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Updated: Mar 15, 2026
Generation and Expansion of Primary, Malignant Pleural Mesothelioma Tumor Lines
Published on: April 21, 2022
Modeling mesothelioma utilizing human mesothelial cells reveals involvement of phospholipase-C beta 4 in YAP-active
Tatsuo Kakiuchi1,2, Taishi Takahara1,2, Yumiko Kasugai1
1Division of Molecular Medicine, Aichi Cancer Center Research Institute , Nagoya 464-8681 , Japan.
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.
Insights
Disrupting the Hippo pathway, often due to NF2 gene alterations, promotes mesothelioma development by activating YAP. Upregulation of PLCB4 by YAP is crucial for mesothelioma cell growth, suggesting PLCB4 as a potential drug target.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Mesotheliomas frequently exhibit Hippo pathway disruption, often involving the neurofibromin 2 (NF2) gene.
- Hippo pathway disruption leads to yes-associated protein (YAP) activation, promoting cell proliferation.
- While the role of Hippo pathway in established mesothelioma is known, its role in human mesothelioma development is less understood.
Purpose of the Study:
- To investigate the role of Hippo pathway disruption and YAP activation in the development of human mesothelioma.
- To identify genes regulated by YAP in mesothelial cells during mesothelioma development.
- To evaluate phospholipase-C beta 4 (PLCB4) as a potential therapeutic target in mesothelioma.
Main Methods:
- Immortalized human mesothelial cells were used to disrupt the Hippo pathway via NF2 knockdown.
- Enforced expression of wild-type or constitutively active YAP was utilized to study mesothelial cell transformation.
- Gene expression analysis and knockdown experiments were performed to identify and validate YAP-regulated genes, including PLCB4.
Main Results:
- NF2 knockdown reduced YAP phosphorylation, altered cell growth, and led to tumor formation in vivo.
- Activated YAP was crucial for mesothelial cell transformation.
- PLCB4 was identified as a key YAP-upregulated gene, and its knockdown inhibited mesothelioma cell growth.
Conclusions:
- Disruption of the Hippo pathway and subsequent YAP activation are critical events in human mesothelioma development.
- PLCB4 plays a significant role in the proliferation of YAP-active mesothelioma cells.
- PLCB4 represents a promising therapeutic target for mesothelioma treatment.
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