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Mechanisms underlying regulation of Wnt signaling pathway against cancer stem-and glioma cells

Wnt 信号通路对癌症干细胞和神经胶质瘤细胞的调控机制

基本信息

批准号：
22791348
负责人：
MIZOBUCHI Yoshifumi
金额：
$ 2.5万
依托单位：
The University of Tokushima
依托单位国家：
日本
项目类别：
Grant-in-Aid for Young Scientists (B)
财政年份：
2010
资助国家：
日本
起止时间：
2010 至 2011
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-22791348/
关键词：
脳腫瘍 REIC-Dkk3 Wntシグナル REIC-DKK-3 遺伝子治療

项目摘要

Reduced expression in immortalized cells/ Dikkofp-3(REIC/ DKK3, REIC), a tumor suppressor gene, has been investigated in gene therapy studies in various cancers. Elsewhere we first demonstrated that REIC was down-regulated in glioblastoma(GBM) cells, and that its over-expression with plasmid vector drastically inhibited their growth via activation of intrinsic apoptotic pathway. However, whether adenovirus-mediated overexpression of REIC(Ad-REIC) contributes to anti-tumor effect in glioma remain unclear. We performed this study to assess the applicability of Ad-REIC in GBM and to verify the molecular mechanisms underlying anti-tumor effect of Ad-REIC We first document that Ad-REIC effectively inhibited the growth of GBM in a time-and dose dependent manner and induced apoptosis. We also found that Ad-REIC reduced expression of Wnt proteins and its receptor LRP6 but not ROR2 Our data suggest that interfering the activation of both canonical-and non-canonical Wnt signaling pathway via overexpression of REIC contributes at least partly to suppress cell survival in GBM.

永生化细胞/Dikkofp-3(reic/DKK3，reic)是一种肿瘤抑制基因，在多种癌症的基因治疗研究中发现其表达降低。在其他方面，我们首次证明了REIC在胶质母细胞瘤(GBM)细胞中表达下调，并且它的过度表达通过激活内在的凋亡途径而显著抑制了GBM细胞的生长。然而，腺病毒介导的reic(Ad-reic)过表达是否有助于胶质瘤的抗肿瘤作用尚不清楚。本研究旨在评估Ad-reic在GBM中的适用性，并验证Ad-reic抗肿瘤作用的分子机制。我们首次证明Ad-reic以时间和剂量依赖的方式有效地抑制GBM的生长，并诱导细胞凋亡。我们还发现，Ad-reic减少了Wnt蛋白及其受体LRP6的表达，而不是ROR2。我们的研究结果表明，通过过度表达reic来干扰规范和非规范Wnt信号通路的激活，至少在一定程度上抑制了GBM细胞的存活。