Bueno María J, Pérez de Castro Ignacio, Gómez de Cedrón Marta, Santos Javier, Calin George A, Cigudosa Juan C, Croce Carlo M, Fernández-Piqueras José, Malumbres Marcos
Cell Division and Cancer Group, Centro Nacional de Investigaciones Oncológicas (CNIO), E-28029 Madrid, Spain.
Cancer Cell. 2008 Jun;13(6):496-506. doi: 10.1016/j.ccr.2008.04.018.
The mammalian genome contains several hundred microRNAs that regulate gene expression through modulation of target mRNAs. Here, we report a fragile chromosomal region lost in specific hematopoietic malignancies. This 7 Mb region encodes about 12% of all genomic microRNAs, including miR-203. This microRNA is additionally hypermethylated in several hematopoietic tumors, including chronic myelogenous leukemias and some acute lymphoblastic leukemias. A putative miR-203 target, ABL1, is specifically activated in these hematopoietic malignancies in some cases as a BCR-ABL1 fusion protein (Philadelphia chromosome). Re-expression of miR-203 reduces ABL1 and BCR-ABL1 fusion protein levels and inhibits tumor cell proliferation in an ABL1-dependent manner. Thus, miR-203 functions as a tumor suppressor, and re-expression of this microRNA might have therapeutic benefits in specific hematopoietic malignancies.
哺乳动物基因组包含数百种微小RNA，它们通过调节靶标mRNA来调控基因表达。在此，我们报告了一个在特定造血系统恶性肿瘤中缺失的脆弱染色体区域。这个7兆碱基的区域编码了所有基因组微小RNA的约12%，包括miR-203。在包括慢性粒细胞白血病和一些急性淋巴细胞白血病在内的几种造血系统肿瘤中，这种微小RNA还存在高甲基化现象。一个假定的miR-203靶标ABL1，在某些情况下作为BCR-ABL1融合蛋白（费城染色体）在这些造血系统恶性肿瘤中被特异性激活。miR-203的重新表达降低了ABL1和BCR-ABL1融合蛋白水平，并以ABL1依赖的方式抑制肿瘤细胞增殖。因此，miR-203起着肿瘤抑制因子的作用，这种微小RNA的重新表达可能对特定的造血系统恶性肿瘤具有治疗益处。
