title: REIC/Dkk-3 induces cell death in human malignant glioma.
abstract: The progression of glioma to more malignant phenotypes results from the stepwise accumulation of genetic alterations and the consequent disruption of the apoptotic pathway and augmentation of survival signaling. REIC/Dkk-3, a member of the human Dickkopf (Dkk) family, plays a role as a suppressor of the growth of several human cancers; however, to date it has not been identified in brain tumors. We compared the gene and protein expression of REIC/Dkk-3 in human malignant glioma and normal brain tissues using quantitative real-time PCR, Western blotting, and immunohistochemistry. We also performed small interfering REIC/Dkk-3 (siREIC/Dkk-3) knockdown and REIC/Dkk-3 overexpression experiments to examine the role of REIC/Dkk-3 in human malignant glioma cells in vitro. In brain tissue from patients with malignant glioma, the gene and protein expression of REIC/Dkk-3 was lower than in normal brain tissue and was related to the malignancy grade. In the primary glioblastoma cell line, REIC/Dkk-3 transfection led to apoptosis owing to the activation of phosphorylated JUN, caspase-9, and caspase-3 and the reduction of beta-catenin; in REIC/Dkk-3 knockdown experiments, cell growth was augmented. Our results suggest that REIC/Dkk-3 regulates the growth and survival of these cells in a caspase-dependent and -independent way via modification of the Wnt signaling pathway. Our work is the first documentation that the gene and protein expression of REIC/Dkk-3 is down-regulated in human malignant glioma. Our demonstration of the mechanisms underlying REIC/Dkk-3-induced cell death indicates that REIC/Dkk-3 plays a pivotal role in the biology of human malignant glioma and suggests that REIC/Dkk-3 is a promising candidate for molecular target therapy.
authors.affiliation: Department of Neurosurgery, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, 3-18-15, Kuramoto-cho, Tokushima, Japan 770-8503. mizo@yj8.so-net.ne.jp
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Mizobuchi
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Matsuzaki
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Kuwayama
authors.forename: Keiko
authors.initials: K
authors.lastname: Kitazato
authors.forename: Hideo
authors.initials: H
authors.lastname: Mure
authors.forename: Teruyoshi
authors.initials: T
authors.lastname: Kageji
authors.forename: Shinji
authors.initials: S
authors.lastname: Nagahiro
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D018925:Chemokines; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D005910:Glioma / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis*; D020411:Oligonucleotide Array Sequence Analysis; D040081:Protein Array Analysis; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection; D051176:beta Catenin / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018925:Chemokines; C498624:DKK3 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; D051176:beta Catenin