Montserrat Lara-Velazquez1,2, Natanael Zarco2, Anna Carrano1, Jordan Phillipps1, Emily S Norton1,3,4, Paula Schiapparelli1, Rawan Al-Kharboosh1,3,4, Jordina Rincon-Torroella5, Stephanie Jeanneret1, Teresa Corona6, Jose Segovia7, Mark E Jentoft8, Kaisorn L Chaichana1, Yan W Asmann9, Alfredo Quiñones-Hinojosa1, Hugo Guerrero-Cazares1. 1. PECEM, UNAM, Mexico City, Mexico. 2. Department of Neurosurgery, Mayo Clinic, Jacksonville, Florida, USA. 3. Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, Minnesota, USA. 4. Regenerative Sciences Training Program, Center for Regenerative Medicine, Mayo Clinic, Rochester, Minnesota, USA. 5. Department of Neurosurgery, Johns Hopkins Hospital, Baltimore, MD, USA. 6. Clinical Laboratory of Neurodegenerative Diseases, National Institute of Neurology and Neurosurgery, Mexico City, Mexico. 7. Department of Physiology, Biophysics and Neurosciences, Cinvestav-IPN, Mexico City, Mexico. 8. Department of Laboratory Medicine and Pathology, Mayo Clinic, Jacksonville, Florida, USA. 9. Department of Health Sciences Research, Mayo Clinic, Jacksonville, Florida, USA.
Abstract
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.
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.
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