Effect of the ribosome biogenesis factor BMS1 on proliferation of neuroblastoma cells

doi:10.3969/j.issn.1006-7795.2025.02.016

Abstract

Abstract: Objective To elucidate the functional role and underlying mechanisms of the ribosome biogenesis factor BMS1 in neuroblastoma (NB) cellular proliferation. Methods We utilized the R2 genomics analysis and visualization platform to analyze the correlation between BMS1 expression levels and clinical characteristics of NB children. The BMS1 mRNA level in three human neuroblastoma cells SK-N-BE(2), BE(2)-C, IMR-32 and two normal cells hTERT RPE-1, IMR-90 was detected by real-time quantitative polymerase chain reaction (RT-qPCR). Two distinct small interfering RNA (siRNA) sequences were used to target BMS1 mRNA in NB cells SK-N-BE(2) and BE(2)-C, with normal cells hTERT RPE-1 serving as controls. We used RT-qPCR to quantify the mRNA levels of BMS1 and two key neuroblastoma-associated molecules (MYCN and p53). After transfection with siRNA, cellular proliferation was detected by various experimental approaches: crystal violet staining, real-time cell analysis (RTCA), colony-forming unit assay and immunofluorescence. Results By analyzing two independent neuroblastoma clinical cohorts (GSE85047/NRC-283 and Westermann-144 datasets), it was found that the BMS1 mRNA level in MYCN-amplified NB was significantly higher than that in MYCN-non-amplified NB (P<0.05). Furthermore, the overall survival rate of NB children in the BMS1 high-expression group was decreased (P<0.05). Consistent with these clinical observations, the BMS1 mRNA level in NB cells SK-N-BE(2), BE(2)-C and IMR-32 was significantly higher than that in normal cells hTERT RPE-1, IMR-90 (P<0.05). The targeted transient knockdown of BMS1 in NB cell lines SK-N-BE(2) and BE(2)-C resulted in decreased intracellular MYCN mRNA expression levels (P<0.05), significantly reduced cell proliferation capacity and colony-forming ability (P<0.05). Immunofluorescence revealed that the expression of Ki-67, a proliferation marker, was decreased (P<0.05). At the molecular level, RT-qPCR showed that the p53 mRNA level was significantly elevated in the BMS1-knockdown groups (siBMS1-1# and siBMS1-2#) compared with the control group (P<0.05). However, transient knockdown of BMS1 had no significant impact on the proliferative capacity of normal cells hTERT RPE-1. Conclusion BMS1 expression was up-regulated in MYCN-amplified NB and negatively correlated with the prognosis of the NB children. Mechanistically, interfering with BMS1 expression may transcriptionally activate p53 in NB cells, thereby inhibiting their proliferative ability, while having minimal impact on normal cells growth kinetics. These findings suggest that BMS1 serves as an important proliferation driver in NB and is expected to be a promising therapeutic target for NB children, particularly MYCN-amplified pediatric patients.

Key words: BMS1, neuroblastoma, cell proliferation, p53, MYCN

CLC Number:

Guo Jinxin, Jia Anna, Zhan Shijia, Zhang Yao, Zhang Xuan, Guo Yongli, Chang Yan. Effect of the ribosome biogenesis factor BMS1 on proliferation of neuroblastoma cells[J]. Journal of Capital Medical University, 2025, 46(2): 296-305.

References

［1］Ambros I M, Tonini G P, Pötschger U, et al. Age dependency of the prognostic impact of tumor genomics in localized resectable MYCN-Nonamplified neuroblastomas. report from the SIOPEN biology group on the LNESG trials and a COG validation group［J］. J Clin Oncol, 2020, 38(31): 3685－3697.
［2］Bosse K R, Maris J M. Advances in the translational genomics of neuroblastoma: from improving risk stratification and revealing novel biology to identifying actionable genomic alterations［J］. Cancer, 2016, 122(1): 20－33.
［3］Epp S, Chuah S M, Halasz M. Epigenetic dysregulation in MYCN-amplified neuroblastoma［J］. Int J Mol Sci, 2023, 24(23): 17085.
［4］Cohn S L, Pearson A D J, London W B, et al. The international neuroblastoma risk group (INRG) classification system: an INRG task force report［J］. J Clin Oncol, 2009, 27(2): 289－297.
［5］Matthay K K, Maris J M, Schleiermacher G, et al. Neuroblastoma［J］. Nat Rev Dis Primers, 2016, 2: 16078.
［6］Qiu B, Matthay K K. Advancing therapy for neuroblastoma［J］. Nat Rev Clin Oncol, 2022, 19(8): 515－533.
［7］Maris J M. Recent advances in neuroblastoma［J］. N Engl J Med, 2010, 362(23): 2202－2211.
［8］Berlanga P, Cañete A, Castel V. Advances in emerging drugs for the treatment of neuroblastoma［J］. Expert Opin Emerg Drugs, 2017, 22(1): 63－75.
［9］Wegierski T, Billy E, Nasr F, et al. Bms1p,a G-domain-containing protein,associates with Rcl1p and is required for 18S rRNA biogenesis in yeast［J］. RNA, 2001, 7(9): 1254－1267.
［10］Karbstein K, Jonas S, Doudna J A. An essential GTPase promotes assembly of preribosomal RNA processing complexes［J］. Mol Cell, 2005, 20(4): 633－643.
［11］Wang Y, Zhao Z Y, Yu H Y, et al. Stability and function of RCL1 are dependent on the interaction with BMS1［J］. J Mol Cell Biol, 2024, 15(7): mjad046.
［12］Pérez-Fernández J, Martín-Marcos P, Dosil M. Elucidation of the assembly events required for the recruitment of Utp20, Imp4 and Bms1 onto nascent pre-ribosomes［J］. Nucleic Acids Res, 2011, 39(18): 8105－8121.
［13］Kornprobst M, Turk M, Kellner N, et al. Architecture of the 90S pre-ribosome: a structural wiew on the birth of the eukaryotic ribosome［J］. Cell, 2016, 166(2): 380－393.
［14］Wang Y, Luo Y, Hong Y H, et al. Ribosome biogenesis factor Bms1-like is essential for liver development in zebrafish［J］. J Genet Genomics, 2012, 39(9): 451－462.
［15］Yanan W, Wenyong Z, Ze L, et al. Identification of genes and pathways in human antigen-presenting cell subsets in response to polio vaccine by bioinformatical analysis［J］. J Med Virol, 2019, 91(10): 1729－1736.
［16］Wang J, Yin Y, Lu Q, et al. Identification of important modules and hub gene in chronic kidney disease based on WGCNA［J］. J Immunol Res, 2022, 2022: 4615292.
［17］Shao J M, Wang S H, West-Szymanski D, et al. Cell-free DNA 5-hydroxymethylcytosine is an emerging marker of acute myeloid leukemia［J］. Sci Rep, 2022, 12(1): 12410.
［18］Suh Y J, Choe J Y, Park H J. Malignancy in pheochromocytoma or paraganglioma: integrative analysis of 176 cases in TCGA［J］. Endocr Pathol, 2017, 28(2): 159－164.
［19］Zafar A, Wang W, Liu G, et al. Molecular targeting therapies for neuroblastoma: Progress and challenges［J］. Med Res Rev, 2021, 41(2): 961－1021.
［20］Gundem G, Levine M F, Roberts S S, et al. Clonal evolution during metastatic spread in high-risk neuroblastoma［J］. Nat Genet, 2023, 55(6): 1022－1033.
［21］Tan J, McLoone J K, Wakefield C E, et al. Neuroblastoma survivors' self-reported late effects, quality of life, health-care use, and risk perceptions［J］. Palliat Support Care, 2024, 22(2): 296－305.
［22］Lane D P. Cancer. p53, guardian of the genome［J］. Nature, 1992, 358(6381): 15－16.
［23］Bieging K T, Mello S S, Attardi L D. Unravelling mechanisms of p53-mediated tumour suppression［J］. Nat Rev Cancer, 2014, 14(5): 359－370.
［24］Stein Y, Rotter V, Aloni-Grinstein R. Gain-of-function mutant p53: all the roads lead to tumorigenesis［J］. Int J Mol Sci, 2019, 20(24): 6197.
［25］Patel K R, Patel H D. p53: an attractive therapeutic target for cancer［J］. Curr Med Chem, 2020, 27(22): 3706－3734.
［26］Carr-Wilkinson J, O'Toole K, Wood K M, et al. High frequency of p53/MDM2/p14ARF pathway abnormalities in relapsed neuroblastoma［J］. Clin Cancer Res, 2010, 16(4): 1108－1118.
［27］Maehama T, Nishio M, Otani J, et al. Nucleolar stress: molecular mechanisms and related human diseases［J］. Cancer Sci, 2023, 114(5): 2078－2086.
［28］Hannan K M, Soo P, Wong M S, et al. Nuclear stabilization of p53 requires a functional nucleolar surveillance pathway［J］. Cell Rep, 2022, 41(5): 111571.
［29］Zhu Y Q, Wang Y, Tao B X, et al. Nucleolar GTPase Bms1 displaces Ttf1 from RFB-sites to balance progression of rDNA transcription and replication［J］. J Mol Cell Biol, 2022, 13(12): 902－917.

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