PMID- 33249487 OWN - NLM STAT- MEDLINE DCOM- 20210520 LR - 20240331 IS - 1523-5866 (Electronic) IS - 1522-8517 (Print) IS - 1522-8517 (Linking) VI - 23 IP - 4 DP - 2021 Apr 12 TI - Alpha 1-antichymotrypsin contributes to stem cell characteristics and enhances tumorigenicity of glioblastoma. PG - 599-610 LID - 10.1093/neuonc/noaa264 [doi] 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. CI - (c) The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. FAU - Lara-Velazquez, Montserrat AU - Lara-Velazquez M AD - PECEM, UNAM, Mexico City, Mexico. AD - Department of Neurosurgery, Mayo Clinic, Jacksonville, Florida, USA. FAU - Zarco, Natanael AU - Zarco N AD - Department of Neurosurgery, Mayo Clinic, Jacksonville, Florida, USA. FAU - Carrano, Anna AU - Carrano A AD - PECEM, UNAM, Mexico City, Mexico. FAU - Phillipps, Jordan AU - Phillipps J AD - PECEM, UNAM, Mexico City, Mexico. FAU - Norton, Emily S AU - Norton ES AD - PECEM, UNAM, Mexico City, Mexico. AD - Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, Minnesota, USA. AD - Regenerative Sciences Training Program, Center for Regenerative Medicine, Mayo Clinic, Rochester, Minnesota, USA. FAU - Schiapparelli, Paula AU - Schiapparelli P AD - PECEM, UNAM, Mexico City, Mexico. FAU - Al-Kharboosh, Rawan AU - Al-Kharboosh R AD - PECEM, UNAM, Mexico City, Mexico. AD - Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, Minnesota, USA. AD - Regenerative Sciences Training Program, Center for Regenerative Medicine, Mayo Clinic, Rochester, Minnesota, USA. FAU - Rincon-Torroella, Jordina AU - Rincon-Torroella J AD - Department of Neurosurgery, Johns Hopkins Hospital, Baltimore, MD, USA. FAU - Jeanneret, Stephanie AU - Jeanneret S AD - PECEM, UNAM, Mexico City, Mexico. FAU - Corona, Teresa AU - Corona T AD - Clinical Laboratory of Neurodegenerative Diseases, National Institute of Neurology and Neurosurgery, Mexico City, Mexico. FAU - Segovia, Jose AU - Segovia J AD - Department of Physiology, Biophysics and Neurosciences, Cinvestav-IPN, Mexico City, Mexico. FAU - Jentoft, Mark E AU - Jentoft ME AD - Department of Laboratory Medicine and Pathology, Mayo Clinic, Jacksonville, Florida, USA. FAU - Chaichana, Kaisorn L AU - Chaichana KL AD - PECEM, UNAM, Mexico City, Mexico. FAU - Asmann, Yan W AU - Asmann YW AD - Department of Health Sciences Research, Mayo Clinic, Jacksonville, Florida, USA. FAU - Quinones-Hinojosa, Alfredo AU - Quinones-Hinojosa A AD - PECEM, UNAM, Mexico City, Mexico. FAU - Guerrero-Cazares, Hugo AU - Guerrero-Cazares H AD - PECEM, UNAM, Mexico City, Mexico. LA - eng GR - K01 NS110930/NS/NINDS NIH HHS/United States GR - R03 NS109444/NS/NINDS NIH HHS/United States GR - R01 CA200399/CA/NCI NIH HHS/United States GR - R01 CA183827/CA/NCI NIH HHS/United States GR - R01 CA195503/CA/NCI NIH HHS/United States GR - R01 CA216855/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - England TA - Neuro Oncol JT - Neuro-oncology JID - 100887420 RN - 0 (SERPINA3 protein, human) RN - 0 (Serpins) RN - 0 (alpha 1-Antichymotrypsin) SB - IM CIN - Neuro Oncol. 2021 Apr 12;23(4):530-532. PMID: 33749775 CIN - Aging (Albany NY). 2021 Sep 29;13(18):21812-21813. PMID: 34587119 MH - Adult MH - Animals MH - *Brain Neoplasms/genetics MH - Cell Line, Tumor MH - Cell Proliferation MH - Gene Expression Regulation, Neoplastic MH - *Glioblastoma/genetics MH - Humans MH - Mice MH - *Neoplastic Stem Cells MH - Serpins MH - *alpha 1-Antichymotrypsin PMC - PMC8041345 OTO - NOTNLM OT - SERPINA3 OT - alpha 1-antichymotrypsin OT - brain tumor OT - cerebrospinal fluid OT - glioblastoma EDAT- 2020/11/30 06:00 MHDA- 2021/05/21 06:00 PMCR- 2021/11/29 CRDT- 2020/11/29 20:35 PHST- 2020/11/30 06:00 [pubmed] PHST- 2021/05/21 06:00 [medline] PHST- 2020/11/29 20:35 [entrez] PHST- 2021/11/29 00:00 [pmc-release] AID - 6010432 [pii] AID - noaa264 [pii] AID - 10.1093/neuonc/noaa264 [doi] PST - ppublish SO - Neuro Oncol. 2021 Apr 12;23(4):599-610. doi: 10.1093/neuonc/noaa264.