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

Abstract

// Prit Benny Malgulwar 1 , Vikas Sharma 1 , Ashutosh Singh Tomar 2 , Chaitenya Verma 1 , Aruna Nambirajan 1 , Manmohan Singh 3 , Vaishali Suri 1 , Chitra Sarkar 1 and Mehar Chand Sharma 1 1 Department of Pathology, All India Institute of Medical Sciences, New Delhi-110029, India 2 Center for Cellular and Molecular Biology&ndash;Council of Scientific and Industrial Research (CCMB-CSIR), Hyderabad, Telangana-500007, India 3 Department of Neurosurgery, All India Institute of Medical Sciences, New Delhi-110029, India Correspondence to: Mehar Chand Sharma, email: sharmamehar@yahoo.co.in Keywords: ependymoma; ST-EPN-RELA and PF-EPN-A molecular groups; co-expression study; Snail and Slug; IL1R1 Received: April 16, 2018&nbsp;&nbsp;&nbsp;&nbsp; Accepted: September 08, 2018&nbsp;&nbsp;&nbsp;&nbsp; Published: October 26, 2018 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-&beta;, 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.