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Progressive aberrant methylation of the RASSF1A gene in simian virus 40 infected human mesothelial cells

Oncogene volume 21, pages 4340–4344 (2002)Cite this article

Abstract

Mesotheliomas are tumors arising from mesothelial cells and are associated with asbestos exposure and approximately 50% contain simian virus 40 (SV40) DNA sequences. SV40 infection of human mesothelial cells (HM) causes early cellular immortalization and late transformation. Aberrant methylation is a major mech-anism for loss of function of tumor suppressor genes (TSGs). We recently reported that of seven genes frequently methylated in epithelial tumors, only RASSF1A gene was frequently methylated in mesotheliomas, and its methylation was correlated with loss of RASSF1A expression and the presence of SV40. We studied whether SV40 infection of normal HM induces aberrant methylation of the genes previously studied in mesotheliomas. Of six infected foci examined at early passages (passages 8–30) there was no methylation of the seven genes examined. Of two foci examined at late passages (passages 51–86) after the appearance of morphological changes suggestive of transformation, methylation and loss of expression of RASSF1A was detected. Sequencing of the CpG dense region around the transcription start site and semi-quantitative real-time methylation specific PCR (MSP) assay for RASSF1A methylation demonstrated progressive methylation during late passages. Exposure to the demethylating agent 5-aza-2′-deoxycytidine restored RASSF1A expression, while exposure to the histone deacetylation inhibitor trichostatin A had no effect. These data, together with our previous findings, support a causal relationship between SV40 infection, progressive RASSF1A methylation and its silencing, and the pathogenesis of mesothelioma.

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Abbreviations

SV40:

simian virus 40

MSP:

methylation specific PCR

TSG:

tumor suppressor gene

RASSF1:

RAS association domain family 1

MM:

malignant mesothelioma

HM:

human mesothelial cells

TSA:

trichostatin A

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Acknowledgements

This work was supported by grants from the Early Detection Research Network (5U01CA8497102) and the UT Specialized Program of Research Excellence in Lung Cancer (P50CA70907), National Cancer Institute, Bethesda, MD, USA to Adi F Gazdar, John D Minna (RO1 CA 71618) and by grants from the American Cancer Society 8632 and the National Cancer Institute, Bethesda, MD, USA (RO1 CA 92657) to Michele Carbone. We are grateful for encouragement by Professor Nobuyoshi Shimizu, Department of Surgical Oncology and Thoracic Surgery, Graduate School of Medicine and Dentistry, Okayama University, Okayama, Japan.

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Authors and Affiliations

  1. Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, 75390, Texas, TX, USA

    Shinichi Toyooka, Kiyomi O Toyooka, Narayan Shivapurkar, John D Minna & Adi F Gazdar

  2. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, 75390, Texas, TX, USA

    Narayan Shivapurkar & Adi F Gazdar

  3. Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, 75390, Texas, TX, USA

    John D Minna

  4. Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, 75390, Texas, TX, USA

    John D Minna

  5. Department of Pathology, Cancer Immunology Program, Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, 60153, Illinois, IL, USA

    Michele Carbone & Maurizio Bocchetta

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  1. Shinichi Toyooka
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  2. Michele Carbone
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  6. John D Minna
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  7. Adi F Gazdar
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Correspondence to Adi F Gazdar.

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Toyooka, S., Carbone, M., Toyooka, K. et al. Progressive aberrant methylation of the RASSF1A gene in simian virus 40 infected human mesothelial cells. Oncogene 21, 4340–4344 (2002). https://doi.org/10.1038/sj.onc.1205381

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