Journal article
LIN28A facilitates the transformation of human neural stem cells and promotes glioblastoma tumorigenesis through a pro-invasive genetic program
Oncotarget, Vol.4(7), pp.1050-1064
2013
DOI: 10.18632/oncotarget.1131
PMCID: PMC3759665
PMID: 23846349
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.
Details
- Title: Subtitle
- LIN28A facilitates the transformation of human neural stem cells and promotes glioblastoma tumorigenesis through a pro-invasive genetic program
- Creators
- Xing-gang Mao - Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MDMarianne Hütt-Cabezas - Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MDBrent A Orr - Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MDMelanie Weingart - Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MDIsabella Taylor - Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MDAnand K.D Rajan - Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MDYazmin Odia - Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MDUlf Kahlert - Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MDJarek Maciaczyk - Department of General Neurosurgery, Neurocenter, University Hospital Freiburg, Freiburg, GermanyGuido Nikkhah - Department of Stereotactic and Functional Neurosurgery, Neurocenter, University Hospital Freiburg, Freiburg, GermanyCharles G Eberhart - Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MDEric H Raabe - Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD
- Resource Type
- Journal article
- Publication Details
- Oncotarget, Vol.4(7), pp.1050-1064
- DOI
- 10.18632/oncotarget.1131
- PMID
- 23846349
- PMCID
- PMC3759665
- NLM abbreviation
- Oncotarget
- ISSN
- 1949-2553
- eISSN
- 1949-2553
- Publisher
- Impact Journals LLC
- Language
- English
- Date published
- 2013
- Academic Unit
- Pathology
- Record Identifier
- 9984047666702771
Metrics
20 Record Views