Author of

• 12364

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  P3.01 - Poster Session 3 - Cancer Biology (ID 147)

  • Event: WCLC 2013
  • Type: Poster Session
  • Track: Biology
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/30/2013, 09:30 - 16:30, Exhibit Hall, Ground Level

  • 12372

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    P3.01-008 - The importance of the Secreted Frizzled-Related Protein (SFRP) tumour suppressor gene family and the effect of long-term asbestos exposure on SFRP expression in malignant pleural mesothelioma (MPM) (ID 3495)

    09:30 - 09:30  |  Author(s): A..M. George
    • Abstract

    Background
    The etiology of malignant pleural mesothelioma (MPM) is closely linked with asbestos exposure. Asbestos is capable of inducing chronic inflammation which potentiates tumour suppressor gene silencing. Epigenetic silencing of the Wnt pathway, well characterized in the progression of colon cancer, is associated with chronic inflammation. As antagonists of Wnt pathways, the SFRPs are functional tumour suppressors of colon, gastric, breast, ovarian and lung cancers, with some members methylated in mesothelioma. In this study, we aimed to investigate the functional significance of the SFRP2 and 5 in MPM, and the effect of long-term asbestos exposure on epigenetic alteration in the immortalised mesothelial cell MeT-5A.

    Methods
    Gene expression and promoter DNA methylation of the SFRP family were analysed in MPM lines and MeT-5A with and without 5’Azacitidine treatment using RT-qPCR, MSP and COBRA. The effect of SFRP2 and SFRP5 re-expression on MPM cells was determined by cell growth and clonogenic assays in 2D and 3D culture. The expression and promoter DNA methylation of SFRP genes was also assessed in MPM patient samples using RT-qPCR and MSP. MeT-5A cells were cultured long-term (12 months) in the presence of asbestos, and SFRP mRNA expression and promoter DNA methylation was analysed.

    Results
    SFRP2 and SFRP5 were either absent or down-regulated MPM lines, and restored after 5’Azacitidine treatment. SFRP1 was highly expressed and unmethylated in MeT-5A line. Expression of the SFRP family was down-regulated in MPM patient samples and this correlated with methylation of promoter CpG islands. Ectopic expression of SFRP2 or SFRP5 inhibited MPM cell growth and colony formation in both 2D and 3D culture. SFRP1 was down-regulated and methylated following prolonged asbestos exposure in MeT-5A cells.

    Conclusion
    Our results indicate that both SFRP2 and SFRP5 function as tumour suppressor genes in MPM and long-term asbestos exposure induce gene silencing via DNA hypermethylation.