Division of Life Science, Center for Cancer Research and State Key Lab for Molecular Neuroscience, Hong Kong University of Science and Technology, Hong Kong, China.
Division of Life Science, Center for Cancer Research and State Key Lab for Molecular Neuroscience, Hong Kong University of Science and Technology, Hong Kong, China; EnKang Pharmaceuticals (Guangzhou), Ltd., Guangzhou, China.
Cancer Lett. 2022 Jul 28;539:215677. doi: 10.1016/j.canlet.2022.215677. Epub 2022 Apr 28.
MicroRNAs are noncoding RNAs with a typical length of 22 nucleotides that post-transcriptionally suppress gene expression by inducing target mRNA degradation and/or impairing translation in eukaryotes. Thousands of miRNA genes in the human genome are involved in various physiological and pathological processes. Each miRNA targets many different mRNAs, while each mRNA may be targeted by various miRNAs. Mini-chromosome maintenance (MCM2-7) protein complex functions as essential components of the pre-replicative complex (pre-RC) and forms a helicase together with other proteins to unwind the DNA duplex in S phase. MCM proteins are overexpressed in all cancer cells, while they are strictly regulated in normal cells, with no expression in non-proliferating normal cells. Here we report that miRNA-214-3p (miR-214) targets both MCM5 and MCM7. The level of miR-214 is lower in HepG2 and Hep3B hepatocellular carcinoma cells than the L-02 normal liver cells. Introduction of miRNA-214 mimic into HepG2 and Hep3B cells reduced the mRNA and protein levels of MCM5/7 and inhibited DNA replication, cell cycle progression, cell proliferation and colony formation. Comparatively, miRNA-214 mimic had little effect in L-02 cells. Importantly, miR-214 mimic can also inhibit the growth of HepG2 xenografts in nude mice. Our data suggest that miRNA-214 regulates DNA replication by targeting MCM5/7 and has the potential to be developed into a liver cancer drug. IMPLICATIONS: This study supports the notion that DNA replication-initiation proteins (DRIPs), including MCM2-7 proteins, are attractive anticancer targets. Furthermore, the potential of miR-214 as an anticancer agent, with activity against liver cancer cells but not normal livre cells, may be of high significance.
微小 RNA 是一类典型长度为 22 个核苷酸的非编码 RNA，通过诱导靶 mRNA 降解和/或在真核生物中阻碍翻译来在后转录水平上抑制基因表达。人类基因组中数千个 miRNA 基因参与各种生理和病理过程。每个 miRNA 靶向许多不同的 mRNA，而每个 mRNA 可能被各种 miRNA 靶向。微型染色体维持 (MCM2-7) 蛋白复合物作为前复制复合物 (pre-RC) 的必需组成部分发挥作用，并与其他蛋白一起形成解旋酶，以在 S 期解开 DNA 双链。MCM 蛋白在所有癌细胞中过度表达，而在正常细胞中受到严格调控，在非增殖的正常细胞中没有表达。在这里，我们报告 miRNA-214-3p (miR-214) 靶向 MCM5 和 MCM7。miR-214 在 HepG2 和 Hep3B 肝癌细胞中的水平低于 L-02 正常肝细胞。将 miRNA-214 模拟物引入 HepG2 和 Hep3B 细胞中降低了 MCM5/7 的 mRNA 和蛋白水平，并抑制了 DNA 复制、细胞周期进程、细胞增殖和集落形成。相比之下，miRNA-214 模拟物在 L-02 细胞中几乎没有影响。重要的是，miRNA-214 模拟物也可以抑制裸鼠中 HepG2 异种移植物的生长。我们的数据表明，miRNA-214 通过靶向 MCM5/7 来调节 DNA 复制，并有可能被开发为肝癌药物。意义：本研究支持这样一种观点，即 DNA 复制起始蛋白 (DRIPs)，包括 MCM2-7 蛋白，是有吸引力的抗癌靶点。此外，miR-214 作为一种抗癌剂的潜力，对肝癌细胞有活性而对正常肝细 胞没有活性，可能具有重要意义。
