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

1
Department of Translational Molecular Medicine, John Wayne Cancer Institute (JWCI) at Providence Saint John’s Health Center, Santa Monica, CA 90404, USA
2
Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200040, China
3
Department of Pathology, Cancer Hospital, Fudan University, Shanghai 200032, China
4
Medical Data Research Center, Providence Saint Joseph’s Health, Portland, OR 97225, USA
5
The David and Janet Polak Cancer and Vascular Biology Research Center, The Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Efron Street, Bat-Galim, Haifa 31096, Israel
6
Pacific Neuroscience Institute, JWCI, Santa Monica, CA 90404, USA
7
Department of Cell Development and Cancer Biology, Knight Cancer Institute, Portland, OR 97239, USA
8
The Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Cancers 2020, 12(5), 1081; https://doi.org/10.3390/cancers12051081
Received: 25 March 2020 / Revised: 22 April 2020 / Accepted: 25 April 2020 / Published: 27 April 2020
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). View Full-Text
Keywords: p50; miR-155; PAI-1; KPC1; NF-κB pathway p50; miR-155; PAI-1; KPC1; NF-κB pathway
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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. Downregulation of the Ubiquitin-E3 Ligase RNF123 Promotes Upregulation of the NF-κB1 Target SerpinE1 in Aggressive Glioblastoma Tumors. Cancers 2020, 12, 1081.

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