Department of Respiratory Medicine, Shandong Provincial Hospital, Shandong University, Jinan, Shandong 250021, P.R. China.
Oncol Rep. 2013 Jul;30(1):313-9. doi: 10.3892/or.2013.2429. Epub 2013 Apr 26.
Malignant pleural mesothelioma (MPM) is a highly aggressive and conventional treatment-resistant tumor with a dismal prognosis. Among the three histological subtypes of MPM, the epithelioid is the most common type. Numb is considered as a tumor suppressor playing a critical role in controlling asymmetric cell division, maintenance of stem cell compartments, ubiquitination of specific substrates and regulating Notch-, Hedgehog- and TP53-activated pathways. The present study was designed to analyze the role of Numb in epithelioid MPM. We investigated the expression of Numb in 39 epithelioid MPM and 22 normal pleural tissues by immunohistochemistry. Furthermore, we overexpressed Numb in NCI-H2452, an epithelioid human MPM cell line, and investigated the effect of Numb overexpression on the proliferation, apoptosis and sensitivity to cisplatin in cells. The expression of Numb was significantly lower in MPM compared to the control group and Numb had an inverse correlation with the ki-67 labeling index. Loss of Numb expression was associated with poor prognosis in epithelioid MPM. Overexpression of Numb in NCI-H2452 cells significantly inhibited proliferation, promoted apoptosis and enhanced sensitivity to cisplatin. Moreover, Numb overexpression activated caspase-9 and caspase-3 through release of cytochrome c as well as downregulation of XIAP and survivin. We speculate that cytochrome c/caspase signaling is a possible mechanism through which Numb enhances the apoptosis of NCI-H2452 cells. These results suggest that Numb may be involved in epithelioid MPM development, and its upregulation may confer sensitivity to cisplatin, suggesting potential therapeutic options for MPM.
恶性胸膜间皮瘤（MPM）是一种高度侵袭性和常规治疗耐药的肿瘤，预后不良。在 MPM 的三种组织学亚型中，上皮型是最常见的类型。Numb 被认为是一种肿瘤抑制因子，在控制不对称细胞分裂、维持干细胞区室、泛素化特定底物以及调节 Notch-、Hedgehog 和 TP53 激活途径方面发挥着关键作用。本研究旨在分析 Numb 在上皮型 MPM 中的作用。我们通过免疫组织化学法检测了 39 例上皮型 MPM 和 22 例正常胸膜组织中 Numb 的表达。此外，我们在 NCI-H2452 上皮型人 MPM 细胞系中过表达 Numb，并研究了 Numb 过表达对细胞增殖、凋亡和对顺铂敏感性的影响。与对照组相比，Numb 在 MPM 中的表达明显降低，且 Numb 的表达与 ki-67 标记指数呈负相关。Numb 表达缺失与上皮型 MPM 的不良预后相关。Numb 在 NCI-H2452 细胞中的过表达显著抑制增殖、促进凋亡并增强对顺铂的敏感性。此外，Numb 过表达通过释放细胞色素 c 以及下调 XIAP 和 survivin 来激活 caspase-9 和 caspase-3。我们推测细胞色素 c/caspase 信号通路是 Numb 增强 NCI-H2452 细胞凋亡的可能机制。这些结果表明，Numb 可能参与上皮型 MPM 的发生发展，其上调可能赋予顺铂敏感性，为 MPM 的治疗提供了潜在的选择。
