新的研究表明一种用于治疗急性早幼粒细胞白血病（*）的维生素A可以诱导白血病细胞中一类称作 （**）的小分子的变化。同时，此项研究还显示了3种miRNAs能够抑制2个对肿瘤发育非常重要的基因的活性，从而揭示了这类药物的作用机制。
该药物的名称是全反式维甲酸（***），被认为是治疗急性早幼粒细胞白血病的临床首选药物。此项研究表明ATRA提高了白血病细胞中3种miRNAs分子的表达水平，同时伴随着2种重要的致癌基因的活性下降。3种miRNAs分子分别是miRNA-15b，miRNA-16-1和let-7。
miRNA-15b和miRNA-16-1降低了Bcl-2基因的活性，我们知道Bcl-2基因在许多癌症发生中都是过度活跃的，该基因表达的蛋白可以阻断正常的细胞死亡过程，帮助癌细胞延长寿命。第三种分子let-7可以降低致癌基因Ras的活性。（致癌基因是指突变会引发癌症的一类正常基因。）
来自俄亥俄州立大学综合癌症中心（****）的研究者完成了此项研究工作，并将成果公布在了最新一期的《Oncogene》杂志上。感兴趣的读者可以参看英文原文。
部分英文原文
Oncogene advance online publication 29 January 2007; doi: 10.1038/sj.onc.1210186
MicroRNA gene expression during retinoic acid-induced differentiation of human acute promyelocytic leukemia
R Garzon1,5, F Pichiorri1,5, T Palumbo1,2, M Visentini3, R Aqeilan1, A Cimmino1, H Wang1, H Sun1, S Volinia1, H Alder1, G A Calin1, C-G Liu1, M Andreeff4 and C M Croce1
1Department of Molecular Virology, Immunology and Medical Genetics and Comprehensive Cancer Center, Ohio State University, Columbus, OH, USA
2Department of Experimental and Clinical Pharmacology, University of Catania, Catania, Italy
3Division of Clinical Immunology, University of Rome 'La Sapienza', Rome, Italy
4Department of Blood and Bone marrow Transplantation, Section of Molecular Hematology and Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Correspondence: Professor CM Croce, Department of Molecular Virology, Immunology and Medical Genetics and Comprehensive Cancer Center, Ohio State University, Wiseman Hall, Room 445C, 400 12th Avenue, Columbus, OH 43210, USA. E-mail: Carlo.Croce@osumc.edu
5These two authors contributed equally to this work.
Received 14 February 2006; Revised 18 October 2006; Accepted 30 October 2006; Published online 29 January 2007.
MicroRNAs (miRNAs) are small non-coding RNAs of 19–25 nucleotides that are involved in the regulation of critical cell processes such as apoptosis, cell proliferation and differentiation. However, little is known about the role of miRNAs in granulopoiesis. Here, we report the expression of miRNAs in acute promyelocytic leukemia patients and cell lines during all-trans-retinoic acid (ATRA) treatment by using a miRNA microarrays platform and quantitative real time–polymerase chain reaction (qRT–PCR). We found upregulation of miR-15a, miR-15b, miR-16-1, let-7a-3, let-7c, let-7d, miR-223, miR-342 and miR-107, whereas miR-181b was downregulated. Among the upregulated miRNAs, miR-107 is predicted to target NFI-A, a gene that has been involved in a regulatory loop involving miR-223 and C/EBPa during granulocytic differentiation. Indeed, we have confirmed that miR-107 targets NF1-A. To get insights about ATRA regulation of miRNAs, we searched for ATRA-modulated transcription factors binding sites in the upstream genomic region of the let-7a-3/let-7b cluster and identified several putative nuclear factor-kappa B (NF-B) consensus elements. The use of reporter gene assays, chromatin immunoprecipitation and site-directed mutagenesis revealed that one proximal NF-B binding site is essential for the transactivation of the let-7a-3/let-7b cluster. Finally, we show that ATRA downregulation of RAS and Bcl2 correlate with the activation of known miRNA regulators of those proteins, let-7a and miR-15a/miR-16-1, respectively.
Keywords:
microRNAs, promyelocytic leukemia, NF-B
相关原文链接：http://www.nature.com/onc/journal/vaop/ncurrent/abs/1210186a.html
