Author of

• 12441

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  P3.06 - Poster Session 3 - Prognostic and Predictive Biomarkers (ID 178)

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

  • 12486

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    P3.06-046 - The tumor suppressor integrin-alpha 7 is frequently downregulated in malignant pleural mesothelioma: biological and prognostic consequences (ID 3071)

    09:30 - 09:30  |  Author(s): V. Laszlo
    • Abstract

    Background
    Malignant pleural mesothelioma (MPM) is a malignancy characterized by therapy resistance and poor outcome. The high mortality of MPM is largely due to its invasive growth, local recurrence and locoregional spread. The identification of molecular changes that lead to this phenotype is indispensable. ITGA7 is a laminin binding receptor and has been identified as a novel tumor suppressor based on its frequent mutation in other malignancies. However, the alterations of ITGA7 have not yet been studied in MPM.

    Methods
    ITGA7 mRNA levels of normal mesothelial and MPM cells were measured by q-RT-PCR. ITGA7 promoter silencing in mesothelioma cell cultures was quantified by methylation-specific PCR analysis and by sequencing. Migratory activity of MPM cells has been investigated by 2D videomicroscopy. In vitro cell proliferation and adhesion assays were performed on siRNA transfected cells to demonstrate the biological consequence of decreased ITGA7 expression. ITGA7 expression in MPM tissue specimens was analysed by immunohistochemistry (IHC) and correlated to clinical outcome data.

    Results
    ITGA7 is highly expressed by normal mesothelial cells while decreased in MPM cells. In most MPM cells the expression of ITGA7 was reduced through promoter hypermethylation. ITGA7 promoter is hypermethylated in a number of tested MPM cell cultures (n=13) and the ratio of promoter methylation inversely correlates with ITGA7 expression. MPM cells with high in vitro migratory activity demonstrated a significantly lower ITGA7 expression when compared to slow migrating MPM cells. Proliferation of normal mesothelial cells is inhibited by laminin and this inhibitory effect is abolished by downregulation of ITGA7 expression via siRNA transfection. Adhesion of normal mesothelial and MPM cells is enhanced by laminin, however, it is not decreased by downregulation of ITGA7. The clinical significance of ITGA7 protein expression was investigated by IHC in a cohort of 89 MPM surgical specimens. Importantly, patients with high ITGA7 expression had significantly longer median overall survival (448 days) than patients with low expression (247 days, log rank test: p=0,0281).

    Conclusion
    ITGA7 is a novel tumor suppressor in MPM and its expression is down-regulated in MPM cells by promoter hypermethylation. Moreover, low ITGA7 expression in tumor cells influences clinical outcome as a negative prognostic factor in human MPM.