Hepatocellular carcinoma (HCC) is one of the fastest-rising causes 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 (circRNA), which was once considered an aberrant splicing by-product, is now drawing new interest in cancer research because of 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 (miRNA) expression profiles. Circ-CDYL (chromodomain Y like) is specifically up-regulated in the early stages of HCC and therefore contributes to the properties of epithelial cell adhesion molecule (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 acting as the sponge of miR-892a and miR-328-3p, respectively. Subsequently, activation of the phosphoinositide 3-kinase (PI3K)-AKT serine/threonine kinase-mechanistic target of rapamycin kinase complex 1/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 circ-CDYL expression or which combined with HDGF and HIF1AN are both independent markers for discrimination of early stages of HCC with the odds ratios of 1.09 (95% confidence interval [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 of HCC and thus provide a possibility for surveillance and early treatment of HCC.

译文

:肝细胞癌(HCC)是世界范围内与癌症相关的死亡的最快上升原因之一,但是其早期缺乏特定的生物标志物和治疗靶标导致HCC的早期诊断和治疗严重不足。共价封闭的环状RNA(circRNA)曾经被认为是异常的剪接副产物,由于其卓越的功能性,现在正引起癌症研究的新兴趣。在主要功能性蛋白质事件的表面之下,这里通过在全基因组范围内对mRNA,circRNA和microRNA(miRNA)表达谱进行分析,揭示了在HCC早期阶段活跃的以circRNA为中心的隐藏非编码调控RNA网络。在HCC的早期阶段,Circ-CDYL(类似Y的色域)被上调,因此有助于上皮细胞粘附分子(EPCAM)阳性的肝肿瘤起始细胞的特性。 Circ-CDYL分别充当miR-892a和miR-328-3p的海绵,与编码肝癌衍生生长因子(HDGF)和缺氧诱导因子天冬酰胺羟化酶(HIF1AN)的mRNA相互作用。随后,激活雷帕霉素激酶复合物1 /β-catenin和NOTCH2途径的磷酸肌醇3-激酶(PI3K)-AKT丝氨酸/苏氨酸激酶机制靶标,从而促进效应蛋白的表达,杆状病毒IAP重复序列包含5(BIRC5或SURVIVIN)和MYC原癌基因,受circ-CDYL的影响。结合了circ-CDYL干扰和靶向PI3K和HIF1AN的传统酶抑制剂的治疗显示出可有效抑制肝癌中的茎样特征和肿瘤生长。最后,我们证明circ-CDYL表达或与HDGF和HIF1AN结合使用都是区分HCC早期阶段的独立标志物,比值比为1.09(95%置信区间[CI],1.02-1.17)和124.58(95 %CI,13.26-1170.56)。结论:这些发现揭示了在HCC早期以circRNA为中心的非编码RNA的网络,从而为HCC的监测和早期治疗提供了可能。

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