Alpha 1-antichymotrypsin contributes to stem cell characteristics and enhances tumorigenicity of glioblastoma

Montserrat Lara-Velazquez, Natanael Zarco, Anna Carrano, Jordan Phillipps, Emily S. Norton, Paula Schiapparelli, Rawan Al-Kharboosh, Jordina Rincon-Torroella, Stephanie Jeanneret, Teresa Corona, Jose Segovia, Mark E. Jentoft, Kaisorn L. Chaichana, Yan W. Asmann, Alfredo Quiñones-Hinojosa, Hugo Guerrero-Cazares

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)599-610
Number of pages12
JournalNeuro-oncology
Volume23
Issue number4
DOIs
StatePublished - Apr 12 2021

Keywords

  • SERPINA3
  • alpha 1-antichymotrypsin
  • brain tumor
  • cerebrospinal fluid
  • glioblastoma

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology
  • Cancer Research

Fingerprint Dive into the research topics of 'Alpha 1-antichymotrypsin contributes to stem cell characteristics and enhances tumorigenicity of glioblastoma'. Together they form a unique fingerprint.

Cite this