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研究背景：曹雪濤課題組與多家醫(yī)院、科研所等合作，研究人員對(duì)人正常肝臟、病毒性肝炎肝臟、肝硬化肝臟和肝癌肝臟的microRNA進(jìn)行深度測(cè)序，發(fā)現(xiàn)microRNA-199的表達(dá)高低與肝癌患者預(yù)后存在密切關(guān)系，同時(shí)證明microRNA-199能夠靶向抑制促肝癌激酶分子PAK4從而顯著抑制肝癌細(xì)胞生長(zhǎng)，為肝癌的預(yù)防、判斷及生物治療提供了新的潛在靶標(biāo)。這一研究成果公布在Cell子刊《Cancer Cell》雜志上。 該研究首次獲得各類(lèi)型肝臟的microRNA組數(shù)據(jù)，了解到肝癌與正常肝臟microRNA的差別，并通過(guò)分析4個(gè)獨(dú)立的肝癌患者臨床隊(duì)列，發(fā)現(xiàn)人正常肝臟高豐度表達(dá)的microRNA-199在人肝癌肝臟中普遍性、顯著性降低，并且microRNA-199的低表達(dá)與肝癌患者的生存期降低顯著相關(guān)。進(jìn)一步發(fā)現(xiàn)肝癌組織中組蛋白甲基化改變是導(dǎo)致microRNA-199表達(dá)降低的原因。 microRNA-199能夠靶向抑制PAK4進(jìn)而抑制下游的ERK信號(hào)通路，從而抑制肝癌細(xì)胞的生長(zhǎng)。通過(guò)肝靶向性腺相關(guān)病毒載體介導(dǎo)的microRNA-199基因治療，顯著延長(zhǎng)了肝癌裸鼠生存期。由此證明microRNA-199是肝癌預(yù)防、判斷與治療新的潛在靶標(biāo)，為肝癌生物治療提出了新方法。 關(guān)鍵技術(shù)：測(cè)序，生物信息學(xué)分析,模型動(dòng)物 研究意義：有關(guān)專(zhuān)家認(rèn)為，該工作揭示的正常肝臟與疾病肝臟的microRNA組數(shù)據(jù)為后期進(jìn)一步研究microRNA在肝臟生理和肝臟疾病中的作用奠定了基礎(chǔ)。測(cè)序是基因組學(xué)研究最基礎(chǔ)的研究手段，單本研究的角度新穎，對(duì)于肝病及其他疾病的研究都具有借鑒意義。 參考文獻(xiàn)： Identification of miRNomes in Human Liver and Hepatocellular Carcinoma Reveals miR-199a/b-3p as Therapeutic Target for Hepatocellular Carcinoma. Highlights Identification of miRNomes in human normal liver, hepatitis liver and HCC miR-199a/b-3p is the most consistently decreased miRNA in HCC Low miR-199-3p expression correlates with poor survival of HCC patients miR-199-3p inhibits PAK4/Raf/MEK/ERK prosurvival pathway in HCC. Summary The full scale of human miRNome in specific cell or tissue, especially in cancers, remains to be determined. An in-depth analysis of miRNomes in human normal liver, hepatitis liver, and hepatocellular carcinoma (HCC) was carried out in this study. We found nine miRNAs accounted for 88.2% of the miRNome in human liver. The third most highly expressed miR-199a/b-3p is consistently decreased in HCC, and its decrement significantly correlates with poor survival of HCC patients. Moreover, miR-199a/b-3p can target tumor-promoting PAK4 to suppress HCC growth through inhibiting PAK4/Raf/MEK/ERK pathway both in vitro and in vivo. Our study provides miRNomes of human liver and HCC and contributes to better understanding of the important deregulated miRNAs in HCC and liver diseases. |
