Downregulation of the ubiquitin-e3 ligase rnf123 promotes upregulation of the nf-κb1 target serpine1 in aggressive glioblastoma tumors

Xiaowen Wang, Matias A. Bustos, Xiaoqing Zhang, Romela Irene Ramos, Cong Tan, Yuuki Iida, Shu Ching Chang, Matthew P. Salomon, Kevin Tran, Rebecca Gentry, Yelena Kravtsova-Ivantsiv, Daniel F. Kelly, Gordon B. Mills, Aaron Ciechanover, Ying Mao, Dave S.B. Hoon

    Research output: Contribution to journalArticle

    Abstract

    This study examined the role of the ubiquitin E3-ligase RNF123 in modulating downstream NF-κB1 targets in glioblastoma (GB) tumor progression. Our findings revealed an oncogenic pathway (miR-155-5p-RNF123-NF-κB1-p50-SerpinE1) that may represent a new therapeutic target pathway for GB patients with isocitrate dehydrogenase 1 and 2 (IDH) WT (wild type). Mechanistically, we demonstrated that RNF123 is downregulated in IDH WT GB patients and leads to the reduction of p50 levels. RNA-sequencing, reverse-phase protein arrays, and in vitro functional assays on IDH WT GB cell lines with RNF123 overexpression showed that SerpinE1 was a downstream target that is negatively regulated by RNF123. SERPINE1 knockdown reduced the proliferation and invasion of IDH WT GB cell lines. Both SerpinE1 and miR-155-5p overexpression negatively modulated RNF123 expression. In clinical translational analysis, RNF123, SerpinE1, and miR-155-5p were all associated with poor outcomes in GB patients. Multivariable analysis in IDH WT GB patients showed that concurrent low RNF123 and high SerpinE1 was an independent prognostic factor in predicting poor overall survival (p < 0.001, hazard ratio (HR) = 2.93, 95% confidence interval (CI) 1.7–5.05), and an increased risk of recurrence (p < 0.001, relative risk (RR) = 3.56, 95% CI 1.61–7.83).

    Original languageEnglish (US)
    Article number1081
    JournalCancers
    Volume12
    Issue number5
    DOIs
    StatePublished - May 2020

    Keywords

    • KPC1
    • MiR-155
    • NF-κB pathway
    • P50
    • PAI-1

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

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  • Cite this

    Wang, X., Bustos, M. A., Zhang, X., Ramos, R. I., Tan, C., Iida, Y., Chang, S. C., Salomon, M. P., Tran, K., Gentry, R., Kravtsova-Ivantsiv, Y., Kelly, D. F., Mills, G. B., Ciechanover, A., Mao, Y., & Hoon, D. S. B. (2020). Downregulation of the ubiquitin-e3 ligase rnf123 promotes upregulation of the nf-κb1 target serpine1 in aggressive glioblastoma tumors. Cancers, 12(5), [1081]. https://doi.org/10.3390/cancers12051081