王红阳院士最新《Hepatology》：瞄准肝细胞癌早期筛查与精准治疗

　　

肝细胞性肝癌（HCC）是世界范围内癌症相关死亡上升最快的疾病之一，因缺乏早期特异性生物标志物和治疗靶点，导致HCC早期诊断率很低以及治疗方法非常匮乏。国家肝癌科学中心、第二军医大学东方肝胆外科医院的研究人员，通过系统性地对极早期肝癌（BCLC 0 期HCC）mRNA、circRNA和microRNA表达谱进行全基因组分析，揭示了HCC早期以circRNA为中心的非编码RNAs调控网络，最新文章在线发表在《Hepatology》杂志上。

王红阳院士是该项研究的主要通讯作者，李亮副研究员是共同通讯作者，四位共同第一作者分别是危晏平硕士、陈昕博士、梁驰硕士和凌妍博士。王红阳院士长期从事肿瘤的基础与临床研究，对肿瘤的信号网络调控、肝癌新分子标志物鉴定及应用等有重要建树，在国际有影响的主流期刊发表论文200余篇。近五年申报发明专利28项，已获授权12项（国际专利2项），主持研发的Glypican-3肝癌检测诊断试剂盒获得国家食品药品监督管理总局（CFDA）颁发的三类医疗器械注册证，是我国第一个以具有完全自主产权的单克隆抗体为基础研发获批的试剂盒。

共价闭合的环状RNA（circRNA）曾被认为是一种异常的剪接副产物，随着其功能的不断挖掘，癌症研究领域升起了一轮有关circRNA的新热潮。

三分之二的HCC癌症患者初次诊断即为晚期，此时有效治疗的手段不多；目前关于肝癌的研究主要集中在肿瘤晚期，有关HCC早期事件的解析仍是空白；考虑到癌症不同阶段的基因组学差异，直接以早期HCC为研究对象是十分必要和迫切的。

这篇文章发现， Circ-CDYL在HCC早期出现特异性高表达，并显著促进肝癌细胞恶性表型和增加EPCAM阳性肝肿瘤起始细胞的比例。Circ-CDYL通过同时扮演miR-892a和miR-328-3p的sponges（竞争性吸附miRNA），与mRNAs编码的肝癌衍生生长因子（HDGF）和组织缺氧诱导因子天冬酰胺羟化酶（HIF1AN）相互作用。随后同时激活PI3K-AKT-mTORC1/β-连环蛋白和NOTCH2途径，促进效应蛋白杆状病毒IAP重复蛋白5（BIRC5，又称SURVIVIN）和MYC的表达。

最后，研究团队证明结合Circ-CDYL干扰和传统靶向PI3K和HIF1AN的酶抑制剂的治疗方法显著抑制了HCC肿瘤起始细胞样特征和肿瘤生长。Circ-CDYL、HDGF以及HIF1AN联合未来可以作为HCC早期监测和高危人群筛查的候选标志物，其早期诊断的效率高于AFP。

这项新研究不仅揭示了以circRNA为中心的非编码RNAs调控网络在早期肝癌中的作用及机制，而且提出了早期HCC监测和高危人群筛查的可行策略，为肝癌的精准治疗提供了新的靶点。

原文摘要：
Hepatocellular carcinoma (HCC) is the fastest-rising cause of cancer-related death worldwide, but its deficiency of specific biomarkers and therapeutic targets in the early stages lead to severe inadequacy in the early diagnosis and treatment of HCC. Covalently closed circular RNA, which was once considered an aberrant splicing byproduct, is now drawing new interest in cancer research due to its remarkable functionality. Beneath the surface of the dominant functional proteins events, a hidden circRNA-centric noncoding regulatory RNAs network active in the very early stage of HCC is here revealed by a genome-wide analysis of mRNA, circRNA and microRNA expression profiles. Circ-CDYL is specifically upregulated in the early stages of HCC and therefore contributes to the properties of EPCAM-positive liver tumor-initiating cells. Circ-CDYL interacts with mRNAs encoding hepatoma-derived growth factor (HDGF) and hypoxia inducible factor asparagine hydroxylase (HIF1AN) by acts as the sponge of miR-892a and miR-328-3p, respectively. Subsequently, activation of the PI3K-AKT-mTORC1/β-catenin and NOTCH2 pathways, which promote the expression of the effect proteins baculoviral IAP repeat containing 5 (BIRC5 or SURVIVIN) and MYC proto-oncogene, is influenced by Circ-CDYL. A treatment incorporating Circ-CDYL interference and traditional enzyme inhibitors targeting PI3K and HIF1AN demonstrated highly effective inhibition of stem-like characteristics and tumor growth in HCC. Finally, we demonstrated that the Circ-CDYL expression or which combined with HDGF and HIF1AN are both independent marker for discrimination of early stages HCC with the odds ratio (OR) of 1.09 (95% CI: 1.02-1.17) and 124.58 (95% CI: 13.26-1170.56), respectively. Conclusion.These findings uncover a circRNA-centric noncoding regulatory RNAs network in the early stages HCC and thus provide a possibility for surveillance and treatment of HCC early.

原文检索：A Noncoding Regulatory RNAs Network Driven by Circ-CDYL Acts Specifically in the Early Stages Hepatocellular Carcinoma
（生物通：伍松）