MUDENG Expression Profiling in Cohorts and Brain Tumor Biospecimens to Evaluate Its Role in Cancer.

Juhyun Shin,Jae-Wook Oh,Jeongheon Oh,Seunghwa Jung,Somi Jeong,Se-Hyuk Kim,Jaehong Ahn,Man Hee Rhee,Jun-Ha Choi,Do-Young Yoon

doi:10.3389/fgene.2019.00884

Abstract

Mu-2-related death-inducing gene (MUDENG, MuD) has been reported to be involved in the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-associated apoptotic pathway of glioblastoma multiforme (GBM) cells; however, its expression level, interactors, and role in tumors are yet to be discovered. To investigate whether MuD expression correlates with cancer progression, we analyzed The Cancer Genome Atlas (TCGA) database using UALCAN and Gene Expression Profiling Interactive Analysis (GEPIA). Differential expression of MuD was detected in 6 and 10 cancer types, respectively. Validation performed using data from the Gene Expression Omnibus database showed that MuD expression is downregulated in KIRC tumor and correlate with higher chance of survival. Upregulation of MuD expression in GBM tumors was detected through GEPIA and high MuD expression correlated with higher survival in proneural GBM, whereas the opposite was observed in classical GBM subtype. GBM biospecimens analysis shows that MuD protein level was upregulated in three of six specimens, whereas mRNA level remained relatively unaltered. Therefore, MuD may exert differential effects according to subtypes, and/or be subjected to post-translational regulation in GBM. Correlation analysis between GBM cohort database and experiments using GBM cell lines revealed its positive effect on regulation of protein phosphatase 2 regulatory subunit B’Epsilon (PPP2R5E) and son of sevenless homolog 2 (SOS2). STRING database analysis indicated that the components of adaptor protein complexes putatively interacted with MuD but showed no correlation in terms of survival of patients with different GBM subtypes. In summary, we analyzed the expression of MuD in publicly available cancer patient data sets, GBM cell lines, and biospecimens to demonstrate its potential role as a biomarker for cancer prognosis and identified its candidate interacting molecules.

Highlights

Glioblastoma multiforme (GBM) is the most common and malignant form of primary brain tumor (Huse and Holland, 2010; Siegel et al, 2017)
MuD expression in tumors was upregulated as compared with that in normal tissues in 9 of the 10 cancer types identified by Gene Expression Profiling Interactive Analysis (GEPIA) versus only two of the eight cancer types identified with UALCAN
MuD expression was downregulated only in kidney renal clear cell carcinoma (KIRC) tumor tissues, as per GEPIA analysis, but three additional cancer types were identified with UALCAN

Summary

Introduction

Glioblastoma multiforme (GBM) is the most common and malignant form of primary brain tumor (Huse and Holland, 2010; Siegel et al, 2017). Aside from the conventional therapies, the selective induction of apoptosis in target cancer cells with pro-apoptotic cytokines, such as tumor necrosis factor-related apoptosisinducing ligand (TRAIL) (Merino et al, 2007) seems promising, as this strategy exhibited low toxicity to non-cancerous cells, including brain cells, in clinical trials (Stuckey and Shah, 2013). The molecular profiling of The Cancer Genome Atlas (TCGA) divides GBM into four distinctive subtypes, namely, classical, neural, proneural, and mesenchymal (Verhaak et al, 2010). Both classical and mesenchymal subtypes are aggressive in nature. A recent report revealed increased sensitivity of patients with proneural GBM to cyclin-dependent kinase 4/6 (CDK4/6) inhibitor treatment (Li et al, 2017) and significantly faster recurrence after bevacizumab treatment in patients with classic GBM (Hovinga et al, 2019), indicating the importance of careful evaluation of the subtypes before treatment

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