title: NOTCH3 is a prognostic factor that promotes glioma cell proliferation, migration and invasion via activation of CCND1 and EGFR.
abstract: Using a GWA analysis of a comprehensive glioma specimen population, we identified whole gain of chromosome 19 as one of the major chromosomal aberrations that correlates to patients' outcomes. Our analysis of significant loci revealed for the first time NOTCH3 as one of the most significant amplification. NOTCH3 amplification is associated with worse outcome compared to tumors with non-amplified locus. NOTCH receptors (NOTCH1-4) are key positive regulators of cell-cell interactions, angiogenesis, cell adhesion and stem cell niche development which have been shown to play critical roles in several human cancers. Our objective is to determine the molecular roles of NOTCH3 in glioma pathogenesis and aggressiveness. Here we show for the first time that NOTCH3 plays a major role in glioma cell proliferation, cell migration, invasion and apoptosis. Therefore, our study uncovers the prognostic value and the oncogenic function of NOTCH3 in gliomagenesis and supports NOTCH3 as a promising target of therapy in high grade glioma. Our studies allowed the identification of a subset of population that may benefit from GSI- or anti-NOTCH3- based therapies. This may lead to the design of novel strategies to improve therapeutic outcome of patients with glioma by establishing medical and scientific basis for personalized chemotherapies.
authors.affiliation: Pharmaceutics and Translational Therapeutics, College of Pharmacy, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Mohammad A Y
authors.initials: MA
authors.lastname: Alqudah
authors.forename: Supreet
authors.initials: S
authors.lastname: Agarwal
authors.forename: Maha S
authors.initials: MS
authors.lastname: Al-Keilani
authors.forename: Zita A
authors.initials: ZA
authors.lastname: Sibenaller
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Ryken
authors.forename: Mahfoud
authors.initials: M
authors.lastname: Assem
mesh_terms: D017209:Apoptosis; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D005910:Glioma / Q000175:diagnosis / Q000235:genetics / Q000473:pathology*; D006801:Humans; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D009857:Oncogenes / Q000235:genetics; D011379:Prognosis; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: C499374:NOTCH3 protein, human; D000071656:Receptor, Notch3; D051880:Receptors, Notch; D019938:Cyclin D1; D066246:ErbB Receptors