title: Modeling mesothelioma utilizing human mesothelial cells reveals involvement of phospholipase-C beta 4 in YAP-active mesothelioma cell proliferation.
abstract: Mesotheliomas are frequently characterized by disruption of Hippo pathway due to deletion and/or mutation in genes, such as neurofibromin 2 ( NF2 ). Hippo disruption attenuates yes-associated protein (YAP) phosphorylation allowing YAP to translocate to the nucleus and regulate gene expression. The role of disrupted Hippo pathway in maintenance of established mesotheliomas has been extensively investigated using cell lines; however, its involvement in development of human mesothelioma has not been explored much. Here, we employed immortalized human mesothelial cells to disrupt Hippo pathway. YAP phosphorylation was reduced on NF2 knockdown and the cells exhibited altered growth in vitro , developing tumors when transplanted into nude mice. Similar results were obtained from enforced expression of wild-type or constitutively active (S127A) YAP, indicating the crucial role of activated YAP in the transformation of mesothelial cells. Gene expression analysis comparing control- and YAP-transduced immortalized human mesothelial cells revealed phospholipase-C beta 4 ( PLCB4 ) to be among the genes highly upregulated by YAP. PLCB4 was upregulated by YAP in immortalized human mesothelial cells and downregulated on YAP knockdown in Hippo-disrupted mesothelioma cell lines. PLCB4 knockdown attenuated the growth of YAP-transduced immortalized mesothelial cells and YAP-active, but not YAP-nonactive, mesothelioma cell lines. Our model system thus provides a versatile tool to investigate the mechanisms underlying mesothelioma development. We suggest that PLCB4 may be an attractive drug target for the treatment of mesothelioma.
authors: Division of Molecular Medicine, Aichi Cancer Center Research Institute , Nagoya 464-8681 , Japan.|Department of Pathology and Clinical Laboratories, Nagoya University Hospital , Nagoya 466-0065 , Japan.
authors: Tatsuo
authors: T
authors: Kakiuchi
authors: Division of Molecular Medicine, Aichi Cancer Center Research Institute , Nagoya 464-8681 , Japan.|Department of Pathology and Clinical Laboratories, Nagoya University Hospital , Nagoya 466-0065 , Japan.
authors: Taishi
authors: T
authors: Takahara
authors: Division of Molecular Medicine, Aichi Cancer Center Research Institute , Nagoya 464-8681 , Japan.
authors: Yumiko
authors: Y
authors: Kasugai
authors: Third Department of Internal Medicine, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama , Toyama 930-0194 , Japan.
authors: Kotaro
authors: K
authors: Arita
authors: Department of Pathology, Kurume University School of Medicine , Kurume 830-0011 , Japan.|Present address: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors: Noriaki
authors: N
authors: Yoshida
authors: Laboratory of Cytopathology, Faculty of Medicine, University of the Ryukyus , Okinawa 903-0215 , Japan.
authors: Kennosuke
authors: K
authors: Karube
authors: Division of Molecular Medicine, Aichi Cancer Center Research Institute , Nagoya 464-8681 , Japan.
authors: Miyuki
authors: M
authors: Suguro
authors: Division of Molecular Medicine, Aichi Cancer Center Research Institute , Nagoya 464-8681 , Japan.
authors: Keitaro
authors: K
authors: Matsuo
authors: Laboratory of Pathology and Clinical Research, Aichi Cancer Center , Aichi Hospital, Okazaki 444-0011 , Japan.
authors: Hayao
authors: H
authors: Nakanishi
authors: Division of Carcinogenesis and Cancer Prevention, National Cancer Center Research Institute , Tokyo 104-0045 , Japan.
authors: Tohru
authors: T
authors: Kiyono
authors: Department of Pathology and Clinical Laboratories, Nagoya University Hospital , Nagoya 466-0065 , Japan.
authors: Shigeo
authors: S
authors: Nakamura
authors: Division of Molecular Oncology, Aichi Cancer Center Research Institute , Nagoya 464-8681 , Japan.|Department of Cancer Genetics, Program in Function Construction Medicine, Nagoya University Graduate School of Medicine , Nagoya 466-8550 , Japan and.
authors: Hirotaka
authors: H
authors: Osada
authors: Division of Molecular Oncology, Aichi Cancer Center Research Institute , Nagoya 464-8681 , Japan.|Department of Cancer Genetics, Program in Function Construction Medicine, Nagoya University Graduate School of Medicine , Nagoya 466-8550 , Japan and.
authors: Yoshitaka
authors: Y
authors: Sekido
authors: Department of Pathology, Kurume University School of Medicine , Kurume 830-0011 , Japan.
authors: Masao
authors: M
authors: Seto
authors: Division of Molecular Medicine, Aichi Cancer Center Research Institute , Nagoya 464-8681 , Japan.|Department of Biochemistry, Aichi Medical University School of Medicine , Nagakute, Aichi 480-1195 , Japan.
authors: Shinobu
authors: S
authors: Tsuzuki