Expression of CD74 in high grade gliomas

A potential role in temozolomide resistance

Gaspar J. Kitange, Brett L. Carlson, Mark A. Schroeder, Paul A. Decker, Bruce W. Morlan, Wenting Wu, Karla V. Ballman, Caterina Giannini, Jann N Sarkaria

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Temozolomide (TMZ) is the most effective chemotherapeutic agent for glioblastoma (GBM). Resistance to this methylating agent is linked to DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT). However, in recent studies MGMT status was not completely accurate as a predictor of TMZ response in GBM, suggesting other mechanisms of resistance. As part of an effort aimed at discovery of genes involved in TMZ resistance in GBM, the expression of CD74 was evaluated in GBM patient samples and the influence of CD74 on TMZ response was evaluated in GBM tumor models. Reverse transcription-polymerase-chain reaction (RT-PCR) demonstrated differential expression of CD74 mRNA among the GBM xenografts; 8 of 20 (40%) expressed CD74 mRNA. In a preliminary evaluation of whether CD74 expression might influence TMZ response, CD74 mRNA expression levels were inversely associated with in vivo TMZ resistance in 20 GBM xenograft lines (median survival 122 vs. 62.5 days; r = -0.48, P = 0.032). In follow up to this observation, CD74 shRNA knock down in U87 cells significantly suppressed in vitro proliferation and increased TMZ sensitivity as compared to a non-specific control shRNA. Consistent with an effect on proliferation and survival, silencing of CD74 by shRNA was associated with reduced Akt and Erk1/2 activation in response to stimulation by CD74 ligand macrophage-migration inhibition factor (MIF). Lastly, expression of CD74 protein was assessed in patient samples [nine anaplastic astrocytoma (AA), and 62 GBM] by immunohistochemistry, and appreciable expression was observed in 28% of samples. Collectively, these findings suggest that CD74 is expressed in a subset of high grade gliomas and may contribute to TMZ resistance.

Original languageEnglish (US)
Pages (from-to)177-186
Number of pages10
JournalJournal of Neuro-Oncology
Volume100
Issue number2
DOIs
StatePublished - Nov 2010

Fingerprint

temozolomide
Glioblastoma
Glioma
Small Interfering RNA
Methyltransferases
Heterografts
Messenger RNA
DNA Repair Enzymes
Macrophage Migration-Inhibitory Factors
Survival
DNA
Astrocytoma
Genetic Association Studies
Reverse Transcription

Keywords

  • CD74
  • Glioblastoma xenografts
  • Resistance
  • Temozolomide

ASJC Scopus subject areas

  • Clinical Neurology
  • Cancer Research
  • Oncology
  • Neurology

Cite this

Kitange, G. J., Carlson, B. L., Schroeder, M. A., Decker, P. A., Morlan, B. W., Wu, W., ... Sarkaria, J. N. (2010). Expression of CD74 in high grade gliomas: A potential role in temozolomide resistance. Journal of Neuro-Oncology, 100(2), 177-186. https://doi.org/10.1007/s11060-010-0186-9

Expression of CD74 in high grade gliomas : A potential role in temozolomide resistance. / Kitange, Gaspar J.; Carlson, Brett L.; Schroeder, Mark A.; Decker, Paul A.; Morlan, Bruce W.; Wu, Wenting; Ballman, Karla V.; Giannini, Caterina; Sarkaria, Jann N.

In: Journal of Neuro-Oncology, Vol. 100, No. 2, 11.2010, p. 177-186.

Research output: Contribution to journalArticle

Kitange, GJ, Carlson, BL, Schroeder, MA, Decker, PA, Morlan, BW, Wu, W, Ballman, KV, Giannini, C & Sarkaria, JN 2010, 'Expression of CD74 in high grade gliomas: A potential role in temozolomide resistance', Journal of Neuro-Oncology, vol. 100, no. 2, pp. 177-186. https://doi.org/10.1007/s11060-010-0186-9
Kitange GJ, Carlson BL, Schroeder MA, Decker PA, Morlan BW, Wu W et al. Expression of CD74 in high grade gliomas: A potential role in temozolomide resistance. Journal of Neuro-Oncology. 2010 Nov;100(2):177-186. https://doi.org/10.1007/s11060-010-0186-9
Kitange, Gaspar J. ; Carlson, Brett L. ; Schroeder, Mark A. ; Decker, Paul A. ; Morlan, Bruce W. ; Wu, Wenting ; Ballman, Karla V. ; Giannini, Caterina ; Sarkaria, Jann N. / Expression of CD74 in high grade gliomas : A potential role in temozolomide resistance. In: Journal of Neuro-Oncology. 2010 ; Vol. 100, No. 2. pp. 177-186.
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abstract = "Temozolomide (TMZ) is the most effective chemotherapeutic agent for glioblastoma (GBM). Resistance to this methylating agent is linked to DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT). However, in recent studies MGMT status was not completely accurate as a predictor of TMZ response in GBM, suggesting other mechanisms of resistance. As part of an effort aimed at discovery of genes involved in TMZ resistance in GBM, the expression of CD74 was evaluated in GBM patient samples and the influence of CD74 on TMZ response was evaluated in GBM tumor models. Reverse transcription-polymerase-chain reaction (RT-PCR) demonstrated differential expression of CD74 mRNA among the GBM xenografts; 8 of 20 (40{\%}) expressed CD74 mRNA. In a preliminary evaluation of whether CD74 expression might influence TMZ response, CD74 mRNA expression levels were inversely associated with in vivo TMZ resistance in 20 GBM xenograft lines (median survival 122 vs. 62.5 days; r = -0.48, P = 0.032). In follow up to this observation, CD74 shRNA knock down in U87 cells significantly suppressed in vitro proliferation and increased TMZ sensitivity as compared to a non-specific control shRNA. Consistent with an effect on proliferation and survival, silencing of CD74 by shRNA was associated with reduced Akt and Erk1/2 activation in response to stimulation by CD74 ligand macrophage-migration inhibition factor (MIF). Lastly, expression of CD74 protein was assessed in patient samples [nine anaplastic astrocytoma (AA), and 62 GBM] by immunohistochemistry, and appreciable expression was observed in 28{\%} of samples. Collectively, these findings suggest that CD74 is expressed in a subset of high grade gliomas and may contribute to TMZ resistance.",
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