Regulation of cell cycle of hepatocellular carcinoma by NF90 through modulation of cyclin E1 mRNA stability.
Regulation of cell cycle of hepatocellular carcinoma by NF90 through modulation of cyclin E1 mRNA stability.
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NF90 通过调节细胞周期蛋白 E1 mRNA 稳定性调节肝细胞癌细胞周期
作者：
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）在内的许多癌症有关。虽然对细胞周期蛋白E1的表达和稳定性的调控已经有了很多了解，但其转录后调控机制仍不完全清楚。在这里，我们报告，核因子90（NF 90），双链RNA（dsRNA）结合蛋白，调节细胞周期蛋白E1在肝癌。我们证明了NF 90在HCC标本中上调，抑制NF 90可降低HCC细胞生长并延迟G1/S转换。我们发现细胞周期蛋白E1是NF 90的一个新靶点，并发现NF 90和细胞周期蛋白E1在HCC中的表达之间存在显著相关性。NF 90敲除后，细胞周期蛋白E1的mRNA和蛋白水平下调。NF 90的抑制导致细胞周期蛋白E1 mRNA的半衰期减少，这是由NF 90的异位表达拯救。此外，在体外和体内，NF 90与cyclin E1 mRNA的3 '非翻译区（3' UTR）结合。在小鼠异种移植模型中，NF 90的敲低也抑制HCC细胞系的肿瘤生长。此外，我们发现抑制NF 90使HCC细胞对细胞周期蛋白依赖性激酶2（CDK 2）抑制剂roscovitine敏感。总之，在HCC细胞系中NF 90的下调可以延迟细胞周期进程，抑制细胞增殖，并降低体内致瘤能力。这些结果表明，NF 90在HCC发病机制中具有重要作用，并可作为HCC治疗的新靶点。
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.
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