Aberrant methylation of trail decoy receptor genes is frequent in multiple tumor types

Authors

  • Narayan Shivapurkar,

    1. Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA
    2. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA
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    • The first two authors contributed equally to this work.

  • Shinichi Toyooka,

    1. Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA
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    • The first two authors contributed equally to this work.

  • Kiyomi O. Toyooka,

    1. Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA
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  • Jyotsna Reddy,

    1. Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA
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  • Kuniharu Miyajima,

    1. Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA
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  • Makoto Suzuki,

    1. Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA
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  • Hisayuki Shigematsu,

    1. Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA
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  • Takao Takahashi,

    1. Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA
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  • Gunjan Parikh,

    1. Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA
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  • Harvey I. Pass,

    1. Department of Thoracic Surgery, Karamanos Cancer Center, Detroit, MI, USA
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  • Preet M. Chaudhary,

    1. Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
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  • Adi F. Gazdar

    Corresponding author
    1. Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA
    2. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA
    • Hamon Center for Therapeutic Oncology Research University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, Texas 75390
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    • Fax: +1-214-648-4940


Abstract

TNF-related apoptosis-inducing ligand (TRAIL) selectively induces programmed cell death (apoptosis) in various cancer cells but not in normal cells. TRAIL is known to bind to 4 different receptors, 2 proapoptotic (DR4 and DR5), and 2 potentially antiapoptotic receptors lacking death domains (DcR1 and DcR2). Aberrant promoter methylation and resultant silencing of tumor suppressor genes play an important role in the pathogenesis of many tumor types. Recently aberrant methylation of TRAIL decoy receptors was reported in pediatric tumor cell lines and neuroblastomas. We examined the methylation and expression status of TRAIL receptor genes in cancers of breast, lung, mesothelioma, prostate, bladder, cervix, ovary, brain and in hematopoietic malignancies. Aberrant methylation of DcR1 or DcR2 was present in 70% of primary breast cancers, 31% of primary lung cancers, in 63% of primary malignant mesothelioma (MM), in 60% of prostate cancer, in 42% of bladder cancer, in 100% of cervical cancer, in 43% of ovarian cancer, in 41% of lymphoma, in 26% of leukemia and in 56% of multiple myeloma. Methylation of DR4 and DR5 was rare in all the tumor types examined. Methylation of all the 4 receptors was rare in non malignant tissues. In cell lines, aberrant methylation of DcR1 was present in 11 of 23 (48%) breast, 10 of 27 (37%) lung and 3 of 7 (43%) MM, whereas aberrant methylation of DcR2 was present in 17 of 23 (74%) breast, 13 of 27 (48%) lung and 5 of 7 (71%) MM. The concordance between loss of gene expression and aberrant methylation ranged from 70–100%. Treatment with 5-aza-2′-deoxycytidine restored DcR1 and DcR2 expression in 9 methylated cell lines confirming that aberrant methylation was the cause for silencing of DcR1 and DcR2 expression. Our results demonstrate that DcR1 and DcR2 genes are frequently methylated in various tumor types, and that the role of decoy receptors in tumor pathogenesis needs to be re-evaluated. © 2004 Wiley-Liss, Inc.

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