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MRP3: a molecular target for human glioblastoma multiforme immunotherapy.

dc.contributor.author Bigner, DD
dc.contributor.author Herndon, James Emmett II
dc.contributor.author Kuan, Chien-Tsun
dc.contributor.author Lipp, Eric S
dc.contributor.author McLendon, Roger E
dc.contributor.author Pegram, CN
dc.contributor.author Rasheed, A
dc.contributor.author Riggins, GJ
dc.contributor.author Szafranski, SE
dc.contributor.author Wakiya, K
dc.contributor.author Wikstrand, CJ
dc.coverage.spatial England
dc.date.accessioned 2011-06-21T17:29:38Z
dc.date.issued 2010-09-01
dc.identifier http://www.ncbi.nlm.nih.gov/pubmed/20809959
dc.identifier 1471-2407-10-468
dc.identifier.uri https://hdl.handle.net/10161/4357
dc.description.abstract 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.
dc.language eng
dc.language.iso en_US
dc.relation.ispartof BMC Cancer
dc.relation.isversionof 10.1186/1471-2407-10-468
dc.relation.isreplacedby 10161/16100
dc.relation.isreplacedby http://hdl.handle.net/10161/16100
dc.subject Animals
dc.subject Antibodies, Monoclonal
dc.subject Blotting, Western
dc.subject Brain
dc.subject Brain Neoplasms
dc.subject Case-Control Studies
dc.subject Cells, Cultured
dc.subject Female
dc.subject Glioblastoma
dc.subject Humans
dc.subject Immunoenzyme Techniques
dc.subject Immunotherapy
dc.subject Male
dc.subject Mice
dc.subject Mice, Inbred BALB C
dc.subject Middle Aged
dc.subject Multidrug Resistance-Associated Proteins
dc.subject Neoplasm Staging
dc.subject Prognosis
dc.subject RNA, Messenger
dc.subject Rabbits
dc.subject Reverse Transcriptase Polymerase Chain Reaction
dc.subject Survival Rate
dc.subject Tumor Cells, Cultured
dc.subject Xenograft Model Antitumor Assays
dc.title MRP3: a molecular target for human glioblastoma multiforme immunotherapy.
dc.title.alternative
dc.type Journal article
dc.description.version Version of Record
duke.date.pubdate 2010-9-1
duke.description.issue
duke.description.volume 10
dc.relation.journal Bmc Cancer
pubs.author-url http://www.ncbi.nlm.nih.gov/pubmed/20809959
pubs.begin-page 468
pubs.organisational-group Basic Science Departments
pubs.organisational-group Biostatistics & Bioinformatics
pubs.organisational-group Clinical Science Departments
pubs.organisational-group Duke
pubs.organisational-group Duke Cancer Institute
pubs.organisational-group Faculty
pubs.organisational-group Institutes and Centers
pubs.organisational-group Neurosurgery
pubs.organisational-group Pathology
pubs.organisational-group School of Medicine
pubs.organisational-group Surgery
pubs.publication-status Published online
pubs.volume 10
dc.identifier.eissn 1471-2407


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