Diagnostic relevance of circulating cell-free and exosomal microRNAs and long non-coding RNAs in blood of cancer patients

Abstract

MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) belong to a large group of non-coding RNA (ncRNA) molecules that possess diverse functions in epigenetic and chromatin structure modifications. In particular, they post-transcriptionally inhibit the protein expression of their target mRNAs and therefore, are involved in different tumor-associated signaling pathways. As the expression of both ncRNAs is frequently dysregulated in cancer and shows unique signatures, they may play a crucial role in cancer pathogenesis. They are passively and actively released into the blood circulation, and accordingly, their plasma/serum and exosomal profiles reflect disease development, tumor load and malignant progression towards metastatic relapse. Considering the biology and nature of ncRNAs in the regulation of different cellular processes, they may have potential clinical utility as blood-based tumor markers and future therapeutic targets in the treatment of cancer patients. The present review focuses on the diagnostic value of cellfree and exosomal ncRNAs in plasma/serum of cancer patients and the challenges to establish them as future tumor markers.Keywords: cell-free miRNAs; cell-free lncRNAs; exosomes; liquid biopsy.Zusammenfassung: MikroRNAs (miRNAs) und lange nicht-kodierende RNAs (lncRNAs) gehören zu einer großen Gruppe von nicht-kodierenden RNA-(ncRNA) Molekülen, die Funktionen bei epigenetischen und Chromatinstruktur-Modifikationen besitzen. Insbesondere inhibiieren sie post-transkriptionell die Proteinexpression ihrer Ziel-RNAs und sind deshalb in verschiedene Tumorassozi ierte Signalwege involviert. Da die Expression der beiden ncRNAs häufig bei Krebs dereguliert ist und einzigartige Signaturen aufweist, spielen sie eine wichtige Rolle in der Pathogenese von Krebs. Sie werden passiv und aktiv in den Blutkreislauf befreit und folglich reflektieren ihre Plasma/Serum-und exosomale Profile die Entwicklung der Krankheit, die Tumorlast und die maligne Progression bis hin zum metastatischen Relaps. Betreffend der Biologie und Natur der ncRNAs in der Regulation der verschiedenen zellulären Prozesse, sind sie als Blut-basierte Marker und zukünftige therapeutische Zielemoleküle bei der Behandlung von Krebspatienten für die Klinik potenziell wichtig. Der vorliegende Reviewartikel befasst sich mit dem diagnostischen Wert von zellfreien und exosomalen ncRNAs im Plasma/Serum von Krebspatienten und den Herausforderungen sie als zukünftige Tumormarker zu etablieren.Schlüsselwörter: Exosomen; flüssige Biopsie; zellfreie miRNAs; zellfreie lncRNAs.

Interplay of lncRNA H19/miR‐675 and lncRNA NEAT1/miR‐204 in breast cancer

“…Apoptotic and necrotic cells release ncRNAs that form complexes with specific RNA-binding proteins, such as AGO2 and HDL proteins, and/or integrate them in apoptotic bodies (Li et al, 2012;Schwarzenbach et al, 2014). ncRNAs are also released by exosomessmall membrane vesicles in size of approximately 100 nm that are actively secreted from multiple cell types, including dendritic cells, lymphocytes, and tumor cells, by exocytosis (Schwarzenbach, 2015(Schwarzenbach, , 2016b. This packaging protects ncRNAs against RNase digestion in the blood circulation and, consequently, provokes their highly stable circulation in blood (Mitchell et al, 2008).…”

“…LncRNAs can also modify gene expression through recruitment of histone modification complexes. Moreover, they are involved in alternative splicing and nuclear import (Schmitt and Chang, 2016;Schwarzenbach, 2016b). A particular feature is their interaction with miRNAs (Liu et al, 2014;Lu et al, 2016;Yoon et al, 2014) and/or to serve as precursors of miRNAs (Schwarzenbach, 2016a).…”

Serum Long-Noncoding RNA H19 and β-Catenin as Biomarkers for Early Diagnosis of Colorectal Cancer in Egyptian Patients: A Case Control Study

“…The H19 lncRNA enhances the invasive and migratory potential of cancer cells by regulating target genes. 11 Also, H19 can regulate the activity of β-catenin, 12 which is a protein encoded via the catenin β1 (CTNNB1) gene. Beta-catenin is a target for miR-148b miR-200a.…”