Gene expression profiles between cystic and solid vestibular schwannoma indicate susceptible molecules and pathways in the cystic formation of vestibular schwannoma

Shuang Yan,Zhihua Zhang,Quan Wang,Zhaoyan Wang,Zirong Huo,Xiaoling Yin,Tao Yang,Hao Wu

doi:10.1007/s10142-019-00672-5

Abstract

Previous research has shown that although NF2 gene mutation is the major cause of vestibular schwannoma (VS), it may not directly participate in cystic VS (CVS). To elucidate the underlying potential genetic mechanisms in the cystic formation of VS, we compared differences in gene expression between solid VS (SVS) and CVS via a bioinformatics analysis. The cDNA microarray method and miRNA sequencing were performed on 29 representative VSs (17 CVSs and 12 SVSs). A differential expression analysis was used to identify differentially expressed mRNAs (DEmRNAs) and miRNAs (DEmiRNAs). Then, miRNA–mRNA regulatory networks were constructed. Gene ontology (GO), a KEGG pathway enrichment analysis, and the protein–protein interaction (PPI) were used to analyze the co-differentially expressed DEmRNAs at the functional level. From the differential expression analyses, 1304 DEmRNAs, 55 DEmiRNAs, and hub genes including PTEN, FOXO1, FOXO3, VEGFA, and SIRT1 were identified. Histological evidence is presented to confirm the makeup of the hubs, which corresponded with the cDNA microarray. Our analysis revealed that the maps of apoptosis, cellular response to hypoxia, and the PI3K-Akt, AMPK, FOXO, and chemokine signaling pathways were significantly enriched. In addition, the TUNEL assay, immunoblotting analysis, and transmission electron microscope revealed increased degenerative changes in CVS. These findings could be the foundation for understanding the potential role of differential genes in the cystic formation of VS and be helpful in exploring the potential biomarkers for the differential diagnosis, prognosis, and development of drug targets for CVS.

Highlights

Vestibular schwannoma (VS) arises from the vestibular branch of the eighth cranial nerve, accounting for 6–8% of all intracranial tumors(Wandong et al 2005; Piccirillo et al 2009)
cystic VS (CVS) is estimated to constitute 6.8 to 20.4% of VS(Jones et al 2007; Sinha and Sharma 2008; Piccirillo et al 2009; Jian et al 2011) and is characterized by aggressive clinical features, such as a rapid rate of tumor expansion(Selesnick and Johnson 1998), frequent adherence to the facial nerve(de Ipolyi et al 2008), and unpredictable biological behavior(Moon et al 2007; Mehrotra et al 2008). It often presents a predicament for neurotologists in choosing management options for cystic vestibular schwannomas: observation will delay the optimal treatment time due to sudden or persistent fast growth, radiotherapy may increase the risk of rapid cyst expansion, and microsurgical resection could achieve poorer postoperative functional outcomes compared with solid lesions(Sinha and Sharma 2008)
The t-distributed stochastic neighbor embedding (t-SNE) of the complementary DNA (cDNA) microarray and miRNA sequencing data demonstrated the global separation of the CVS and solid VS (SVS) samples (Supplementary Fig. 2A and Fig. 2b)

Summary

Introduction

Vestibular schwannoma (VS) arises from the vestibular branch of the eighth cranial nerve, accounting for 6–8% of all intracranial tumors(Wandong et al 2005; Piccirillo et al 2009). CVS is estimated to constitute 6.8 to 20.4% of VS(Jones et al 2007; Sinha and Sharma 2008; Piccirillo et al 2009; Jian et al 2011) and is characterized by aggressive clinical features, such as a rapid rate of tumor expansion(Selesnick and Johnson 1998), frequent adherence to the facial nerve(de Ipolyi et al 2008), and unpredictable biological behavior(Moon et al 2007; Mehrotra et al 2008) It often presents a predicament for neurotologists in choosing management options for cystic vestibular schwannomas: observation will delay the optimal treatment time due to sudden or persistent fast growth, radiotherapy may increase the risk of rapid cyst expansion (de Ipolyi et al 2008), and microsurgical resection could achieve poorer postoperative functional outcomes compared with solid lesions(Sinha and Sharma 2008)

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