Copyright 2008 by the Society for Neuro-Oncology
REIC/Dkk-3 induces cell death in human malignant glioma
Department of Neurosurgery, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Kuramoto-cho, Tokushima, Japan
Address all correspondence to Yoshifumi Mizobuchi, Department of Neurosurgery, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, 3-18-15, Kuramoto-cho, Tokushima, Japan 770-8503 (mizo{at}yj8.so-net.ne.jp).
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Abstract |
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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 β-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.
Keywords: apoptosis, β-catenin, caspase, malignant glioma, REIC/Dkk-3
Received April 19, 2007; Accepted October 3, 2007
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