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.

恶性胸膜间皮瘤（MPM）是一种侵袭性胸膜恶性肿瘤，由于缺乏有效的早期诊断方法和特定药物，目前无法治愈。的CDKN2A（p16蛋白）和NF2基因均在MPM中频繁突变。为了解这些突变如何促进MPM肿瘤生长，我们使用人类MeT-5A和HOMC-B1间皮细胞系生成了NF2 / p16双敲除（DKO）细胞克隆。与亲代细胞相比，DKO中的细胞生长和迁移活性显着增加。cDNA微阵列分析揭示了DKO与亲代细胞之间全局基因表达谱的差异。定量PCR和Western印迹分析显示DKO克隆中CD24的上调与AKT，p70S6K和c-Jun磷酸化的增加有关。NF2和p16的外源表达消除了这种上调。CD24DKO细胞的基因敲低显着降低了TGF-β1的表达，并增加了上皮-间质转化标记E-钙粘蛋白的表达。CD24在人间皮瘤组织中高表达（28/45例，62％），并与NF2和p16的丢失有关。公开数据分析显示，具有高CD24基因表达水平的MPM患者的生存时间明显缩短。这些结果强烈表明CD24可能作为MPM的预后标志物以及新的诊断和治疗靶标。