研究背景：曹雪涛课题组与多家医院、科研所等合作，研究人员对人正常肝脏、病毒性肝炎肝脏、肝硬化肝脏和肝癌肝脏的microRNA进行深度测序，发现microRNA-199的表达高低与肝癌患者预后存在密切关系，同时证明microRNA-199能够靶向抑制促肝癌激酶分子PAK4从而显著抑制肝癌细胞生长，为肝癌的预防、判断及生物治疗提供了新的潜在靶标。这一研究成果公布在Cell子刊《Cancer Cell》杂志上。

该研究首次获得各类型肝脏的microRNA组数据，了解到肝癌与正常肝脏microRNA的差别，并通过分析4个独立的肝癌患者临床队列，发现人正常肝脏高丰度表达的microRNA-199在人肝癌肝脏中普遍性、显著性降低，并且microRNA-199的低表达与肝癌患者的生存期降低显著相关。进一步发现肝癌组织中组蛋白甲基化改变是导致microRNA-199表达降低的原因。

microRNA-199能够靶向抑制PAK4进而抑制下游的ERK信号通路，从而抑制肝癌细胞的生长。通过肝靶向性腺相关病毒载体介导的microRNA-199基因治疗，显著延长了肝癌裸鼠生存期。由此证明microRNA-199是肝癌预防、判断与治疗新的潜在靶标，为肝癌生物治疗提出了新方法。

关键技术：测序，生物信息学分析,模型动物

研究意义：有关专家认为，该工作揭示的正常肝脏与疾病肝脏的microRNA组数据为后期进一步研究microRNA在肝脏生理和肝脏疾病中的作用奠定了基础。测序是基因组学研究最基础的研究手段，单本研究的角度新颖，对于肝病及其他疾病的研究都具有借鉴意义。

参考文献： 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.