Jiang W, Huang H, Ding L, Zhu P, Saiyin H, Ji G, Zuo J, Han D, Pan Y, Ding D, Ma X, Zhang Y, Wu J, Yi Q, Liu J O, Huang H, Dang Y, Yu L
State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Science, Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Fudan University, Shanghai, China.
Department of Biochemistry and Molecular Biology, Department of Urology, Mayo Clinic Cancer Center, Mayo Clinic College of Medicine, Rochester, NY, USA.
Oncogene. 2015 Aug 20;34(34):4460-70. doi: 10.1038/onc.2014.373. Epub 2014 Nov 17.
Activation of cyclin E1, a key regulator of the G1/S cell-cycle transition, has been implicated in many cancers including hepatocellular carcinoma (HCC). Although much is known about the regulation of cyclin E1 expression and stability, its post-transcriptional regulation mechanism remains incompletely understood. Here, we report that nuclear factor 90 (NF90), a double-stranded RNA (dsRNA) binding protein, regulates cyclin E1 in HCC. We demonstrate that NF90 is upregulated in HCC specimens and that suppression of NF90 decreases HCC cell growth and delays G1/S transition. We identified cyclin E1 as a new target of NF90 and found a significant correlation between NF90 and cyclin E1 expression in HCC. The mRNA and protein levels of cyclin E1 were downregulated upon NF90 knockdown. Suppression of NF90 caused a decrease in the half-life of cyclin E1 mRNA, which was rescued by ectopic expression of NF90. Furthermore, NF90 bound to the 3' untranslated regions (3'UTRs) of cyclin E1 mRNA in vitro and in vivo. Knockdown of NF90 also inhibited tumor growth of HCC cell lines in mouse xenograft model. Moreover, we showed that inhibition of NF90 sensitized HCC cells to the cyclin-dependent kinase 2 (CDK2) inhibitor, roscovitine. Taken together, downregulation of NF90 in HCC cell lines can delay cell-cycle progression, inhibit cell proliferation, and reduce tumorigenic capacity in vivo. These results suggest that NF90 has an important role in HCC pathogenesis and that it can serve as a novel therapeutic target for HCC.
细胞周期蛋白E1是G1/S细胞周期转换的关键调节因子，其激活与包括肝细胞癌（HCC）在内的多种癌症有关。尽管人们对细胞周期蛋白E1表达和稳定性的调节了解很多，但其转录后调节机制仍未完全清楚。在此，我们报告核因子90（NF90），一种双链RNA（dsRNA）结合蛋白，在肝癌中调节细胞周期蛋白E1。我们证明NF90在肝癌标本中上调，抑制NF90可降低肝癌细胞生长并延迟G1/S转换。我们将细胞周期蛋白E1鉴定为NF90的新靶点，并发现肝癌中NF90与细胞周期蛋白E1表达之间存在显著相关性。NF90敲低后，细胞周期蛋白E1的mRNA和蛋白水平下调。抑制NF90导致细胞周期蛋白E1 mRNA半衰期缩短，而异位表达NF90可挽救这种缩短。此外，NF90在体外和体内均与细胞周期蛋白E1 mRNA的3'非翻译区（3'UTR）结合。在小鼠异种移植模型中，NF90敲低也抑制了肝癌细胞系的肿瘤生长。此外，我们表明抑制NF90可使肝癌细胞对细胞周期蛋白依赖性激酶2（CDK2）抑制剂罗斯考维汀敏感。综上所述，肝癌细胞系中NF90的下调可延迟细胞周期进程、抑制细胞增殖并降低体内致瘤能力。这些结果表明NF90在肝癌发病机制中起重要作用，并且它可以作为肝癌的新型治疗靶点。
