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

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.

SUBMITTER: Yu A

PROVIDER: S-EPMC7052364 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Yu Anze A Li Minghao M Xing Changsheng C Chen Danlei D Wang Cikui C Xiao Qiao Q Zhang Liang L Pang Yingxian Y Wang Yong Y Zu Xiongbing X Liu Longfei L

Frontiers in genetics 20200225

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 ...[more]

PMID: 32161614

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Project description:Pheochromocytomas and paragangliomas are neuroendocrine tumors shown to be responsive to multitargeted tyrosine kinase inhibitor (TKI) treatment. Despite growing knowledge regarding their genetic basis, the ability to predict behavior in these tumors remains challenging. There is also limited knowledge of their tyrosine kinase receptor expression and whether the clinical response observed to the TKI sunitinib relates only to its anti-angiogenic properties or also due to a direct effect on tumor cells. To answer these questions, an in vitro model of sunitinib treatment of a pheochromocytoma cell line was created. Sunitinib targets (VEGFRs, PDGFRs, and C-KIT), FGFRs, and cell cycle regulatory proteins were investigated in human tissue microarrays. SDHB immunohistochemistry was used as a surrogate marker for the presence of succinate dehydrogenase mutations. The FGFR4 G388R single nucleotide polymorphism was also investigated. Sunitinib treatment in vitro decreases cell proliferation mainly by targeting cell cycle, DNA metabolism, and cell organization genes. FGFR1, -2, and -4, VEGFR2, PDGFRα, and p16 were overexpressed in primary human pheochromocytomas and paragangliomas. Discordant results were observed for VEGFR1, p27, and p21 overexpressed in paragangliomas but underexpressed in pheochromocytomas; PDGFRβ, Rb, and Cyclin D1 overexpressed in paragangliomas only; and FGFR3 overexpressed in pheochromocytomas and underexpressed in paragangliomas. Low expression of C-KIT, p53, and Aurora kinase A and B was observed. Nuclear FGFR2 expression was associated with increased risk of metastasis (odds ratio (OR)=7.61, P=0.008), as was membranous PDGFRα (OR=13.71, P=0.015), membranous VEGFR1 (OR=8.01, P=0.037), nuclear MIB1 (OR=1.26, P=0.008), and cytoplasmic p27 (OR=1.037, P=0.030). FGFR3, VEGFR2, and C-KIT levels were associated with decreased risk of metastasis. We provide new insights into the mechanistic actions of sunitinib in pheochromocytomas and paragangliomas, and support current evidence that multitargeted TKIs might be a suitable treatment alternative for these tumors.

Dataset Information

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

Publications

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

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