Functional inactivation of NF2/merlin in human mesothelioma

Our plain-English summary of Functional inactivation of NF2/merlin in human mesothelioma, by C. Thurneysen, I. Opitz, S. Kurtz, et al (Lung Cancer, 2009).

The study

• Authors: C. Thurneysen, I. Opitz, S. Kurtz, W. Weder, R.A. Stahel, E. Felley-Bosco
• Journal: Lung Cancer
• Published: 2009;64(2):140-7
• Cited by: 114 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

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.

In plain English

This laboratory study from University Hospital Zürich examined the NF2 gene, which makes a tumor-suppressing protein called merlin, in malignant pleural mesothelioma. The authors analyzed 51 tumor samples from 44 patients, three samples from patients with asbestos exposure and asbestosis, and six normal pleura samples from patients having unrelated chest surgery. The article reports no measurements of the patients' asbestos exposure. Shortened (truncated) NF2 transcripts appeared in nine mesothelioma samples and one asbestosis sample. Combining these findings with protein tests on cell cultures grown from 25 patients' tumors, the authors found that 19 (43%) mesothelioma patients lacked NF2 tumor suppressor activity. Where full-length merlin was present in tumor cultures, it carried a chemical change (phosphorylation at Ser518) that inactivates it. CPI-17 blocks merlin's reactivation. Its RNA levels, measured by quantitative PCR, were on average 65-fold higher in tumor samples without detectable NF2 alterations than in normal pleura and truncated samples. The authors concluded that NF2 is functionally inactivated in human malignant pleural mesothelioma, possibly explained in part by CPI-17.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (molecular) study of surgical tissue samples and primary cell cultures, analyzing NF2 transcripts, NF2/merlin protein and CPI-17 expression
• Who was studied: Malignant pleural mesothelioma patients at University Hospital Zürich: 51 tumor samples from 44 patients (26 epithelioid, 18 biphasic; seven patients sampled twice). Also studied were 3 tissue samples from patients with asbestosis and 6 normal pleura samples from patients having thoracic surgery unrelated to mesothelioma. Primary cultures were established from 25 mesothelioma patients.
• Exposure: The article reports no measurements of asbestos exposure and names no fiber types. The study examined genetic and protein changes in tumors. The three asbestosis patients are described as having a history of asbestos exposure, and clinical records were reviewed for sex, age and histology.
• Main results:
  • Truncated NF2 transcripts were found in nine malignant pleural mesothelioma samples; two tumor samples showed isoform II only.
  • NF2 truncation was also found in one of the three asbestosis patient samples.
  • Counting transcript and protein findings, 19 (43%) of the mesothelioma patients showed no NF2 tumor suppressor activity.
  • In every tumor-derived primary culture where full-length merlin protein was detected, it was phosphorylated at Ser518, which the authors describe as inactive merlin.
  • In tumor tissue, mean relative CPI-17 expression measured by quantitative PCR (an RNA measurement) was 65-fold higher in samples with no detectable NF2 alterations (n = 29) than in normal pleura and samples with truncated NF2 (p less than 0.001).
  • In primary cultures, mean relative CPI-17 expression (quantitative PCR) was 34-fold higher in mesothelioma cultures without detectable NF2 truncation than in cultures from normal pleura and from mesothelioma with truncated NF2 (p less than 0.001). CPI-17 protein was detected by Western blot only in cultures with relative mRNA expression above 40.
  • In the two asbestosis samples expressing full-length NF2, mean CPI-17 expression was 32 times higher than in normal pleura (p less than 0.001).
• The authors' conclusion: The authors concluded that NF2 is completely functionally inactivated in human malignant pleural mesothelioma. They suggested that CPI-17 expression might explain at least part of this inactivation, and that this indicates possible new treatment approaches.
• Limitations the authors state:
  • The method used could not tell the delE2 and delE3 splice variants apart.
  • In samples expressing full-length NF2, the meaning of the other splice variants detected is difficult to interpret.
  • Transcript-size analysis could miss point mutations or small insertions or deletions.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Merlin, Mesothelioma, Pleura.

Related studies

• Inactivation of Merlin in malignant mesothelioma cells and the Hippo signaling cascade dysregulation — Y. Sekido (2011)
• NF2/Merlin Inactivation and Potential Therapeutic Targets in Mesothelioma — T. Sato, Y. Sekido (2018)
• Low Merlin expression and high Survivin labeling index are indicators for poor prognosis in patients with malignant pleural mesothelioma — M. Meerang, K. Bérard, et al. (2016)
• Group I p21-activated kinases (PAKs) promote tumor cell proliferation and survival through the AKT1 and Raf-MAPK pathways — C.W. Menges, E. Sementino, et al. (2012)
• Merlin deficiency predicts FAK inhibitor sensitivity: a synthetic lethal relationship — I.M. Shapiro, V.N. Kolev, et al. (2014)
• Merlin, a "magic" linker between extracellular cues and intracellular signaling pathways that regulate cell motility, proliferation, and survival — I. Stamenkovic, Q. Yu (2010)

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