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首页> 中文期刊> 《骨研究：英文》 >Loss of the vitamin D receptor in human breast and prostate cancers strongly induces cell apoptosis through downregulation of Wnt/β-catenin signaling

Loss of the vitamin D receptor in human breast and prostate cancers strongly induces cell apoptosis through downregulation of Wnt/β-catenin signaling

         
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摘要

Vitamin D co-regulates cell proliferation, differentiation and apoptosis in numerous tissues, including cancers. The known anti-proliferative and pro-apoptotic actions of the active metabolite of vitamin D,1,25-dihydroxy-vitamin D [1,25(OH)2 D] are mediated through binding to the vitamin D receptor(VDR). Here,we report on the unexpected finding that stable knockdown of VDR expression in the human breast and prostate cancer cell lines, MDA-MB-231 and PC3, strongly induces cell apoptosis and inhibits cell proliferation in vitro. Implantation of these VDR knockdown cells into the mammary fat pad(MDA-MB-231),subcutaneously(PC3) or intra-tibially(both cell lines) in immune-incompetent nude mice resulted in reduced tumor growth associated with increased apoptosis and reduced cell proliferation compared with controls.These growth-retarding effects of VDR knockdown occur in the presence and absence of vitamin D and are independent of whether cells were grown in bone or soft tissues. Transcriptome analysis of VDR knockdown and non-target control cell lines demonstrated that loss of the VDR was associated with significant attenuation in the Wnt/β-catenin signaling pathway. In particular, cytoplasmic and nuclear β-catenin protein levels were reduced with a corresponding downregulation of downstream genes such as Axin2, Cyclin D1,interleukin-6(IL-6), and IL-8. Stabilization of β-catenin using the GSK-3β inhibitor BIO partly reversed the growth-retarding effects of VDR knockdown. Our results indicate that the unliganded VDR possesses hitherto unknown functions to promote breast and prostate cancer growth, which appear to be operational not only within but also outside the bone environment. These novel functions contrast with the known anti-proliferative nuclear actions of the liganded VDR and may represent targets for new diagnostic and therapeutic approaches in breast and prostate cancer.

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  • 来源
    《骨研究：英文》 |2017年第003期|P.195-206|共12页
  • 作者

    Yu Zheng; Trupti Trivedi; Ruby CY Lin; Colette Fong-Yee; Rick Nolte; Jeline Manibo; Yunzhao Chen; Musharraf Hossain; Konstantin Horas; Colin Dunstan; Hong Zhou; Markus J Seibel;

  • 作者单位

    [1]Bone Research Program, ANZAC Research Institute, Sydney, New South Wales, Australia [2]Asbestos Diseases Research Institute, Cardiothoracic Genomics, Sydney, New South Wales, Australia [3]School of Medical Sciences, University of New South Wales, Sydney, New South Wales 2052,Australia [4]Department of Pathology, Shihezi University School of Medicine, Shihezi, China [5]Biomedical Engineering, AMME, University of Sydney,Sydney, New South Wales, Australia [6]Concord Clinical .School, The University of Sydney, Sydney, New South Wales, Australia;

    [1]Bone Research Program, ANZAC Research Institute, Sydney, New South Wales, Australia [2]Asbestos Diseases Research Institute, Cardiothoracic Genomics, Sydney, New South Wales, Australia [3]School of Medical Sciences, University of New South Wales, Sydney, New South Wales 2052,Australia [4]Department of Pathology, Shihezi University School of Medicine, Shihezi, China [5]Biomedical Engineering, AMME, University of Sydney,Sydney, New South Wales, Australia [6]Concord Clinical .School, The University of Sydney, Sydney, New South Wales, Australia;

    [1]Bone Research Program, ANZAC Research Institute, Sydney, New South Wales, Australia [2]Asbestos Diseases Research Institute, Cardiothoracic Genomics, Sydney, New South Wales, Australia [3]School of Medical Sciences, University of New South Wales, Sydney, New South Wales 2052,Australia [4]Department of Pathology, Shihezi University School of Medicine, Shihezi, China [5]Biomedical Engineering, AMME, University of Sydney,Sydney, New South Wales, Australia [6]Concord Clinical .School, The University of Sydney, Sydney, New South Wales, Australia;

    [1]Bone Research Program, ANZAC Research Institute, Sydney, New South Wales, Australia [2]Asbestos Diseases Research Institute, Cardiothoracic Genomics, Sydney, New South Wales, Australia [3]School of Medical Sciences, University of New South Wales, Sydney, New South Wales 2052,Australia [4]Department of Pathology, Shihezi University School of Medicine, Shihezi, China [5]Biomedical Engineering, AMME, University of Sydney,Sydney, New South Wales, Australia [6]Concord Clinical .School, The University of Sydney, Sydney, New South Wales, Australia;

    [1]Bone Research Program, ANZAC Research Institute, Sydney, New South Wales, Australia [2]Asbestos Diseases Research Institute, Cardiothoracic Genomics, Sydney, New South Wales, Australia [3]School of Medical Sciences, University of New South Wales, Sydney, New South Wales 2052,Australia [4]Department of Pathology, Shihezi University School of Medicine, Shihezi, China [5]Biomedical Engineering, AMME, University of Sydney,Sydney, New South Wales, Australia [6]Concord Clinical .School, The University of Sydney, Sydney, New South Wales, Australia;

    [1]Bone Research Program, ANZAC Research Institute, Sydney, New South Wales, Australia [2]Asbestos Diseases Research Institute, Cardiothoracic Genomics, Sydney, New South Wales, Australia [3]School of Medical Sciences, University of New South Wales, Sydney, New South Wales 2052,Australia [4]Department of Pathology, Shihezi University School of Medicine, Shihezi, China [5]Biomedical Engineering, AMME, University of Sydney,Sydney, New South Wales, Australia [6]Concord Clinical .School, The University of Sydney, Sydney, New South Wales, Australia;

    [1]Bone Research Program, ANZAC Research Institute, Sydney, New South Wales, Australia [2]Asbestos Diseases Research Institute, Cardiothoracic Genomics, Sydney, New South Wales, Australia [3]School of Medical Sciences, University of New South Wales, Sydney, New South Wales 2052,Australia [4]Department of Pathology, Shihezi University School of Medicine, Shihezi, China [5]Biomedical Engineering, AMME, University of Sydney,Sydney, New South Wales, Australia [6]Concord Clinical .School, The University of Sydney, Sydney, New South Wales, Australia;

    [1]Bone Research Program, ANZAC Research Institute, Sydney, New South Wales, Australia [2]Asbestos Diseases Research Institute, Cardiothoracic Genomics, Sydney, New South Wales, Australia [3]School of Medical Sciences, University of New South Wales, Sydney, New South Wales 2052,Australia [4]Department of Pathology, Shihezi University School of Medicine, Shihezi, China [5]Biomedical Engineering, AMME, University of Sydney,Sydney, New South Wales, Australia [6]Concord Clinical .School, The University of Sydney, Sydney, New South Wales, Australia;

    [1]Bone Research Program, ANZAC Research Institute, Sydney, New South Wales, Australia [2]Asbestos Diseases Research Institute, Cardiothoracic Genomics, Sydney, New South Wales, Australia [3]School of Medical Sciences, University of New South Wales, Sydney, New South Wales 2052,Australia [4]Department of Pathology, Shihezi University School of Medicine, Shihezi, China [5]Biomedical Engineering, AMME, University of Sydney,Sydney, New South Wales, Australia [6]Concord Clinical .School, The University of Sydney, Sydney, New South Wales, Australia;

    [1]Bone Research Program, ANZAC Research Institute, Sydney, New South Wales, Australia [2]Asbestos Diseases Research Institute, Cardiothoracic Genomics, Sydney, New South Wales, Australia [3]School of Medical Sciences, University of New South Wales, Sydney, New South Wales 2052,Australia [4]Department of Pathology, Shihezi University School of Medicine, Shihezi, China [5]Biomedical Engineering, AMME, University of Sydney,Sydney, New South Wales, Australia [6]Concord Clinical .School, The University of Sydney, Sydney, New South Wales, Australia;

    [1]Bone Research Program, ANZAC Research Institute, Sydney, New South Wales, Australia [2]Asbestos Diseases Research Institute, Cardiothoracic Genomics, Sydney, New South Wales, Australia [3]School of Medical Sciences, University of New South Wales, Sydney, New South Wales 2052,Australia [4]Department of Pathology, Shihezi University School of Medicine, Shihezi, China [5]Biomedical Engineering, AMME, University of Sydney,Sydney, New South Wales, Australia [6]Concord Clinical .School, The University of Sydney, Sydney, New South Wales, Australia;

    [1]Bone Research Program, ANZAC Research Institute, Sydney, New South Wales, Australia [2]Asbestos Diseases Research Institute, Cardiothoracic Genomics, Sydney, New South Wales, Australia [3]School of Medical Sciences, University of New South Wales, Sydney, New South Wales 2052,Australia [4]Department of Pathology, Shihezi University School of Medicine, Shihezi, China [5]Biomedical Engineering, AMME, University of Sydney,Sydney, New South Wales, Australia [6]Concord Clinical .School, The University of Sydney, Sydney, New South Wales, Australia;

    [1]Bone Research Program, ANZAC Research Institute, Sydney, New South Wales, Australia [2]Asbestos Diseases Research Institute, Cardiothoracic Genomics, Sydney, New South Wales, Australia [3]School of Medical Sciences, University of New South Wales, Sydney, New South Wales 2052,Australia [4]Department of Pathology, Shihezi University School of Medicine, Shihezi, China [5]Biomedical Engineering, AMME, University of Sydney,Sydney, New South Wales, Australia [6]Concord Clinical .School, The University of Sydney, Sydney, New South Wales, Australia;

    [1]Bone Research Program, ANZAC Research Institute, Sydney, New South Wales, Australia [2]Asbestos Diseases Research Institute, Cardiothoracic Genomics, Sydney, New South Wales, Australia [3]School of Medical Sciences, University of New South Wales, Sydney, New South Wales 2052,Australia [4]Department of Pathology, Shihezi University School of Medicine, Shihezi, China [5]Biomedical Engineering, AMME, University of Sydney,Sydney, New South Wales, Australia [6]Concord Clinical .School, The University of Sydney, Sydney, New South Wales, Australia;

    [1]Bone Research Program, ANZAC Research Institute, Sydney, New South Wales, Australia [2]Asbestos Diseases Research Institute, Cardiothoracic Genomics, Sydney, New South Wales, Australia [3]School of Medical Sciences, University of New South Wales, Sydney, New South Wales 2052,Australia [4]Department of Pathology, Shihezi University School of Medicine, Shihezi, China [5]Biomedical Engineering, AMME, University of Sydney,Sydney, New South Wales, Australia [6]Concord Clinical .School, The University of Sydney, Sydney, New South Wales, Australia;

    [1]Bone Research Program, ANZAC Research Institute, Sydney, New South Wales, Australia [2]Asbestos Diseases Research Institute, Cardiothoracic Genomics, Sydney, New South Wales, Australia [3]School of Medical Sciences, University of New South Wales, Sydney, New South Wales 2052,Australia [4]Department of Pathology, Shihezi University School of Medicine, Shihezi, China [5]Biomedical Engineering, AMME, University of Sydney,Sydney, New South Wales, Australia [6]Concord Clinical .School, The University of Sydney, Sydney, New South Wales, Australia;

  • 原文格式 PDF
  • 正文语种 CHI
  • 中图分类 动物胚胎学（动物发生学、动物胎生学）;
  • 关键词

    β-catenin 维生素D受体 Wnt信号通路 细胞凋亡 前列腺癌 乳腺癌 诱导 白细胞介素-6;

    机译：β-catenin 维生素D受体 Wnt信号通路 细胞凋亡 前列腺癌 乳腺癌 诱导 白细胞介素-6;
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