TGFβ-Responsive HMOX1 Expression Is Associated with Stemness and Invasion in Glioblastoma Multiforme

Dhiman Ghosh*, Ilya V. Ulasov, Li Ping Chen, Lualhati E. Harkins, Karolina Wallenborg, Parvinder Hothi, Steven Rostad, Leroy Hood, Charles S. Cobbs

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

Abstract

Glioblastoma multiforme (GBM) is the most common and lethal adult brain tumor. Resistance to standard radiation and chemotherapy is thought to involve survival of GBM cancer stem cells (CSCs). To date, no single marker for identifying GBM CSCs has been able to capture the diversity of CSC populations, justifying the needs for additional CSC markers for better characterization. Employing targeted mass spectrometry, here we present five cell-surface markers HMOX1, SLC16A1, CADM1, SCAMP3, and CLCC1 which were found to be elevated in CSCs relative to healthy neural stem cells (NSCs). Transcriptomic analyses of REMBRANDT and TCGA compendiums also indicated elevated expression of these markers in GBM relative to controls and non-GBM diseases. Two markers SLC16A1 and HMOX1 were found to be expressed among pseudopalisading cells that reside in the hypoxic region of GBM, substantiating the histopathological hallmarks of GBM. In a prospective study (N = 8) we confirmed the surface expression of HMOX1 on freshly isolated primary GBM cells (P0). Employing functional assays that are known to evaluate stemness, we demonstrate that elevated HMOX1 expression is associated with stemness in GBM and can be modulated through TGFβ. siRNA-mediated silencing of HMOX1 impaired GBM invasion—a phenomenon related to poor prognosis. In addition, surgical resection of GBM tumors caused declines (18% ± 5.1SEM) in the level of plasma HMOX1 as measured by ELISA, in 8/10 GBM patients. These findings indicate that HMOX1 is a robust predictor of GBM CSC stemness and pathogenesis. Further understanding of the role of HMOX1 in GBM may uncover novel therapeutic approaches. Stem Cells 2016;34:2276–2289.

Original languageEnglish (US)
Pages (from-to)2276-2289
Number of pages14
JournalStem Cells
Volume34
Issue number9
DOIs
StatePublished - Sep 1 2016

Funding

We are grateful to Dr. Paul Mischel of UC San Diego for providing us with the U87 isogenic cell lines. We are also thankful to Dr. Cory Funk and Katherine Rouleau of Institute for Systems Biology, Seattle for critical discussions and suggestions. Mass spectrometry and flow cytometry facilities at ISB, Seattle, and flow cytometry resource at Fred Hutchinson Cancer Research Center, Seattle are duly acknowledged. The work was supported by NIH/NCI NanoSystems Biology Cancer Center grant U54 CA151819A (LH) and NIH R01 NS070289 (CC).

Keywords

  • CSC
  • GBM
  • Invasion
  • NSC
  • Neurosphere
  • Pseudopalisading

ASJC Scopus subject areas

  • General Medicine

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