Cabezas, Brent A. Orr, Melanie Weingart, Isabella Taylor, Anand K.D. Rajan, Yazmin Odia, Ulf Kahlert, Jarek Maciaczyk, Guido Nikkhah, Charles G. Eberhart and Eric H. Raabe _

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Oncotarget. 2013; 4:1050-1064. https://doi.org/10.18632/oncotarget.1131

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Abstract

Xing-gang Mao1,2, Marianne Hütt-Cabezas1, Brent A. Orr1, Melanie Weingart1, Isabella Taylor1, Anand K.D. Rajan1, Yazmin Odia3,4, Ulf Kahlert5, Jarek Maciaczyk6, Guido Nikkhah5, Charles G. Eberhart1, Eric H. Raabe 1,7

1 Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD

2 Current address: Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi Province, China

3 Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD

4 Current address: Neuro-Oncology Branch, National Cancer Institute, Bethesda, MD

5 Department of Stereotactic and Functional Neurosurgery, Neurocenter, University Hospital Freiburg, Freiburg, Germany

6 Department of General Neurosurgery, Neurocenter, University Hospital Freiburg, Freiburg, Germany

7 Division of Pediatric Oncology, Johns Hopkins University School of Medicine, Baltimore, MD

Correspondence:

Charles G. Eberhart, email:

Eric Raabe, email:

Keywords: let-7, stem cell, microRNA, HMGA2, SNAI1

Received: June 26, 2013 Accepted: July 4, 2013 Published: July 6, 2013

Abstract

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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