Abstract
MiRNAs are increasingly recognized as biomarkers for the diagnosis of cancers where they are profiled from tumor tissue (intracellular miRNAs) or serum/plasma samples (extracellular miRNAs). To improve detection of reliable biomarkers from blood samples, we first compiled a healthy reference miRNome and established a well-controlled analysis pipeline allowing for standardized quantification of circulating miRNAs. Using whole miRNome and custom qPCR arrays, miRNA expression profiles were analyzed in 126 serum, whole blood and tissue samples of healthy volunteers and melanoma patients and in primary melanocyte and keratinocyte cell lines. We found characteristic signatures with excellent prognostic scores only in late stage but not in early stage melanoma patients. Upon comparison of melanoma tissue miRNomes with matching serum samples, several miRNAs were identified to be exclusively tissue-derived (miR-30b-5p, miR-374a-5p and others) while others had higher expression levels in serum (miR-3201 and miR-122-5p). Here we have compiled a healthy and widely applicable miRNome from serum samples and we provide strong evidence that levels of cell-free miRNAs only change significantly at later stages of melanoma progression, which has serious implications for miRNA biomarker studies in cancer.
Highlights
A key prerequisite to any successful cancer therapy is its early diagnosis
MiRNA expression patterns were compared between melanoma tissues and blood samples, which revealed a subset of selectively secreted miRNAs
We have recently shown that miR-211-5p has no evident role in inhibiting invasion of melanoma cells [34] as was claimed before [35,36,37] and we describe here that miR-2115p is highly overexpressed in serum of stage IV melanoma patients when compared to healthy controls
Summary
A key prerequisite to any successful cancer therapy is its early diagnosis. In order to detect malignancies as early as possible, a large number of tailored laboratory tests for detection of marker proteins, metabolites, specific mutations and imaging of concerned body regions as well as biomarker profiling are routinely used in various clinical settings (Cancer Facts and Figures, American Cancer Society, 2014). Considerable therapeutical progress has been made in recent years with the introduction of specific kinase www.impactjournals.com/oncotarget inhibitors targeting constitutively active BRAF present in more than 50% of melanoma patients Most such treated patients rapidly develop resistance against the drug requiring new and better therapies [9]. Using different profiling platforms and inputs and variable techniques for quality control, normalisation and statistical evaluation, reported results show very limited congruence Along these lines and regardless of the many publications claiming identification of specific miRNA biomarkers for cancer, several critical voices have recently summarised the technical and biological challenges of circulating miRNA profiling studies and they all together highlight the lack of consistency among published miRNA cancer signatures [6, 7, 18,19,20,21,22,23,24,25]. MiRNA expression patterns were compared between melanoma tissues and blood samples, which revealed a subset of selectively secreted miRNAs
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