Functional inactivation of NF2/merlin in human mesothelioma.
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.
Laboratory of Molecular Oncology, Clinic and Policlinic of Oncology, University Hospital of Zürich, Häldeliweg 4, 8044 Zürich, Switzerland.
Claudio
C
Thurneysen
Isabelle
I
Opitz
Stefanie
S
Kurtz
Walter
W
Weder
Rolf A
RA
Stahel
Emanuela
E
Felley-Bosco
D000328:Adult; D000368:Aged; D015153:Blotting, Western; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016515:Genes, Neurofibromatosis 2; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008654:Mesothelioma / Q000378:metabolism*; D008875:Middle Aged; D009124:Muscle Proteins; D025581:Neurofibromin 2 / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D020033:Protein Isoforms
D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D025581:Neurofibromin 2; C107507:PPP1R14A protein, human; D020033:Protein Isoforms; D010749:Phosphoprotein Phosphatases