Thoracic Surgery, NYU Langone Medical Center, New York, New York 10016, USA.
Cancer Res. 2010 Mar 1;70(5):1916-24. doi: 10.1158/0008-5472.CAN-09-3993. Epub 2010 Feb 16.
The inability to forecast outcomes for malignant mesothelioma prevents clinicians from providing aggressive multimodality therapy to the most appropriate individuals who may benefit from such an approach. We investigated whether specific microRNAs (miR) could segregate a largely surgically treated group of mesotheliomas into good or bad prognosis categories. A training set of 44 and a test set of 98 mesothelioma tumors were analyzed by a custom miR platform, along with 9 mesothelioma cell lines and 3 normal mesothelial lines. Functional implications as well as downstream targets of potential prognostic miRs were investigated. In both the training and test sets, hsa-miR-29c* was an independent prognostic factor for time to progression as well as survival after surgical cytoreduction. The miR was expressed at higher levels in epithelial mesothelioma, and the level of this miR could segregate patients with this histology into groups with differing prognosis. Increased expression of hsa-miR-29c* predicted a more favorable prognosis, and overexpression of the miR in mesothelioma cell lines resulted in significantly decreased proliferation, migration, invasion, and colony formation. Moreover, major epigenetic regulation of mesothelioma is mediated by hsa-miR-29c* and was shown through downregulation of DNA methyltransferases as well as upregulation of demethylating genes. A single miR has the potential to be a prognostic biomarker in mesothelioma, and validation of these findings as well as investigation of its downstream targets may give insight for potential therapies in the future.
由于无法预测恶性间皮瘤的结果，临床医生无法为可能受益于这种方法的最合适患者提供积极的多模式治疗。我们研究了特定的 microRNA（miR）是否可以将主要接受手术治疗的间皮瘤患者分为预后良好或不良的类别。通过定制的 miR 平台分析了一个包含 44 例和一个包含 98 例间皮瘤肿瘤的训练集，以及 9 种间皮瘤细胞系和 3 种正常间皮细胞系。研究了潜在预后 miR 的功能意义和下游靶标。在训练集和测试集中，hsa-miR-29c* 是手术减瘤后进展时间和生存的独立预后因素。miR 在上皮性间皮瘤中的表达水平更高，并且该 miR 的水平可以将具有这种组织学特征的患者分为具有不同预后的组。hsa-miR-29c* 的表达增加预测预后更有利，并且在间皮瘤细胞系中过表达 miR 可导致增殖、迁移、侵袭和集落形成明显减少。此外，miR-29c* 通过下调 DNA 甲基转移酶和上调去甲基化基因来介导间皮瘤的主要表观遗传调控。单个 miR 有可能成为间皮瘤的预后生物标志物，验证这些发现并研究其下游靶标可能为未来的潜在治疗方法提供思路。
