Transcriptional co-expression regulatory network analysis for Snail and Slug identifies IL1R1, an inflammatory cytokine receptor, to be preferentially expressed in ST-EPN-RELA and PF-EPN-A molecular subgroups of intracranial ependymomas.

Prit Benny Malgulwar,Chitra Sarkar,Chaitenya Verma,Vikas Sharma,Ashutosh Singh Tomar,Manmohan Singh,Mehar Chand Sharma,Aruna Nambirajan,Vaishali Suri

doi:10.18632/oncotarget.26211

Abstract

Recent molecular subgrouping of ependymomas (EPN) by DNA methylation profiling has identified ST-EPN-RELA and PF-EPN-A subgroups to be associated with poor outcome. Snail/Slug are cardinal epithelial-to-mesenchymal transcription factors (EMT-TFs) and are overexpressed in several CNS tumors, including EPNs. A systematic analysis of gene-sets/modules co-expressed with Snail and Slug genes using published expression microarray dataset (GSE27279)identified 634 genes for Snail with enriched TGF-β, PPAR and PI3K signaling pathways, and 757 genes for Slug with enriched focal adhesion, ECM-receptor interaction and regulation of actin cytoskeleton related pathways. Of 37 genes commonly expressed with both Snail and Slug, IL1R1, a cytokine receptor of interleukin-1 receptor family, was positively correlated with Snail (r=0.43) and Slug (r=0.51), preferentially expressed in ST-EPN-RELA and PF-EPN-A molecular groups, and enriched for pathways related to inflammation, angiogenesis and glycolysis. IL1R1 expression was fairly specific to EPNs among various CNS tumors analyzed. It also showed significant positive correlation with EMT, stemness and MDSC (myeloid derived suppressor cell) markers. Our study reports IL1R1 as a poor prognostic marker associated with EMT-like phenotype and stemness in EPNs. Our findings emphasize the need to further examine and validate IL1R1 as a novel therapeutic target in aggressive subsets of intracranial EPNs.

Highlights

Ependymomas (EPN) are uncommon gliomas that recapitulate the ependymal cells lining the ventricles and spinal cord [1]
A total of 75 in-house samples of Grade II/III ependymomas were included in the study, subdivided into five clinico-pathologic-molecular subgroups, viz. STRELA+, ST-RELA, posterior fossa (PF)-A, PF-B and SP, based on site, C11orf95-RELA fusions, and age
Among the 37 genes, the expression of IL1R1, a cytokine receptor belonging to the interleukin-1 receptor family, was selectively high in the most aggressive molecular subgroups viz. STEPN-RELA and PF-EPN-A leading us to explore IL1R1 further

Summary

Introduction

Ependymomas (EPN) are uncommon gliomas that recapitulate the ependymal cells lining the ventricles and spinal cord [1]. They occur throughout the neuraxis and are the third most common central nervous system (CNS) neoplasm in children [1]. Large scale DNA methylation profiling has delineated nine molecular subgroups that predict www.oncotarget.com outcome better than World Health Organisation (WHO) histological grade [1, 6]. The two largest subgroups: ST-EPN-RELA and PF-EPN-A, represented by supratentorial (ST) WHO Grade II/III EPNs harboring RELA fusions and posterior fossa (PF) WHO Grade II/III childhood EPNs with a CpG island methylator phenotype (CIMP) respectively, are associated with extremely poor outcomes [1, 6,7,8]. Further insights into the pathogenesis of these enigmatic tumors, of the aggressive subgroups, are necessary to identify newer prognostic markers and therapeutic targets and thereby, devise alternate treatment modalities

Objectives

Methods

Results

Conclusion