MicroRNAs, Long Non-Coding RNAs, and Circular RNAs: Potential Biomarkers and Therapeutic Targets in Pheochromocytoma/Paraganglioma

Abstract

Around 40% of pheochromocytomas/paragangliomas (PPGL) harbor germline mutations, representing the highest heritability among human tumors. All PPGL have metastatic potential, but metastatic PPGL is overall rare. There is no available molecular marker for the metastatic potential of these tumors, and the diagnosis of metastatic PPGL can only be established if metastases are found at "extra-chromaffin" sites. In the era of precision medicine with individually targeted therapies and advanced care of patients, the treatment options for metastatic pheochromocytoma/paraganglioma are still limited. With this review we would like to nurture the idea of the quest for non-coding ribonucleic acids as an area to be further investigated in tumor biology. Non-coding RNA molecules encompassing microRNAs, long non-coding RNAs, and circular RNAs have been implicated in the pathogenesis of various tumors, and were also proposed as valuable diagnostic, prognostic factors, and even potential treatment targets. Given the fact that the pathogenesis of tumors including pheochromocytomas/paragangliomas is linked to epigenetic dysregulation, it is reasonable to conduct studies related to their epigenetic expression profiles and in this brief review we present a synopsis of currently available findings on the relevance of these molecules in these tumors highlighting their diagnostic potential.

Keywords: biomarker; genetics; malignancy; non-coding RNA; paraganglioma; pheochromocytoma; treatment.

Figure 1

Clinically relevant functions of the four molecular pathways contributing to pheochromocytomas/paragangliomas (PPGL). (A) Wnt-Hedgehog overexpressed subtype included mainly adrenal sporadic pheochromocytomas and high chromogranin A levels. MAML3 and CSDE1 are independently important driver mutations leading to Wnt-Hedgehog activation. (B) Kinase signaling pathway is correlated to pheochromocytomas of adrenergic phenotype due to overexpression of PNMT, comprising somatic- and germline mutations and chromosomal deletions, as well. (C): Pseudohypoxia subtype, in addition to somatic- and germline mutations and chromosomal amplification, also exhibited overexpression of miR-210. (D) Overexpression of CYP11B1, CYP21A2, and STAR adrenal cortex markers was characteristic to cortical admixture subtype, along with MAX mutation in PPGL. g. mutation: germline mutation; s. mutation: somatic mutation; s.g. mutation: somatic and germline mutation; WNT4: wingless-related integration site 4; DVL3: dishevelled 3; CHGA: encodes chromogranin A (CgA); NET: neuroendocrine tumor; MAML3: mastermind-like transcriptional coactivator 3; CSDE1: cold shock domain containing E1; RAS: rat entry sarcoma; MAPK: mitogen-activated protein kinase; PNMT: phenylethanolamine N-methyltransferase; NE: norepineprhrine; E: epinephrine; RET: rearranged during transfection; TMEM127: transmembrane protein 127; HRAS: Harvey rat sarcoma viral oncogene homolog; NF1: neurofibromatosis 1; BRAF: v-raf murine sarcoma viral oncogene homolog B1; NGFR: nerve growth factor receptor; SDH: succinate dehydrogenase; VHL: Von-Hippel Lindau; EPAS1: endothelial PAS domain 1; CYP11B1: cytochrome P450 family 11 subfamily B member 1; CYP21A2: cytochrome P450 family 21 subfamily A member 2; STAR: steroid acute regulatory protein; MAX: myc associated factor X.

Figure 2

Overview of functions and localization of non-coding RNAs. RBP: RNA binding protein; NPC: nuclear pore complex. Faded arrowhead lines indicate activation; faded blunt-head lines indicate inhibition.

Figure 3

miRNA interactions in pheochromocytoma: Transmembrane tyrosine kinase receptor activation is the first step in the mTOR signaling pathway; thunderbolt represents activation of mTOR pathway in pheochromocytoma; P indicates phosphorylation sites; blunt-head lines indicate inhibition; faded arrows indicate downstream activation; solid arrows indicate direct activation; right-angle arrow indicates gene expression. Abbreviations: BSN-AS2: long non-coding RNA BSN-AS2; OS: overall survival; PTPRJ: receptor-type tyrosine-protein phosphatase eta; TGFBR3: transforming growth factor beta receptor 3; PI3K: phosphoinositide 3-kinase; PTEN: phosphatase and tensin homolog; PDK1: phosphoinositide-dependent kinase 1; AKT1: a serine/threonine protein kinase; TSC1/2: tuberous sclerosis complex subunit 1; Rheb: Ras homolog enriched in brain; GTP: guanosine triphosphate; GDP: guanosine diphosphate; mTROC1: mammalian target of rapamycin complex 1; rapamycin: mTOR inhibitor; UCA1: long non-coding RNA urothelial cancer associated 1; SOX6: SRY (sex determining region Y)-box 6; HIF-1 α/β: hypoxia inducible factor 1 subunit α/β; HRE: hypoxia response element; PC-12: pheochromocytoma 12 cell line, OS: overall survival. Note that miR-18 mediated down-regulation of HIF-1α has only been established in lung cancer stem-like cells, choroidal endothelial cells, and in breast cancer xenograft model and not yet in pheochromocytoma cells.