Abstract 3082: TGF-β synergistically stimulates malignant mesothelioma growth with defects in the Hippo pathway by inducing CTGF expression

Abstract

Abstract Malignant mesothelioma (MM) arises from the serosal cells of the pleural, peritoneal and pericardial cavities with poor prognosis because of its frequent diagnosis in advanced stages. The primary cause of this disease has often been linked to asbestos exposure, and the number of patients worldwide is expected to peak in the next two decades. There is no known curative therapy for MM and further understanding in molecular mechanism is needed to identify new candidates for targeted treatment. We found that the TGF-β pathway is associated with oncogenic mutations and loss of the tumor suppressor NF2, and induces pro-oncogenic biological activities. Loss of NF2 is one of the genetic lesions which have been related to the growth of human MM. The NF2 gene is responsible for neurofibromatosis type II syndrome and encodes Merlin which negatively regulates YAP function. Nearly 75% MM cases have inactivating mutations in the NF2 gene or in downstream signaling molecules of Hippo signaling cascade. We examined a functional interaction between the Hippo and TGF-β pathways and found that endothelin-1 and connective tissue growth factor (CTGF) are the only proteins affected by these two pathways in MM cells. The CTGF promoter contains both a YAP/TEAD-binding site and a consensus Smad-binding site adjacent to each other. The expression of CTGF induced by TGF-β in MM cell lines was greatly affected by the existence of YAP, by its binding with Smad3, forming a complex on CTGF promoter lesion. Knocking down CTGF expression in MM cells prolonged the survival of mice, and a significant association was seen between CTGF expression and extracellular matrix deposition in MM xenografts and in patient tissue specimens. This study elucidates a novel molecular mechanism induced by the TGF-β pathway, which may be applicable to malignancies with defective NF2 and of mesenchymal origin. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3082. doi:1538-7445.AM2012-3082