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MRP3: a molecular target for human glioblastoma multiforme immunotherapy.

Publication ,  Journal Article
Kuan, C-T; Wakiya, K; Herndon, JE; Lipp, ES; Pegram, CN; Riggins, GJ; Rasheed, A; Szafranski, SE; McLendon, RE; Wikstrand, CJ; Bigner, DD
Published in: BMC Cancer
September 1, 2010

BACKGROUND: Glioblastoma multiforme (GBM) is refractory to conventional therapies. To overcome the problem of heterogeneity, more brain tumor markers are required for prognosis and targeted therapy. We have identified and validated a promising molecular therapeutic target that is expressed by GBM: human multidrug-resistance protein 3 (MRP3). METHODS: We investigated MRP3 by genetic and immunohistochemical (IHC) analysis of human gliomas to determine the incidence, distribution, and localization of MRP3 antigens in GBM and their potential correlation with survival. To determine MRP3 mRNA transcript and protein expression levels, we performed quantitative RT-PCR, raising MRP3-specific antibodies, and IHC analysis with biopsies of newly diagnosed GBM patients. We used univariate and multivariate analyses to assess the correlation of RNA expression and IHC of MRP3 with patient survival, with and without adjustment for age, extent of resection, and KPS. RESULTS: Real-time PCR results from 67 GBM biopsies indicated that 59/67 (88%) samples highly expressed MRP3 mRNA transcripts, in contrast with minimal expression in normal brain samples. Rabbit polyvalent and murine monoclonal antibodies generated against an extracellular span of MRP3 protein demonstrated reactivity with defined MRP3-expressing cell lines and GBM patient biopsies by Western blotting and FACS analyses, the latter establishing cell surface MRP3 protein expression. IHC evaluation of 46 GBM biopsy samples with anti-MRP3 IgG revealed MRP3 in a primarily membranous and cytoplasmic pattern in 42 (91%) of the 46 samples. Relative RNA expression was a strong predictor of survival for newly diagnosed GBM patients. Hazard of death for GBM patients with high levels of MRP3 RNA expression was 2.71 (95% CI: 1.54-4.80) times that of patients with low/moderate levels (p = 0.002). CONCLUSIONS: Human GBMs overexpress MRP3 at both mRNA and protein levels, and elevated MRP3 mRNA levels in GBM biopsy samples correlated with a higher risk of death. These data suggest that the tumor-associated antigen MRP3 has potential use for prognosis and as a target for malignant glioma immunotherapy.

Duke Scholars

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Published In

BMC Cancer

DOI

EISSN

1471-2407

Publication Date

September 1, 2010

Volume

10

Start / End Page

468

Location

England

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Tumor Cells, Cultured
  • Survival Rate
  • Reverse Transcriptase Polymerase Chain Reaction
  • Rabbits
  • RNA, Messenger
  • Prognosis
  • Oncology & Carcinogenesis
  • Neoplasm Staging
  • Multidrug Resistance-Associated Proteins
 

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Kuan, C.-T., Wakiya, K., Herndon, J. E., Lipp, E. S., Pegram, C. N., Riggins, G. J., … Bigner, D. D. (2010). MRP3: a molecular target for human glioblastoma multiforme immunotherapy. BMC Cancer, 10, 468. https://doi.org/10.1186/1471-2407-10-468
Kuan, Chien-Tsun, Kenji Wakiya, James E. Herndon, Eric S. Lipp, Charles N. Pegram, Gregory J. Riggins, Ahmed Rasheed, et al. “MRP3: a molecular target for human glioblastoma multiforme immunotherapy.BMC Cancer 10 (September 1, 2010): 468. https://doi.org/10.1186/1471-2407-10-468.
Kuan C-T, Wakiya K, Herndon JE, Lipp ES, Pegram CN, Riggins GJ, et al. MRP3: a molecular target for human glioblastoma multiforme immunotherapy. BMC Cancer. 2010 Sep 1;10:468.
Kuan, Chien-Tsun, et al. “MRP3: a molecular target for human glioblastoma multiforme immunotherapy.BMC Cancer, vol. 10, Sept. 2010, p. 468. Pubmed, doi:10.1186/1471-2407-10-468.
Kuan C-T, Wakiya K, Herndon JE, Lipp ES, Pegram CN, Riggins GJ, Rasheed A, Szafranski SE, McLendon RE, Wikstrand CJ, Bigner DD. MRP3: a molecular target for human glioblastoma multiforme immunotherapy. BMC Cancer. 2010 Sep 1;10:468.
Journal cover image

Published In

BMC Cancer

DOI

EISSN

1471-2407

Publication Date

September 1, 2010

Volume

10

Start / End Page

468

Location

England

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Tumor Cells, Cultured
  • Survival Rate
  • Reverse Transcriptase Polymerase Chain Reaction
  • Rabbits
  • RNA, Messenger
  • Prognosis
  • Oncology & Carcinogenesis
  • Neoplasm Staging
  • Multidrug Resistance-Associated Proteins