3月14日,，國(guó)際知名雜志《致癌基因》（Oncogene）發(fā)表了中國(guó)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在急性骨髓性白血病（Acute myeloid leukemia,，AML）中抑制了c-kit表達(dá),，證實(shí)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(guó)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(xì)胞移植等方面具有豐富的臨床經(jīng)驗(yàn),，主要研究方向?yàn)檠合到y(tǒng)惡性腫瘤的診斷、治療及造血干細(xì)胞移植,。于力教授曾在國(guó)際上首次發(fā)現(xiàn)兩個(gè)白血病相關(guān)基因LRP15和LRP16,，并在國(guó)際基因庫(kù)中注冊(cè),。他還在國(guó)際上首次證明ID4基因具有抑制白血病細(xì)胞增長(zhǎng)的功能，這一研究成果發(fā)表在國(guó)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(dá)于肥大細(xì)胞、黑色素細(xì)胞,、造血干細(xì)胞,、腸間質(zhì)細(xì)胞和生殖細(xì)胞中。大量的研究證實(shí)多種惡性腫瘤如急性骨髓性白血病細(xì)胞中存在c-kit的異常激活,，與癌癥的發(fā)生,、增生、浸潤(rùn)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(guó)人民解放軍總醫(yī)院的研究人員利用熒光報(bào)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(xì)胞和原發(fā)性AML芽細(xì)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(jí)化,。進(jìn)而，研究人員在9種白血病細(xì)胞系和27名原發(fā)性AML患者血液樣品中證實(shí)miR-193a水平與c-kit水平呈現(xiàn)負(fù)相關(guān),。
在進(jìn)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(shí)，在c-kit 突變和C-kit過表達(dá)的AML細(xì)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(xì)胞生長(zhǎng),。當(dāng)研究人員在細(xì)胞中加入miR-193a抑制劑時(shí)，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(xì)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(xì)胞樣白血病的發(fā)病機(jī)理,，并為c-kit陽(yáng)性的AML的治療指明了新的有潛力的治療靶點(diǎn),。（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
