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RNA-binding motif protein 43 (RBM43) suppresses hepatocellular carcinoma progression through modulation of cyclin B1 expression

Oncogene volume 39, pages 5495–5506 (2020)Cite this article

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Abstract

RNA-binding proteins play key roles in the posttranscriptional regulation of mRNA during cancer progression. Here, we show that RNA-binding motif protein 43 (RBM43) is significantly downregulated in human tumors, and its low expression is correlated with poor prognosis in patients with HCC. Overexpression of RBM43 suppressed cell proliferation in culture and resulted in the growth arrest of tumor xenografts, whereas downregulating RBM43 played an opposite role. We have also demonstrated that overexpression or knockdown of RBM43 affects the cell-cycle progression of liver cancer cells. Mechanistically, RBM43 directly associated with the 3′UTR of Cyclin B1 mRNA and regulated its expression. Moreover, loss of Rbm43 in mice promoted liver carcinogenesis and HCC development after diethylnitrosamine (DEN)-carbon tetrachloride (CCl4) treatment. Taken together, our data indicate that RBM43 is a tumor suppressor that controls the cell cycle through modulation of Cyclin B1 expression, providing evidence that RBM43 is particularly important in HCC.

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Fig. 1: RBM43 is downregulated in HCC, and its low expression is negatively correlated with the survival of HCC patients.
Fig. 2: Overexpression of RBM43 inhibits liver cancer cell growth.
Fig. 3: Knockdown of RBM43 promotes liver cancer cell growth.
Fig. 4: RBM43 is a cell cycle regulator.
Fig. 5: RBM43 associates with Cyclin B1 mRNA and regulates its stability.
Fig. 6: Loss of Rbm43 increases susceptibility to drug-induced liver carcinogenesis in mice.
Fig. 7: The hypothetical working model.

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References

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66:7–30.

    Article  Google Scholar 

  2. Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, et al. Cancer statistics in China, 2015. CA Cancer J Clin. 2016;66:115–32.

    Article  Google Scholar 

  3. El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 2007;132:2557–76.

    Article  CAS  Google Scholar 

  4. Stefanie G, Markus H, Thomas T. A census of human RNA-binding proteins. Nat Rev Cancer. 2014;15:829–45.

    Article  Google Scholar 

  5. Hentze MW, Castello A, Schwarzl T, Preiss T. A brave new world of RNA-binding proteins. Nat Rev Mol Cell Biol. 2018;19:327.

    Article  CAS  Google Scholar 

  6. Castello A, Fischer B, Eichelbaum K, Horos R, Beckmann BM, Strein C, et al. Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 2012;149:1393–406.

    Article  CAS  Google Scholar 

  7. Wang Y, Chen D, Qian H, Tsai YS, Shao S, Liu Q, et al. The splicing factor RBM4 controls apoptosis, proliferation, and migration to suppress tumor progression. Cancer Cell 2014;26:374–89.

    Article  CAS  Google Scholar 

  8. Sakurai T, Isogaya K, Sakai S, Morikawa M, Morishita Y, Ehata S, et al. RNA-binding motif protein 47 inhibits Nrf2 activity to suppress tumor growth in lung adenocarcinoma. Oncogene 2016;35:5000.

    Article  CAS  Google Scholar 

  9. Dang H, Takai A, Forgues M, Pomyen Y, Mou H, Xue W, et al. Oncogenic activation of the RNA binding protein NELFE and MYC signaling in hepatocellular carcinoma. Cancer Cell 2017;32:101–114.e108.

    Article  CAS  Google Scholar 

  10. Zhao L, Cao J, Hu K, Wang P, Li G, He X, et al. RNA-binding protein RPS3 contributes to hepatocarcinogenesis by post-transcriptionally up-regulating SIRT1. Nucleic Acids Res. 2018;47:2011–28.

    Article  Google Scholar 

  11. Guan M, Keaton JM, Dimitrov L, Hicks PJ, Xu J, Palmer ND, et al. Genome-wide association study identifies novel loci for type 2 diabetes-attributed end-stage kidney disease in African Americans. Hum Genom. 2019;13:21.

    Article  Google Scholar 

  12. Albertsen HM, Chettier R, Farrington P, Ward K. Genome-wide association study link novel loci to endometriosis. PLoS ONE 2013;8:e58257.

    Article  CAS  Google Scholar 

  13. Dong J, Levine DM, Buas MF, Zhang R, Onstad L, Fitzgerald RC, et al. Interactions between genetic variants and environmental factors affect risk of esophageal adenocarcinoma and Barrett’s esophagus. Clin Gastroenterol Hepatol. 2018;16:1598–1606.e1594.

    Article  CAS  Google Scholar 

  14. Jiang DK, Sun J, Cao G, Liu Y, Lin D, Gao YZ, et al. Genetic variants in STAT4 and HLA-DQ genes confer risk of hepatitis B virus-related hepatocellular carcinoma. Nat Genet. 2013;45:72–75.

    Article  CAS  Google Scholar 

  15. Dapito DH, Mencin A, Gwak G-Y, Pradere J-P, Jang M-K, Mederacke I, et al. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell 2012;21:504–16.

    Article  CAS  Google Scholar 

  16. Nurse P. Universal control mechanism regulating onset of M-phase. Nature 1990;344:503.

    Article  CAS  Google Scholar 

  17. Wang W, Caldwell MC, Lin S, Furneaux H, Gorospe M. HuR regulates cyclin A and cyclin B1 mRNA stability during cell proliferation. EMBO J 2000;19:2340–50.

    Article  CAS  Google Scholar 

  18. Nakahata S, Kotani T, Mita K, Kawasaki T, Katsu Y, Nagahama Y, et al. Involvement of Xenopus Pumilio in the translational regulation that is specific to cyclin B1 mRNA during oocyte maturation. Mech Dev. 2003;120:865–80.

    Article  CAS  Google Scholar 

  19. Takahashi K, Ishii Kana, Masakane Yamashita. Staufen1, Kinesin1 and microtubule function in cyclin B1 mRNA transport to the animal polar cytoplasm of zebrafish oocytes. Biochem Biophys Res Commu. 2018;503:2778–83.

    Article  CAS  Google Scholar 

  20. Van Assche E, Van Puyvelde S, Vanderleyden J, Steenackers HP. RNA-binding proteins involved in post-transcriptional regulation in bacteria. Front Microbiol. 2015;6:141.

    PubMed  PubMed Central  Google Scholar 

  21. Glisovic T, Bachorik JL, Yong J, Dreyfuss G. RNA-binding proteins and post-transcriptional gene regulation. FEBS Lett. 2008;582:1977–86.

    Article  CAS  Google Scholar 

  22. Hartwell LH, Kastan MB. Cell cycle control and cancer. Science 1994;266:1821–8.

    Article  CAS  Google Scholar 

  23. Kastan MB, Bartek J. Cell-cycle checkpoints and cancer. Nature 2004;432:316.

    Article  CAS  Google Scholar 

  24. Evan GI, Vousden KH. Proliferation, cell cycle and apoptosis in cancer. Nature 2001;411:342.

    Article  CAS  Google Scholar 

  25. Denicourt C, Dowdy SF. Cip/Kip proteins: more than just CDKs inhibitors. Genes Dev. 2004;18:851–5.

    Article  CAS  Google Scholar 

  26. Aaltonen K, Amini RM, Heikkila P, Aittomaki K, Tamminen A, Nevanlinna H, et al. High cyclin B1 expression is associated with poor survival in breast cancer. Br J Cancer. 2009;100:1055–60.

    Article  CAS  Google Scholar 

  27. Zhang H, Zhang X, Li X, Meng WB, Bai ZT, Rui SZ, et al. Effect of CCNB1 silencing on cell cycle, senescence, and apoptosis through the p53 signaling pathway in pancreatic cancer. J Cell Physiol. 2019;234:619–31.

    Article  CAS  Google Scholar 

  28. EGLOFF AM, WEISSFELD J, SR LAND, FINN OJ. Evaluation of anticyclin B1 serum antibody as a diagnostic and prognostic biomarker for lung cancer. Ann NY Acad Sci. 2005;1062:29–40.

    Article  CAS  Google Scholar 

  29. Covini G, Chan E, Nishioka M, Morshed SA, Reed SI, Tan EM. Immune response to cyclin B1 in hepatocellular carcinoma. Hepatology 1997;25:75–80.

    Article  CAS  Google Scholar 

  30. Wang Z, Fan M, Candas D, Zhang TQ, Qin L, Eldridge A, et al. Cyclin B1/Cdk1 coordinates mitochondrial respiration for cell-cycle G2/M progression. Dev Cell 2014;29:217–32.

    Article  Google Scholar 

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Acknowledgements

We thank professor Ting Ni from the School of Life Sciences, Fudan University for advice in the analysis of RBM43 target genes. We thank Gang Wei, Ziya Re, and Yicheng Le (School of Life Sciences, Fudan University) for their helpful discussions and comments. We would like to thank Changjuan Shao, Yahui Zhao, Dan Song, Juanjuan Wang, Xiaoding Hu, Yi He, and Lifang You and Bingying Li (School of Life Sciences, Fudan University) for their advice and assistance in experimental skills and helpful discussions and comments.

Funding

This work was supported by the National Natural Science Foundation of China (81702742 to SS and 81972712 to JW).

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Authors and Affiliations

  1. State Key Laboratory of Genetic Engineering, Zhongshan Hospital and School of Life Sciences, Fudan University, Shanghai, P.R. China

    Huan Feng, Juan Liu, Yangyang Qiu, Yao Liu, Hexig Saiyin, Xiao Liang, Fen Zheng, Ying Wang, Long Yu, Wei Su, Suqin Shen & Jiaxue Wu

  2. Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, P.R. China

    Deke Jiang

  3. Department of Oncology, Changhai Hospital, Second Military Medical University, Shanghai, P.R. China

    Ying Wang

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  1. Huan Feng
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Contributions

HF and SS designed the study, conducted most of the experiments and wrote the paper. JL, YQ, YL, XL, FZ, YW, YZ, CS, JW and DS provided advice about the experiments. WS, DJ and LY contributed to the paper completion. JW conceived the study, provided overall guidance, and contributed to the paper completion.

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Correspondence to Suqin Shen or Jiaxue Wu.

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Feng, H., Liu, J., Qiu, Y. et al. RNA-binding motif protein 43 (RBM43) suppresses hepatocellular carcinoma progression through modulation of cyclin B1 expression. Oncogene 39, 5495–5506 (2020). https://doi.org/10.1038/s41388-020-1380-7

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