ELMOD2 Overexpression Predicts Adverse Outcomes and Regulates Tumor Progression in Gliomas

Abstract

Objective

Glioma is a highly heterogeneous and malignant intracranial tumor that presents challenges for clinical treatment. ELMO domain containing 2 (ELMOD2) is a GTPase-activating protein that regulates a range of cellular biological processes. However, its specific role and prognostic value in tumorigenesis are still unknown. This study aimed to assess the prognostic relevance and signaling function of ELMOD2 in gliomas.

Methods

The Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA) databases were utilized to conduct a comprehensive analysis of the expression profile of ELMOD2 in gliomas, elucidating its associations with clinicopathological parameters and patient prognosis. Single-cell analysis was performed to characterize ELMOD2 expression across distinct glioma cell subpopulations. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, and Gene Set Variation Analysis (GSVA) were employed to evaluate the potential biological functions of ELMOD2 in gliomagenesis. Specific small interfering RNAs (siRNAs) were used to knock down ELMOD2 in the glioma cell lines U251 and A172 to assess their cellular behaviors and examine the levels of multiple key signaling molecules associated with the occurrence of gliomas.

Results

ELMOD2 was overexpressed in gliomas, and this upregulation was correlated with tumor grade, isocitrate dehydrogenase mutation, and 1p/19q codeletion status. Notably, ELMOD2 expression was elevated in classical and mesenchymal subtypes, and single-cell resolution analysis revealed predominant enrichment within malignant cells. Functionally, ELMOD2 regulated cell cycle progression, and its overexpression was related to independent adverse outcomes. In vitro experiments revealed that ELMOD2 was located in the cytoplasm and nucleoplasm. Furthermore, ELMOD2 knockdown reduced proliferation, migration, and invasion and increased apoptosis in U251 and A172 cell lines. Finally, ELMOD2 knockdown significantly decreased p-Erk1/2.

Conclusions

ELMOD2 expression in glioma is positively correlated with tumorigenesis and is a crucial independent prognostic marker. Thus, ELMOD2 is a promising biomarker and therapeutic target for glioma treatment.

Keywords

ELMO domain containing 2 / Glioma / Prognostic marker / Tumor progression / Cell cycle regulation / GTPase-activating protein

References

[1] GBD 2016 Brain and Other CNS Cancer Collaborators. Global regional, and national burden of brain and other CNS cancer 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol., 2019, 18(4): 376-393.

[2] StuppR, van den BentMJ, HegiME. Optimal role of temozolomide in the treatment of malignant gliomas. Curr Neurol Neurosci Rep., 2005, 5(3): 198-206.

[3] HuH, MuQ, BaoZ, et al.. Mutational landscape of secondary glioblastoma guides MET-targeted trial in brain tumor. Cell., 2018, 175(6): 1665-1678.e18.

[4] EastMP, BowzardJB, DacksJB, et al.. ELMO domains, evolutionary and functional characterization of a novel GTPase-activating protein (GAP) domain for Arf protein family GTPases. J Biol Chem., 2012, 287(47): 39538-39553.

[5] ZhouCX, ShiLY, LiRC, et al.. GTPase-activating protein Elmod2 is essential for meiotic progression in mouse oocytes. Cell Cycle., 2017, 16(9): 852-860.

[6] TurnRE, EastMP, PrekerisR, et al.. The ARF GAP ELMOD2 acts with different GTPases to regulate centrosomal microtubule nucleation and cytokinesis. Mol Biol Cell., 2020, 31(18): 2070-2091.

[7] NewmanLE, SchiavonCR, TurnRE, et al.. The ARL2 GTPase regulates mitochondrial fusion from the intermembrane space. Cell Logist., 2017, 73e1340104.

[8] SchiavonCR, TurnRE, NewmanLE, et al.. ELMOD2 regulates mitochondrial fusion in a mitofusin-dependent manner, downstream of ARL2. Mol Biol Cell., 2019, 30(10): 1198-1213.

[9] TocciS, IbeawuchiSR, DasS, et al.. Role of ELMO1 in inflammation and cancer-clinical implications. Cell Oncol (Dordr)., 2022, 45(4): 505-525.

[10] WangY, LiH, LiF. ELMO2 association with Gαi2 regulates pancreatic cancer cell chemotaxis and metastasis. PeerJ., 2020, 8e8910.

[11] HuY, YuQ, ZhongY, et al.. Silencing ELMO3 inhibits the growth, invasion, and metastasis of gastric cancer. Biomed Res Int., 2018, 20183764032.

[12] ZhaoZ, ZhangKN, WangQ, et al.. Chinese glioma genome atlas (CGGA): a comprehensive resource with functional genomic data from chinese glioma patients. Genom Proteom Bioinf., 2021, 19(1): 1-12.

[13] VerhaakRG, HoadleyKA, PurdomE, et al.. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell., 2010, 17(1): 98-110.

[14] HuseJT, PhillipsHS, BrennanCW. Molecular subclassification of diffuse gliomas: seeing order in the chaos. Glia., 2011, 59(8): 1190-1199.

[15] PhillipsHS, KharbandaS, ChenR, et al.. Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell., 2006, 9(3): 157-173.

[16] SherrCJ. Cancer cell cycles. Science., 1996, 274(5293): 1672-1677.

[17] WongRS. Apoptosis in cancer: from pathogenesis to treatment. J Exp Clin Cancer Res., 2011, 30187.

[18] HuangY, HongW, WeiX. The molecular mechanisms and therapeutic strategies of EMT in tumor progression and metastasis. J Hematol Oncol., 2022, 151129.

[19] CaoZQ, WangZ, LengP. Aberrant N-cadherin expression in cancer. Biomed Pharmacother., 2019, 118109320.

[20] BlaschukOW. N-cadherin antagonists as oncology therapeutics. Philos Trans R Soc Lond B Biol Sci., 2015, 370166120140039.

[21] MariottiA, PerottiA, SessaC, et al.. N-cadherin as a therapeutic target in cancer. Expert Opin Investig Drugs., 2007, 16(4): 451-465.

[22] ZhuM, LiuD, LiuG, et al.. Caspase-linked programmed cell death in prostate cancer: from apoptosis, necroptosis, and pyroptosis to PANoptosis. Biomolecules., 2023, 13121715.

[23] FuY, YangG, ZhuF, et al.. Antioxidants decrease the apoptotic effect of 5-Fu in colon cancer by regulating Src-dependent caspase-7 phosphorylation. Cell Death Dis., 2014, 51e983.

[24] LeeSY, ChoiYY, ChoiJE, et al.. Polymorphisms in the caspase genes and the risk of lung cancer. J Thorac Oncol., 2010, 5(8): 1152-1158.

[25] RoskoskiRJr. ERK1/2 MAP kinases: structure, function, and regulation. Pharmacol Res., 2012, 66(2): 105-143.

[26] UllahR, YinQ, SnellAH, et al.. RAF-MEK-ERK pathway in cancer evolution and treatment. Semin Cancer Biol., 2022, 85: 123-154.

Funding

Natural Science Foundation of Guangxi Province(No: 2022GXNSFAA035639)

National Natural Science Foundation of China(NO.81860445)

the Innovation Project of Guangxi Graduate Education(NO.YCBZ2024118)

RIGHTS & PERMISSIONS

The Author(s), under exclusive licence to Huazhong University of Science and Technology