Abstract
Malignant pleural mesothelioma (MPM) is an aggressive malignancy of the pleura that is currently incurable due to the lack of an effective early diagnostic method and specific medication. The CDKN2A (p16) and NF2 genes are both frequently mutated in MPM. To understand how these mutations contribute to MPM tumor growth, we generated NF2/p16 double-knockout (DKO) cell clones using human MeT-5A and HOMC-B1 mesothelial cell lines. Cell growth and migration activities were significantly increased in DKO compared with parental cells. cDNA microarray analysis revealed differences in global gene expression profiles between DKO and parental cells. Quantitative PCR and western blot analyses showed upregulation of CD24 concomitant with increased phosphorylation of AKT, p70S6K, and c-Jun in DKO clones. This upregulation was abrogated by exogenous expression of NF2 and p16. CD24 knockdown in DKO cells significantly decreased TGF-β1 expression and increased expression of E-cadherin, an epithelial–mesenchymal transition marker. CD24 was highly expressed in human mesothelioma tissues (28/45 cases, 62%) and associated with the loss of NF2 and p16. Public data analysis revealed a significantly shorter survival time in MPM patients with high CD24 gene expression levels. These results strongly indicate the potential use of CD24 as a prognostic marker as well as a novel diagnostic and therapeutic target for MPM.
Highlights
Malignant pleural mesothelioma (MPM) is an aggressive malignancy of the pleura that is associated with asbestos exposure after 30–40 years of latency[1,2]
Our findings strongly suggest that CD24 expression occurs downstream of neurofibromatosis 2 (NF2) and p16 in mesothelial cells and is correlated with overall survival of MPM patients
The present study focused on CD24, as its expression is increased in DKO clones
Summary
Malignant pleural mesothelioma (MPM) is an aggressive malignancy of the pleura that is associated with asbestos exposure after 30–40 years of latency[1,2]. Molecular biological studies in MPM have revealed frequent genetic alterations of tumor suppressor genes, including neurofibromatosis 2 (NF2), cyclin-dependent kinase inhibitor 2A (p16), and BAP18–15. Official journal of the Cell Death Differentiation Association. We recently reported that fibroblast growth factor receptor 2 is highly expressed in NF2knockout mesothelial cell lines and is a candidate molecule for the development of therapeutic and diagnostic strategies targeting MPM18. A previous study using NF2 and p16 double-knockout (DKO) mice indicated that these genes, when mutated, contribute to mesothelioma development[19]. It remains unclear how these complex mutations contribute to tumor formation in MPM. We established NF2/p16-DKO cell clones in human immortalized mesothelial cell lines and identified several genes regulated by NF2 and p16
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