新的研究表明一種用于治療急性早幼粒細(xì)胞白血?。?）的維生素A可以誘導(dǎo)白血病細(xì)胞中一類稱作 （**）的小分子的變化,。同時(shí),，此項(xiàng)研究還顯示了3種miRNAs能夠抑制2個對腫瘤發(fā)育非常重要的基因的活性，從而揭示了這類藥物的作用機(jī)制,。
該藥物的名稱是全反式維甲酸（***）,，被認(rèn)為是治療急性早幼粒細(xì)胞白血病的臨床首選藥物。此項(xiàng)研究表明ATRA提高了白血病細(xì)胞中3種miRNAs分子的表達(dá)水平,，同時(shí)伴隨著2種重要的致癌基因的活性下降,。3種miRNAs分子分別是miRNA-15b，miRNA-16-1和let-7,。
miRNA-15b和miRNA-16-1降低了Bcl-2基因的活性,，我們知道Bcl-2基因在許多癌癥發(fā)生中都是過度活躍的，該基因表達(dá)的蛋白可以阻斷正常的細(xì)胞死亡過程,，幫助癌細(xì)胞延長壽命,。第三種分子let-7可以降低致癌基因Ras的活性。（致癌基因是指突變會引發(fā)癌癥的一類正?；?。）
來自俄亥俄州立大學(xué)綜合癌癥中心（****）的研究者完成了此項(xiàng)研究工作，并將成果公布在了最新一期的《Oncogene》雜志上,。感興趣的讀者可以參看英文原文,。
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: [email protected]
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
相關(guān)原文鏈接：http://www.nature.com/onc/journal/vaop/ncurrent/abs/1210186a.html
