Journal
CELL CYCLE
Volume 11, Issue 18, Pages 3373-3379Publisher
TAYLOR & FRANCIS INC
DOI: 10.4161/cc.21397
Keywords
CTGF; Hippo pathway; malignant mesothelioma; mesothelial cells; p300; Smad; targeted therapy; TEAD; TGF beta; YAP
Categories
Funding
- 24th General Assembly of the Japanese Association of Medical Sciences
- Aichi Cancer Research Foundation
- Japan Society for the Promotion of Science [20590420, 23592788, 22300338]
- Ministry of Health, Labor and Welfare of Japan
- Ministry of Education, Culture, Sports, Science and Technology of Japan
- Grants-in-Aid for Scientific Research [20590420, 23592788, 22300338] Funding Source: KAKEN
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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 TGF beta, and that TGF beta 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.
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