Pheochromocytoma (PCC) and paraganglioma (PGL) are rare neuroendocrine neoplasias of neural crest origin that can be part of several inherited syndromes. Although their mRNA profiles are known to depend on genetic background, a number of questions related to tumor biology and clinical behavior remain unanswered. Since microRNAs are key players in the modulation of gene expression, their comprehensive analysis could resolve some of these issues. Through characterization of microRNA profiles in 69 frozen tumors with germline mutations in the genes SDHD, SDHB, VHL, RET, NF1, TMEM127, and MAX, we identified microRNA signatures specific to, as well as common among, the genetic groups of PCC/PGLs. MicroRNA expression profiles were validated in an independent series of 30 composed of VHL-, SDHB-, SDHD- and RET-related formalin-fixed paraffin-embedded PCC/PGL samples using qRT-PCR. Up-regulation of miR-210 in VHL- and SDHB-related PCC/PGL, while miR-137 and miR-382 were confirmed as generally up-regulated in PCC/PGL (except in MAX-related tumors). Also, we confirmed over-expression of miR-133b as VHL-specific, miR-488 and miR-885-5p as RET-specific, and miR-183 and miR-96 as SDHB-specific microRNAs.To determine the potential roles microRNAs play in PCC/PGL pathogenesis, we performed bioinformatic integration and pathway analysis using matched mRNA profiling data that indicated a common enrichment of pathways associated with neuronal and neuroendocrine-like differentiation. We demonstrated that miR-183 and/or miR-96 impede NGF-induced differentiation in PC12 cells. Finally, global proteomic analysis in SDHB and MAX-tumors allowed us to determine that microRNA regulation occurs primarily through mRNA degradation in PCC/PGL, which partially confirmed our miRNA-mRNA integration results.

Integrative analysis of miRNA and mRNA expression profiles in pheochromocytoma and paraganglioma identifies genotype-specific markers and potentially regulated pathways.

OPOCHER, GIUSEPPE;
2013

Abstract

Pheochromocytoma (PCC) and paraganglioma (PGL) are rare neuroendocrine neoplasias of neural crest origin that can be part of several inherited syndromes. Although their mRNA profiles are known to depend on genetic background, a number of questions related to tumor biology and clinical behavior remain unanswered. Since microRNAs are key players in the modulation of gene expression, their comprehensive analysis could resolve some of these issues. Through characterization of microRNA profiles in 69 frozen tumors with germline mutations in the genes SDHD, SDHB, VHL, RET, NF1, TMEM127, and MAX, we identified microRNA signatures specific to, as well as common among, the genetic groups of PCC/PGLs. MicroRNA expression profiles were validated in an independent series of 30 composed of VHL-, SDHB-, SDHD- and RET-related formalin-fixed paraffin-embedded PCC/PGL samples using qRT-PCR. Up-regulation of miR-210 in VHL- and SDHB-related PCC/PGL, while miR-137 and miR-382 were confirmed as generally up-regulated in PCC/PGL (except in MAX-related tumors). Also, we confirmed over-expression of miR-133b as VHL-specific, miR-488 and miR-885-5p as RET-specific, and miR-183 and miR-96 as SDHB-specific microRNAs.To determine the potential roles microRNAs play in PCC/PGL pathogenesis, we performed bioinformatic integration and pathway analysis using matched mRNA profiling data that indicated a common enrichment of pathways associated with neuronal and neuroendocrine-like differentiation. We demonstrated that miR-183 and/or miR-96 impede NGF-induced differentiation in PC12 cells. Finally, global proteomic analysis in SDHB and MAX-tumors allowed us to determine that microRNA regulation occurs primarily through mRNA degradation in PCC/PGL, which partially confirmed our miRNA-mRNA integration results.
2013
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11577/2578076
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