TY - JOUR
T1 - Alpha 1-antichymotrypsin contributes to stem cell characteristics and enhances tumorigenicity of glioblastoma
AU - Lara-Velazquez, Montserrat
AU - Zarco, Natanael
AU - Carrano, Anna
AU - Phillipps, Jordan
AU - Norton, Emily S.
AU - Schiapparelli, Paula
AU - Al-Kharboosh, Rawan
AU - Rincon-Torroella, Jordina
AU - Jeanneret, Stephanie
AU - Corona, Teresa
AU - Segovia, Jose
AU - Jentoft, Mark E.
AU - Chaichana, Kaisorn L.
AU - Asmann, Yan W.
AU - Quiñones-Hinojosa, Alfredo
AU - Guerrero-Cázares, Hugo
N1 - Publisher Copyright:
© 2020 The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved.
PY - 2021/4/1
Y1 - 2021/4/1
N2 - Background: Glioblastomas (GBMs) are the main primary brain tumors in adults with almost 100% recurrence rate. Patients with lateral ventricle proximal GBMs (LV-GBMs) exhibit worse survival compared to distal locations for unknown reasons. One hypothesis is the proximity of these tumors to the cerebrospinal fluid (CSF) and its chemical cues that can regulate cellular phenotype. We therefore investigated the role of CSF on GBM gene expression and the role of a CSF-induced gene, SERPINA3, in GBM malignancy in vitro and in vivo. Methods: We utilized human CSF and GBM brain tumor-initiating cells (BTICs). We determined the impact of SERPINA3 expression in glioma patients using The Cancer Genome Atlas (TCGA) database. SERPINA3 expression changes were evaluated at mRNA and protein levels. The effects of knockdown (KD) and overexpression (OE) of SERPINA3 on cell migration, viability and cell proliferation were evaluated. Stem cell characteristics on KD cells were evaluated by differentiation and colony formation experiments. Tumor growth was studied by intracranial and flank injections. Results: GBM-CSF increased BTIC migration accompanied by upregulation of the SERPINA3 gene. In patient samples and TCGA data, we observed SERPINA3 to correlate directly with brain tumor grade and indirectly with GBM patient survival. SERPINA3 KD induced a decrease in cell proliferation, migration, invasion, and stem cell characteristics, while SERPINA3 OE increased cell migration. In vivo, SERPINA3 KD BTICs showed increased survival in a murine model. Conclusions: SERPINA3 plays a key role in GBM malignancy and its inhibition results in a better outcome using GBM preclinical models.
AB - Background: Glioblastomas (GBMs) are the main primary brain tumors in adults with almost 100% recurrence rate. Patients with lateral ventricle proximal GBMs (LV-GBMs) exhibit worse survival compared to distal locations for unknown reasons. One hypothesis is the proximity of these tumors to the cerebrospinal fluid (CSF) and its chemical cues that can regulate cellular phenotype. We therefore investigated the role of CSF on GBM gene expression and the role of a CSF-induced gene, SERPINA3, in GBM malignancy in vitro and in vivo. Methods: We utilized human CSF and GBM brain tumor-initiating cells (BTICs). We determined the impact of SERPINA3 expression in glioma patients using The Cancer Genome Atlas (TCGA) database. SERPINA3 expression changes were evaluated at mRNA and protein levels. The effects of knockdown (KD) and overexpression (OE) of SERPINA3 on cell migration, viability and cell proliferation were evaluated. Stem cell characteristics on KD cells were evaluated by differentiation and colony formation experiments. Tumor growth was studied by intracranial and flank injections. Results: GBM-CSF increased BTIC migration accompanied by upregulation of the SERPINA3 gene. In patient samples and TCGA data, we observed SERPINA3 to correlate directly with brain tumor grade and indirectly with GBM patient survival. SERPINA3 KD induced a decrease in cell proliferation, migration, invasion, and stem cell characteristics, while SERPINA3 OE increased cell migration. In vivo, SERPINA3 KD BTICs showed increased survival in a murine model. Conclusions: SERPINA3 plays a key role in GBM malignancy and its inhibition results in a better outcome using GBM preclinical models.
KW - SERPINA3
KW - alpha 1-antichymotrypsin
KW - brain tumor
KW - cerebrospinal fluid
KW - glioblastoma
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UR - http://www.scopus.com/inward/citedby.url?scp=85102872563&partnerID=8YFLogxK
U2 - 10.1093/neuonc/noaa264
DO - 10.1093/neuonc/noaa264
M3 - Article
C2 - 33249487
AN - SCOPUS:85102872563
SN - 1522-8517
VL - 23
SP - 599
EP - 610
JO - Neuro-oncology
JF - Neuro-oncology
IS - 4
ER -