Department of Cardiothoracic Surgery, NYU Langone Medical Center, New York, NY, USA.
Translational Oncogenomic Unit, Italian National Cancer Institute 'Regina Elena', Rome, Italy.
Oncogene. 2014 Nov 13;33(46):5319-31. doi: 10.1038/onc.2013.476. Epub 2013 Nov 18.
We identified a discrete number of microRNAs differentially expressed in benign or malignant mesothelial tissues. We focused on mir-145 whose levels were significantly downregulated in malignant mesothelial tissues and malignant pleural mesothelioma (MPM) cell lines as compared to benign tissues (pleura, peritoneum or cysts). We show that promoter hyper-methylation caused very low levels in MPM cell lines and specimens. Treatment of MPM cell lines with mir-145 agonists negatively modulated some protumorigenic properties of MPM cells, such as clonogenicity, cell migration and resistance to pemetrexed treatment. The main effector mechanism of the clonogenic death induced by mir-145 was that of accelerated senescence. We found that mir-145 targeted OCT4 via specific binding to its 3'-UTR. Increased intracellular levels of mir-145 decreased the levels of OCT4 and its target gene ZEB1, thereby counteracting the increase of OCT4 induced by pemetrexed treatment which is known to favor the development of chemoresistant cells. In line with this, reintroduction of OCT4 into mimic-145 treated cells counteracted the effects on clonogenicity and replicative senescence. This further supports the relevance of the mir-145-OCT4 interaction for the survival of MPM cells. The potential use of mir-145 expression levels to classify benign vs malignant mesothelial tissues and the differences between pemetrexed-induced senescence and that induced by the re-expression of mir-145 are discussed.
我们鉴定了一些在良性或恶性间皮组织中差异表达的微小 RNA。我们重点关注 mir-145，与良性组织（胸膜、腹膜或囊肿）相比，其水平在恶性间皮组织和恶性胸膜间皮瘤（MPM）细胞系中显著下调。我们表明，启动子超甲基化导致 MPM 细胞系和标本中的水平非常低。用 mir-145 激动剂处理 MPM 细胞系可负调控 MPM 细胞的一些促肿瘤特性，如集落形成、细胞迁移和对培美曲塞治疗的耐药性。mir-145 诱导集落形成死亡的主要效应机制是加速衰老。我们发现 mir-145 通过与 OCT4 的 3'-UTR 特异性结合来靶向 OCT4。细胞内 mir-145 水平的增加降低了 OCT4 及其靶基因 ZEB1 的水平，从而抵消了培美曲塞治疗诱导的 OCT4 增加，已知培美曲塞治疗有利于耐药细胞的发展。与此一致的是，将 OCT4 重新引入 mimic-145 处理的细胞中，可抵消对集落形成和复制性衰老的影响。这进一步支持了 mir-145-OCT4 相互作用对于 MPM 细胞存活的相关性。讨论了 mir-145 表达水平用于分类良性与恶性间皮组织的潜在用途，以及培美曲塞诱导的衰老与 mir-145 重新表达诱导的衰老之间的差异。
