Regulation of cell cycle of hepatocellular carcinoma by NF90 through modulation of cyclin E1 mRNA stability.
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.
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.
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Jiang
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.
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Huang
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.
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Ding
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.
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Zhu
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.
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Saiyin
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.
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Ji
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.
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Zuo
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.
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Han
Department of Biochemistry and Molecular Biology, Department of Urology, Mayo Clinic Cancer Center, Mayo Clinic College of Medicine, Rochester, NY, USA.
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Pan
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.
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Ding
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.
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Ma
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.
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Zhang
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.
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Wu
Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
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Yi
Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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Liu
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.
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Huang
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.
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Y
Dang
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.
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Yu
D020413:3' Untranslated Regions; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000473:pathology*; D002453:Cell Cycle; D019927:Cyclin E / Q000235:genetics*; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D050779:Nuclear Factor 90 Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D015513:Oncogene Proteins / Q000235:genetics*; D011687:Purines / Q000627:therapeutic use; D020871:RNA Stability; D000077546:Roscovitine
D020413:3' Untranslated Regions; C475820:CCNE1 protein, human; D019927:Cyclin E; C429643:ILF3 protein, human; D050779:Nuclear Factor 90 Proteins; D015513:Oncogene Proteins; D011687:Purines; D000077546:Roscovitine; D051357:Cyclin-Dependent Kinase 2