title: NPAS3 demonstrates features of a tumor suppressive role in driving the progression of Astrocytomas.
abstract: Malignant astrocytomas, the most common primary brain tumors, are predominantly fatal. Improved treatments will require a better understanding of the biological features of high-grade astrocytomas. To better understand the role of neuronal PAS 3 (NPAS3) in diseases in human beings, it was investigated as a candidate for astrocytomagenesis based on the presence of aberrant protein expression in greater than 70% of a human astrocytoma panel (n = 433) and most notably in surgically resected malignant lesions. In subsequent functional studies, it was concluded that NPAS3 exhibits features of a tumor-suppressor, which drives the progression of astrocytomas by modulating the cell cycle, proliferation, apoptosis, and cell migration/invasion and has a further influence on the viability of endothelial cells. Of clinical importance, absence of NPAS3 expression in glioblastomas was a significantly negative prognostic marker of survival. In addition, malignant astrocytomas lacking NPAS3 expression demonstrated loss of function mutations, which were associated with loss of heterozygosity. While overexpressed NPAS3 in malignant glioma cell lines significantly suppressed transformation, the converse decreased expression considerably induced more aggressive growth. In addition, knockdown NPAS3 expression in a human astrocyte cell line in concert with the human papillomavirus E6 and E7 oncogenes induced growth of malignant astrocytomas. In conclusion, NPAS3 drives the progression of human malignant astrocytomas as a tumor suppressor and is a negative prognostication marker for survival.
authors.affiliation: Centre de Recherche de l'Hôtel-Dieu de Québec, Québec, Québec, Canada.
authors.forename: Frederico
authors.initials: F
authors.lastname: Moreira
authors.forename: Tim-Rasmus
authors.initials: TR
authors.lastname: Kiehl
authors.forename: Kelvin
authors.initials: K
authors.lastname: So
authors.forename: Norbert F
authors.initials: NF
authors.lastname: Ajeawung
authors.forename: Carmelita
authors.initials: C
authors.lastname: Honculada
authors.forename: Peter
authors.initials: P
authors.lastname: Gould
authors.forename: Russell O
authors.initials: RO
authors.lastname: Pieper
authors.forename: Deepak
authors.initials: D
authors.lastname: Kamnasaran
mesh_terms: D000818:Animals; D017209:Apoptosis; D001254:Astrocytoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D051792:Basic Helix-Loop-Helix Proteins; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion; D002453:Cell Cycle; D002465:Cell Movement; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D019175:DNA Methylation; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D019656:Loss of Heterozygosity; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D025521:Tumor Suppressor Proteins
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C502963:NPAS3 protein, human