A Comprehensive Analysis Identified the Key Differentially Expressed Circular Ribonucleic Acids and Methylation-Related Function in Pheochromocytomas and Paragangliomas.

Anze Yu,Danlei Chen,Changsheng Xing,Yingxian Pang,Qiao Xiao,Longfei Liu,Xiongbing Zu,Liang Zhang,Minghao Li,Cikui Wang,Yong Wang

doi:10.3389/fgene.2020.00015

Abstract

We investigated differentially expressed circular RNAs (circRNAs) and their potential functions in pheochromocytomas and paragangliomas (PCC/PGLs). Expression levels of circRNAs in tumor and adjacent normal tissues from seven PCC/PGL patients were analyzed through RNA sequencing. Real-time PCR was conducted to verify the key candidates identified in the sequencing data. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to predict the functions of these circRNAs. A total of 367 circRNAs were found differentially expressed between tumor and normal samples. The top three histone methylation-related circRNAs (hsa_circ_0000567, hsa_circ_0002897, and hsa_circ_0004473) and their target microRNAs (miRNAs) were identified and validated. We then mapped the circRNA-miRNA-messenger RNA (mRNA) coding-noncoding gene co-expression (CNC) networks to show the potential binding relationships between circRNAs and their targets in PCC/PGLs. The top five mRNAs, 88 miRNAs, and 132 circRNAs related to pathogenesis were utilized to map the CNC network, and we observed that the interactions of these candidates with their target miRNAs regulated histone methylation and further mediated PCC/PGL pathogenesis. This study is the first to provide the whole profile of differentially expressed circRNAs in PCC/PGLs. Our data indicate that altered circRNAs may control the pathogenesis of PCC/PGLs by regulating histone methylation processes, highlighting their role as potential biomarkers.

Highlights

Pheochromocytomas and paragangliomas (PCC/PGLs) are highly genetically related, neuroendocrine tumors that have been listed as rare diseases by the World Health Organization (Neumann et al, 2019)
The density distribution of circRNAs on the chromosome is shown in Figure 1A. (Chromosome 1–9 and X were shown in the panel, details of circRNAs on all the chromosome can be seen in Supplementary Table 1 the density distribution of circRNAs on all the chromosome)
It has been reported that circRNAs act as RNA sponges, binding to their corresponding miRNAs to regulate the expression of target genes (Memczak et al, 2013)

Summary

Introduction

Pheochromocytomas and paragangliomas (PCC/PGLs) are highly genetically related, neuroendocrine tumors that have been listed as rare diseases by the World Health Organization (Neumann et al, 2019). Adrenal chromaffin cells secrete catecholamines and give rise to PCC/PGLs (Neumann et al, 2007; Neary et al, 2011; Gill et al, 2011). The major clinical manifestations of PCC/PGLs are unpredictable hypertension, cardiovascular crisis, hyperhidrosis, palpitations, and elevated basal metabolic rate, which are induced by the excessive secretion of catecholamines (Jochmanova and Pacak, 2016; Loper et al, 2016). Over 15 genomic and transcriptomic molecules reported to regulate PCC/PGL development, such as SDHx, VHL, TMEM127, HRAS, FGFR1, ATRX, RET, EPAS1, MAX, EGLN1, and NF1, were found mutated in the germline of PCC/PGLs patients (Gill et al, 2011; Castro-Vega et al, 2015; Rednam et al, 2017; Taieb and Pacak, 2017; Remacha et al, 2017; Pang et al, 2018)

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Results

Conclusion