Journal Article

Regulation of cell cycle of hepatocellular carcinoma by NF90 through modulation of cyclin E1 mRNA stability

Jiang, W, Ding, D, Yu, L, Dang, Y, Pan, Y, Wu, J, Liu, J O, Ding, L, Zhang, Y, Saiyin, H, Huang, H, Zhu, P, Ji, G, Ma, X, Zuo, J, Yi, Q, Han, D

2015

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/109 / 13/31 / 13/44 / 13/51 / 13/89 / 14/1 / 14/69 / 3' Untranslated Regions / 38/109 / 38/77 / 38/89 / 38/90 / 631/67/1504/1610 / 64/60 / 82/1 / 82/29 / 82/51 / 82/80 / 82/83 / Animals / Apoptosis / Cancer / Carcinoma, Hepatocellular - drug therapy / Carcinoma, Hepatocellular - pathology / Cell Biology / Cell Cycle / Cell growth / Cell proliferation / Cyclin E - genetics / Cyclin-dependent kinase 2 / Cyclin-Dependent Kinase 2 - antagonists & inhibitors / Cyclin-dependent kinases / Development and progression / Double-stranded RNA / Ectopic expression / Enzyme inhibitors / Gene expression / Gene regulation / Genetic aspects / Health aspects / Hepatocellular carcinoma / Hepatoma / Human Genetics / Humans / Internal Medicine / Kinases / Liver cancer / Liver Neoplasms - drug therapy / Liver Neoplasms - pathology / Medicine / Medicine & Public Health / Messenger RNA / Mice / Mice, Inbred BALB C / MicroRNAs / mRNA stability / Nuclear Factor 90 Proteins - antagonists & inhibitors / Nuclear Factor 90 Proteins - physiology / Oncogene Proteins - genetics / Oncology / original-article / Post-transcription / Properties / Purines - therapeutic use / RNA Stability / Roscovitine / Therapeutic applications / Transcription factors / Tumor cell lines / Xenografts