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Defining Gene Functions in Tumorigenesis by Ex vivo Ablation of Floxed Alleles in Malignant Peripheral Nerve Sheath Tumor Cells
Published on: August 25, 2021
Functional inactivation of NF2/merlin in human mesothelioma
Claudio Thurneysen1, Isabelle Opitz, Stefanie Kurtz
1Laboratory of Molecular Oncology, Clinic and Policlinic of Oncology, University Hospital of Zürich, Häldeliweg 4, 8044 Zürich, Switzerland.
Abstract:
The tumor suppressor merlin is encoded by the neurofibromatosis type 2 gene (NF2) which is located on chromosome 22q12 and mutations in this gene have been found in 40% of mesothelioma. Mutations including deletions and insertions lead to truncated and inactivated merlin. Experimental animal models indicate that disruption of the NF2 signalling pathway, together with a deficiency in ink4a, is essential for mesothelioma development. Our hypothesis was that in human mesothelioma without detectable NF2 mutations, regulators of NF2/merlin activity such as CPI-17 would be altered. CPI-17 is an oncogene inhibiting the NF2/merlin phosphatase which is necessary to maintain NF2/merlin activity. Samples obtained from 44 mesothelioma, 3 asbestosis patients and 6 normal pleura from non-asbestos related disease patients were analyzed. Truncated NF2 transcripts or presence of isoform II only were observed in 11 mesothelioma samples. In all other mesothelioma samples only NF2 isoform I or isoforms I and II were detected. 18 mesothelioma and 1 normal pleura samples also expressed splicing variant delE2/3. Unexpected variants in addition to wild-type were identified in 24 mesothelioma samples. NF2 protein was either truncated or phosphorylated on Ser 518 in primary cultures derived from 25 tumors. CPI-17 expression was significantly increased in tumor samples without deleted NF2 compared to normal pleura and tumor expressing truncated NF2. Our results support the hypothesis that the disruption of NF2 signalling is essential for the development of human mesothelioma. In tumors where no NF2 truncation can be detected, NF2 is rendered inactive by phosphorylation of Ser 518 and this can be explained at least in part by an increased expression of CPI-17.
Insights
The neurofibromatosis type 2 gene (NF2) is crucial for preventing mesothelioma. In tumors lacking NF2 mutations, increased CPI-17 expression inactivates merlin, promoting cancer development.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- The tumor suppressor merlin, encoded by the neurofibromatosis type 2 gene (NF2), is critical in preventing mesothelioma.
- NF2 mutations are found in 40% of mesotheliomas, leading to merlin inactivation.
- NF2 signaling pathway disruption, alongside ink4a deficiency, is implicated in mesothelioma development.
Purpose of the Study:
- To investigate the role of CPI-17, a regulator of NF2/merlin activity, in human mesothelioma lacking detectable NF2 mutations.
- To understand how NF2/merlin activity is altered in mesothelioma when NF2 gene mutations are not the primary cause.
Main Methods:
- Analysis of NF2 transcripts, isoforms, and protein phosphorylation in 44 mesothelioma samples, 3 asbestosis samples, and 6 normal pleura samples.
- Assessment of CPI-17 expression levels in tumor samples with and without NF2 truncations.
- Utilized techniques including transcript analysis, isoform detection, and protein phosphorylation assays.
Main Results:
- NF2 mutations or truncations were identified in a subset of mesothelioma samples.
- In mesotheliomas without NF2 truncations, NF2 protein was inactivated via phosphorylation at Ser 518.
- CPI-17 expression was significantly elevated in tumors with intact NF2 but inactivated merlin, compared to normal pleura and tumors with truncated NF2.
Conclusions:
- Disruption of NF2 signaling is essential for human mesothelioma development.
- In tumors without NF2 truncations, increased CPI-17 expression contributes to merlin inactivation through phosphorylation, driving mesothelioma progression.
- CPI-17 emerges as a key factor in mesothelioma pathogenesis, particularly in cases with wild-type NF2.
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