3月14日,，國際知名雜志《致癌基因》（Oncogene）發(fā)表了中國人民解放軍總醫(yī)院血液科和基礎(chǔ)醫(yī)學(xué)研究所的一篇研究性文章，在文章中研究人員利用microRNA-193a在急性骨髓性白血?。ˋcute myeloid leukemia，AML）中抑制了c-kit表達,，證實其可發(fā)揮重要的腫瘤抑制子功能,。
領(lǐng)導(dǎo)這一研究的是中國人民解放軍總醫(yī)院血液科主任醫(yī)師于力教授，其從事血液科臨床工作20余年,，在血液系統(tǒng)疑難病癥的診斷,、白血病和淋巴瘤的治療及造血干細胞移植等方面具有豐富的臨床經(jīng)驗，主要研究方向為血液系統(tǒng)惡性腫瘤的診斷,、治療及造血干細胞移植,。于力教授曾在國際上首次發(fā)現(xiàn)兩個白血病相關(guān)基因LRP15和LRP16，并在國際基因庫中注冊,。他還在國際上首次證明ID4基因具有抑制白血病細胞增長的功能,，這一研究成果發(fā)表在國際著名雜志《自然遺傳學(xué)》（Nature Genetics）上,。
原癌基因c-kit是一種III型酪氨酸激酶受體，廣泛地表達于肥大細胞,、黑色素細胞,、造血干細胞、腸間質(zhì)細胞和生殖細胞中,。大量的研究證實多種惡性腫瘤如急性骨髓性白血病細胞中存在c-kit的異常激活,，與癌癥的發(fā)生、增生,、浸潤和轉(zhuǎn)移密切相關(guān),。近年來有一些研究表明腫瘤通過表觀遺傳學(xué)修飾沉默腫瘤抑制性microRNAs (miRNAs)從而導(dǎo)致了原癌基因激活。
在這篇文章中,，中國人民解放軍總醫(yī)院的研究人員利用熒光報告分析方法在急性骨髓性白血病中篩查了幾種有可能與人類c-kit mRNA的3′UTR區(qū)結(jié)合的miRNAs,。在急性骨髓性白血病細胞和原發(fā)性AML芽細胞中研究人員發(fā)現(xiàn)內(nèi)嵌在c-kit mRNA CpG島上的miR-193a序列發(fā)生了超甲級化,。進而,，研究人員在9種白血病細胞系和27名原發(fā)性AML患者血液樣品中證實miR-193a水平與c-kit水平呈現(xiàn)負相關(guān)。
在進一步的研究中,，科研人員利用合成miR-193a轉(zhuǎn)染和DNA低甲基化試劑5-氮胞苷(5-aza)處理等方法證實,，在c-kit 突變和C-kit過表達的AML細胞中恢復(fù)miR-193a可顯著降低c-kit的RNA和蛋白質(zhì)水平，并抑制細胞生長,。當研究人員在細胞中加入miR-193a抑制劑時,，發(fā)現(xiàn)其部分地阻斷了5-aza誘導(dǎo)的c-kit抑制，逆轉(zhuǎn)了5-aza的抗增殖以及促凋亡效應(yīng),。這些數(shù)據(jù)表明甲基化抑制miR-193a在急性髓細胞樣白血病的發(fā)病過程中發(fā)揮了關(guān)鍵性的作用,。
新研究發(fā)現(xiàn)使研究人員更深入地了解了急性髓細胞樣白血病的發(fā)病機理，并為c-kit陽性的AML的治療指明了新的有潛力的治療靶點,。（生物谷Bioon.com）
生物谷推薦原文出處：
Oncogene advance online publication 14 March 2011; doi: 10.1038/onc.2011
MicroRNA-193a represses c-kit expression and functions as a methylation-silenced tumor suppressor in acute myeloid leukemia
X-N Gao1,3, J Lin2,3, Y-H Li1, L Gao1, X-R Wang1, W Wang1, H-Y Kang1, G-T Yan2, L-L Wang1 and L Yu1
Aberrant activation of c-kit proto-oncogene contributes to abnormal cell proliferation by altering the tyrosine kinase signaling and constitutes a crucial impetus for leukemogenesis. Epigenetic silencing of tumor-suppressive microRNAs (miRNAs) is a key oncogenic mechanism for the activation of oncogenes in tumors. In this study, several miRNAs potentially binding to the 3′-untranslated region of human c-kit mRNA were screened by luciferase reporter assays. Among these miRNAs, miR-193a was embedded in a CpG island and epigenetically repressed by promoter hypermethylation in acute myeloid leukemia (AML) cell lines and primary AML blasts, but not in normal bone marrow cells. Importantly, miR-193a levels were inversely correlated with c-kit levels measured in 9 leukemia cell lines and 27 primary AML samples. Restoring miR-193a expression in AML cells harboring c-kit mutation and/or overexpression, either by synthetic miR-193a transfection or by DNA hypomethylating agent 5-azacytidine (5-aza) treatment, resulted in a significant reduction in c-kit expression at both RNA and protein levels and inhibition of cell growth. The growth-inhibitory activity of miR-193a was associated with apoptosis and granulocytic differentiation. Moreover, 5-aza-induced c-kit reduction could be partially blocked by miR-193a inhibitor, leading to a reversal of antiproliferative and proapoptotic effects of 5-aza. These data reveal a critical role for methylation-repressed miR-193a in myeloid leukemogenesis and the therapeutic promise of upregulating miR-193a expression for c-kit-positive AML.
Keywords: c-kit; microRNAs; DNA methylation; acute myeloid leukemia; proto-oncogenes; tumor suppressor genes
