演題抄録

基調講演

開催概要
開催回
第51回・2013年・京都
 

Molecular alterations in mesothelioma: Diagnostic and therapeutic potential?

演題番号 : KL-7

[筆頭演者]
Rolf A. Stahel:1 

1:Clinic of Oncology, University Hospital of Zurich, Switzerland

 

Among the large number of molecular alterations found in malignant mesothelioma, several alterations have been identified to be responsible for the development of malignant mesothelioma. These include the cycline-dependent kinase inhibitor 2a (CDKN 2A/ARF), the neurofibromatosis type 2 gene (NF2) and the BRCA-1 associated protein BAP-1, the latter two alterations being characteristic of malignant mesothelioma. Our working hypothesis is that chronic inflammation/injury activates stem cell signaling and continuous stimulation of repair in an inflammatory setting leads to oncogenic events and escape from the immune control. The transcription factor YAP1 is the main target of the Hippo growth regulatory signaling pathway, a key regulator of tumorigenesis. Activation of Hippo signaling downstream of NF2 leads to the phosphorylation of YAP1, leading to its retention in cytoplasm, thereby inhibiting its function. Alteration of NF2 activity plays a key role in MPM tumorigenesis and recent data support the hypothesis that NF2/Hippo signaling is disrupted in most MPM. When Hippo signaling is attenuated, e.g. when NF2 signaling is disrupted, YAP phosphorylation is decreased, resulting in YAPs nuclear localization and regulation of target genes involved in proliferation and cell motility. In addition, YAP1 expression and nuclear localization have been shown to be regulated by the hedgehog (Hh) pathway. We have shown in our primary human MPM cultures that inhibition of Hh signaling with the antagonist agent HhAntag downregulates YAP and its downstream target survivin, while overexpression of Gli-1 or YAP1 rescued survivin expression. We are postulating that deregulated stem signaling is the driving force in MPM because of increased transcription factor YAP1 function resulting from deficient NF2/Hippo signaling control and/or increased Hh activation signaling. The potential implication of these molecular findings for diagnosis and therapy will be discussed.

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