Extra Views

Convergent signaling in the regulation of connective tissue growth factor in malignant mesothelioma: TGFβ signaling and defects in the Hippo signaling cascade

Volume 11, Issue 18   September 15, 2012
Pages 3373 - 3379
http://dx.doi.org/10.4161/cc.21397
Keywords: CTGF, Hippo pathway, Smad, TEAD, TGF-β, YAP, malignant mesothelioma, mesothelial cells, p300, targeted therapy
Authors: Makiko Fujii, Hayao Nakanishi, Takeshi Toyoda, Ichidai Tanaka, Yutaka Kondo, Hirotaka Osada and Yoshitaka Sekido

View affiliations

Abstract:
Malignant mesothelioma (MM) is a neoplasm that arises from serosal surfaces of the pleural, peritoneal and pericardial cavities with worldwide incidence, much of which is caused by asbestos exposure. Patients suffer from pain and dyspnea due to direct invasion of the chest wall, lungs and vertebral or intercostal nerves by masses of thick fibrotic tumors. Although there has been recent progress in the clinical treatment, current therapeutic approaches do not provide satisfactory results. Therefore, development of a molecularly targeted therapy for MM is urgently required. Our recent studies suggest that normal mesothelial and MM cell growth is promoted by TGFβ, and that TGFβ signaling together with intrinsic disturbances in neurofibromatosis type 2 (NF2) and Hippo signaling cascades in MM cells converges upon further expression of connective tissue growth factor (CTGF). The formation of a YAP-TEAD4–Smad3-p300 complex on the specific CTGF promoter site with an adjacent TEAD and Smad binding motif is a critical and synergistic event caused by the dysregulation of these two distinct cascades. Furthermore, we demonstrated the functional importance of CTGF through the mouse studies and human histological analyses, which may elucidate the clinical features of MM with severe fibrosis in the thoracic cavity.

Received: June 29, 2012; Accepted: July 6, 2012; Published Online: August 23, 2012

Preview:



Advertisements