Downregulation of the Ubiquitin-E3 Ligase RNF123 Promotes Upregulation of the NF-κB1 Target SerpinE1 in Aggressive Glioblastoma Tumors.

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

doi:10.3390/cancers12051081

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).

Highlights

Glioblastoma (GB) is one of the most common, and most aggressive, intracranial malignancies in humans [1]
By using the RNA-sequencing data from the The Cancer Genome Atlas (TCGA) dataset for GB, brain tumors with isocitrate dehydrogenase and 2 (IDH) WT status showed a significant reduction in RNF123 expression compared to normal brain tissue, but not in IDH mutated GB compared to normal brain tissue (Figure 1C)
The results demonstrated that GB patients with IDH WT and low

Summary

Introduction

Glioblastoma (GB) is one of the most common, and most aggressive, intracranial malignancies in humans [1]. In the current standard of care, the median survival time in GB patients is around. Considerable basic and clinical research advancement has occurred over the past decade, there is still a need for: (a) improvement in staging and treatment,. (b) understanding the molecular pathways that drive pathobiology in GB patients, (c) identifying targets for treatment, and (d) finding prognostic factors associated with overall survival (OS) and recurrence in particular subgroup GB populations [2,4,5]. According to the WHO (World Health Organization), GB patients are classified into three subgroups based on the isocitrate dehydrogenase 1 (IDH1) and 2. Despite the efforts made to classify GB tumors, the majority of GB patients receive the same treatments [4]

Methods

Results

Discussion

Conclusion