title: TGF-β synergizes with defects in the Hippo pathway to stimulate human malignant mesothelioma growth.
abstract: Malignant mesothelioma (MM) is an incurable malignancy that is caused by exposure to asbestos and is accompanied by severe fibrosis. Because MM is usually diagnosed at an advanced stage and clinical identification of early lesions is difficult, its molecular pathogenesis has not been completely elucidated. Nearly 75% of MM cases have inactivating mutations in the NF2 (neurofibromatosis type 2; Merlin) gene or in downstream signaling molecules of the Hippo signaling cascade, which negatively regulates the transcription factor Yes-associated protein (YAP). In this study, we demonstrate a functional interaction between the Hippo and TGF-β pathways in regulating connective tissue growth factor (CTGF). Expression of CTGF in MM cells was induced by the formation of a YAP-TEAD4-Smad3-p300 complex on the CTGF promoter. Knocking down CTGF expression in MM cells prolonged the survival of xenografted mice, and a significant association was seen between CTGF expression and extracellular matrix deposition in MM xenografts and in patient tissue specimens. We further suggest that CTGF may influence the malignancy of mesothelioma because of the different histological expression patterns observed in human MM tissues. These data suggest that CTGF is an important modulator of MM growth and pathology and represents a novel therapeutic target for this disease.
authors.affiliation: Division of Molecular Oncology, Aichi Cancer Center Research Institute, Chikusa-ku, Nagoya 464-8681, Japan. fujiim@aichi-cc.jp
authors.forename: Makiko
authors.initials: M
authors.lastname: Fujii
authors.forename: Takeshi
authors.initials: T
authors.lastname: Toyoda
authors.forename: Hayao
authors.initials: H
authors.lastname: Nakanishi
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Yatabe
authors.forename: Ayuko
authors.initials: A
authors.lastname: Sato
authors.forename: Yasue
authors.initials: Y
authors.lastname: Matsudaira
authors.forename: Hidemi
authors.initials: H
authors.lastname: Ito
authors.forename: Hideki
authors.initials: H
authors.lastname: Murakami
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kondo
authors.forename: Eisaku
authors.initials: E
authors.lastname: Kondo
authors.forename: Toyoaki
authors.initials: T
authors.lastname: Hida
authors.forename: Tohru
authors.initials: T
authors.lastname: Tsujimura
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Osada
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Sekido
mesh_terms: D000818:Animals; D001483:Base Sequence; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D055513:Connective Tissue Growth Factor / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics; D005109:Extracellular Matrix / Q000502:physiology; D005260:Female; D015870:Gene Expression; D016515:Genes, Neurofibromatosis 2; D006801:Humans; D008654:Mesothelioma / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000502:physiology; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D051785:Smad Proteins / Q000502:physiology; D014157:Transcription Factors / Q000502:physiology; D015533:Transcriptional Activation; D016212:Transforming Growth Factor beta / Q000502:physiology*
chemical_list: C526317:CCN2 protein, human; D018797:Cell Cycle Proteins; D004273:DNA, Neoplasm; D009687:Nuclear Proteins; D051785:Smad Proteins; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; C456659:YY1AP1 protein, human; D055513:Connective Tissue Growth Factor