Protumorigenic effects of mir-145 loss in malignant pleural mesothelioma.
Protumorigenic effects of mir-145 loss in malignant pleural mesothelioma.
复制标题
DOI：
10.1038/onc.2013.476
复制
发表时间：
2014-11-13
期刊：
影响因子：
8
通讯作者：
Blandino G
中科院分区：
文献类型：
--
作者：
Cioce M;Ganci F;Canu V;Sacconi A;Mori F;Canino C;Korita E;Casini B;Alessandrini G;Cambria A;Carosi MA;Blandino R;Panebianco V;Facciolo F;Visca P;Volinia S;Muti P;Strano S;Croce CM;Pass HI;Blandino G
我们鉴定了在良性或恶性间皮组织中差异表达的离散数量的microRNA。我们集中于mir-145，与良性组织（胸膜、腹膜或囊肿）相比，其水平在恶性间皮瘤组织和恶性胸膜间皮瘤（MPM）细胞系中显著下调。我们发现，启动子超甲基化导致非常低的水平在MPM细胞系。用mir-145激动剂处理MPM细胞系负面调节MPM细胞的一些促肿瘤发生特性，如克隆形成、细胞迁移和对培美曲塞处理的抗性。mir-145诱导的克隆性死亡的主要效应机制是加速衰老。我们发现mir-145通过与OCT 4的3 '-UTR特异性结合而靶向OCT 4。mir-145的细胞内水平增加降低了OCT 4及其靶基因ZEB 1的水平，从而抵消了培美曲塞治疗诱导的OCT 4增加，已知培美曲塞治疗有利于化学耐药细胞的发展。与此一致，将OCT 4重新引入模拟物-145处理的细胞抵消了对克隆形成和复制性衰老的影响。这进一步支持了mir-145- 0 CT 4相互作用与MPM细胞存活的相关性。潜在的使用mir-145的表达水平，以分类良性与恶性间皮瘤组织和pemeed-induced衰老和诱导的mir-145的重新表达之间的差异进行了讨论。
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. 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.