Sex-Specific miRNA Differences in Liquid Biopsies from Subjects with Solid Tumors and Healthy Controls (original) (raw)
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New Concepts in Cancer Biomarkers: Circulating miRNAs in Liquid Biopsies
International journal of molecular sciences, 2016
The effective and efficient management of cancer patients relies upon early diagnosis and/or the monitoring of treatment, something that is often difficult to achieve using standard tissue biopsy techniques. Biological fluids such as blood hold great possibilities as a source of non-invasive cancer biomarkers that can act as surrogate markers to biopsy-based sampling. The non-invasive nature of these "liquid biopsies" ultimately means that cancer detection may be earlier and that the ability to monitor disease progression and/or treatment response represents a paradigm shift in the treatment of cancer patients. Below, we review one of the most promising classes of circulating cancer biomarkers: microRNAs (miRNAs). In particular, we will consider their history, the controversy surrounding their origin and biology, and, most importantly, the hurdles that remain to be overcome if they are really to become part of future clinical practice.
Enumeration of deregulated miRNAs in liquid and tissue biopsies of cervical cancer
Gynecologic Oncology, 2019
Established miRNA signatures in cervical cancer serum and tissue specimens • miRNAs from exonic regions were downregulated in cervical cancer specimens. • Key miRNA clusters were identified, and they show similar patterns of expression. • miR-409-3p and miR-454-3p targets MTF2 and ST18 respectively. • miR-17, miR-32, miR-454 and miR-409 may be suitable as biosignature using serum specimens
Development of a circulating miRNA assay to monitor tumor burden: From mouse to man
Molecular Oncology, 2015
Circulating miRNA stability suggests potential utility of miRNA based biomarkers to monitor tumor burden and/or progression, particularly in cancer types where serial biopsy is impractical. Assessment of miRNA specificity and sensitivity is challenging within the clinical setting. To address this, circulating miRNAs were examined in mice bearing human SCLC tumor xenografts and SCLC patient derived circulating tumor cell explant models (CDX). We identified 49 miRNAs using human TaqMan Low Density Arrays readily detectable in 10 ml tail vein plasma from mice carrying H526 SCLC xenografts that were low or undetectable in non-tumor bearing controls. Circulating miR-95 measured serially in mice bearing CDX was detected with tumor volumes as low as 10 mm 3 and faithfully reported subsequent tumor growth. Having established assay sensitivity in mouse models, we identified 26 miRNAs that were elevated in a stage dependent manner in a pilot study of plasma from SCLC patients (n ¼ 16) compared to healthy controls (n ¼ 11) that were also elevated in the mouse models. We selected a smaller panel of 10 previously reported miRNAs (miRs 95, 141, 200a, 200b, 200c, 210, 335#, 375, 429) that were consistently elevated in SCLC, some of which are reported to be elevated in other cancer types. Using a multiplex qPCR assay, elevated levels of miRNAs across the panel were also observed in a further 66 patients with non-small cell lung, colorectal or pancreatic cancers. The utility of this circulating miRNA panel as an early warning of tumor progression across several tumor types merits further evaluation in larger studies.
Challenges in Using Circulating miRNAs as Cancer Biomarkers
BioMed Research International, 2015
In the last years, circulating miRNAs have emerged as a new class of promising cancer biomarkers. Independent studies have shown the feasibility of using these small RNAs as tools for the diagnosis and prognosis of different types of malignancies as well as for predicting and possibly monitoring treatment response. However, despite an initial enthusiasm for their possible clinical application, widespread inconsistencies have been observed among the studies, and miRNA-based tools still represent the object of research within clinical diagnostic or treatment protocols. The poor overlap of results could be explained, at least in part, by preanalytical and analytical variables and donor-related factors that could generate artefacts, impairing an accurate quantification of circulating miRNAs. In fact, critical issues are represented by nonuniform sample choice, handling, and processing, as well as by blood cell contamination in sample preparation and lack of consensus for data normalizat...
Discordant Reports of miRNA Expression in Cervical Cancer: An Upshot of Overlapping Factors
Background: miRNAs are a class of small non-coding RNAs that are approximately 21-24 nucleotides in length and regulate gene expression post-transcriptionally by way of translational repression or transcript cleavage. They are undoubtedly dysregulated in several neoplastic events but the discordant reports trailing some of them have limited their application in diagnostic pathology. The aim of this review was to evaluate reports of miRNA dysregulation in cervical cancer in a bid to finding explanation for the discordance and to identify the best diagnostic and prognostic biomarker for cervical cancer. Method: Articles on miRNA expression in cervical cancer were downloaded from journal websites, Google scholar, Pubmed and Researchgate. The MiRNAs were classified using two criteria; 1) Frequency of reports using a scale of: 6-5 for Class I, 4-3 for Class II, 2 for Class III and 1 report for Class IV; 2) status of controversy, which included: Controversial (C) and Uncontroversial (UC). The controversial group was subdivided into Most Controversial (MC; >25%) and Less Controversial (LC; ≤25%). Result: Sixty-six (66) miRNAs were found to be dysregulated in cervical cancers, out of which 9 (13.6%) miRNAs were controversial, 20 (30.3%) miRNAs were uncontroversial and 37 (56.1%) miRNAs are yet to be validated by other reports. Considering frequency of reports, 5 miRNAs (7.7%), 13 miRNAs (20%), 10 miRNAs (15.4%) and 37 (56.9%) were grouped into Class I, II, III and IV, respectively. In all, only 8 (12%) miRNAs (miR-21, miR-18a, miR-20a, miR-29a, miR-25, miR-183, miR-196a, miR-218) were found to be most reported and without controversy. Conclusions: the expression of miRNAs is affected by overlapping factors such as cancer stage, type of sample analyzed, technique employed, type of viral agent and oncoprotein present. In is important that this factors be considered prior to sample analysis. Since miR-21 is more frequently reported without any discordance when compared with other miRNAs, it should be adopted as the best biomarker in monitoring and management of cervical cancer patients.
The Journal of Pathology, 2011
Mature microRNAs (miRNAs) are single-stranded RNA molecules of 20-23 nucleotide (nt) length that control gene expression in many cellular processes. These molecules typically reduce the stability of mRNAs, including those of genes that mediate processes in tumorigenesis, such as inflammation, cell cycle regulation, stress response, differentiation, apoptosis and invasion. miRNA targeting is mostly achieved through specific basepairing interactions between the 5 end ('seed' region) of the miRNA and sites within coding and untranslated regions (UTRs) of mRNAs; target sites in the 3 UTR lead to more effective mRNA destabilization. Since miRNAs frequently target hundreds of mRNAs, miRNA regulatory pathways are complex. To provide a critical overview of miRNA dysregulation in cancer, we first discuss the methods currently available for studying the role of miRNAs in cancer and then review miRNA genomic organization, biogenesis and mechanism of target recognition, examining how these processes are altered in tumorigenesis. Given the critical role miRNAs play in tumorigenesis processes and their disease-specific expression, they hold potential as therapeutic targets and novel biomarkers. Figure 2. miRNA genomic and functional organization. The genomic and functional organization of four miRNA clusters/families is clarified: (A) let-7/mir-98; (B) mir-141/200; (C) mir-21; and (D) mir . The genomic locations for each of the miRNA members are defined. Grey lines denote intronic regions. miRNA mature sequences are colour-coded according to the sequence family to which they belong (eg in the let-7 cluster, red signifies the let-7/mir-98 sequence family). The star sequence is defined with a grey bar. The sequence families are depicted as sequence alignments compared to the most highly expressed miRNA family member shown on top, based on profiles of over 1000 human specimens (Tuschl, unpublished data). Shaded residues denote differences from the most highly expressed miRNA family member.
Reliability of miRNA Analysis from Fixed and Paraffin-Embedded Tissues
International Journal of Molecular Sciences, 2019
In clinical practice, patients’ tissues are fixed and paraffin-embedded in order to enable histological diagnosis. Nowadays, those tissues are also used for molecular characterization. Formalin is the most used fixative worldwide, and Bouin’s solution in some worldwide institutions. Among molecular targets, micro RNAs (miRNAs), the single-stranded non-coding RNAs comprised of 18 to 24 nucleotides, have been demonstrated to be resistant to fixation and paraffin-embedding processes, with consequent possible application in clinical practice. In the present study, let-7e-5p, miR-423-3p, miR-92a-1-5p, miR-30d-5p, miR-155-5p, miR-200a-3p, and miR-429 were investigated in formalin and matched Bouin’s solution-fixed tissues of high grade serous ovarian cancers by means of real-time and droplet digital PCR (ddPCR). Micro RNAs were detectable and analyzable in both formalin- and Bouin’s-fixed specimens, but on average, higher Ct values and lower copies/µL were found in Bouin’s-fixed samples. ...
Oncology Letters
Epithelial ovarian cancer (EOC) is the type of OC with the highest mortality rate. Due to the asymptomatic nature of the disease and few available diagnostic tests, it is mostly diagnosed at the advanced stage. Therefore, the present study aimed to discover predictive and/or early diagnostic novel circulating microRNAs (miRNAs or miRs) for EOC. Firstly, microarray analysis of miRNA expression levels was performed on 32 samples of female individuals: Eight plasma samples from patients with pathologically confirmed EOC (mean age, 45 (30-54) years), eight plasma samples from matched healthy individuals (HIs) (mean age, 44 (30-65) years), eight EOC tissue samples (mean age, 45 (30-54) years) and eight benign ovarian (mean age, 35 (17-70) years) neoplastic tissue samples A total of 31 significantly dysregulated miRNAs in serum and three miRNAs in tissue were identified by microarray. The results were validated using reverse transcription-quantitative PCR on samples from 10 patients with pathologically confirmed EOC (mean age, 47(30-54) years), 10 matched His (mean age, 40(26-65) years], 10 EOC tissue samples (mean age, 47(30-54) years) and 10 benign ovarian neoplastic tissue samples (mean age, 40(17-70) years). The 'Kyoto Encyclopedia of Genes and Genomes' (KEGG) database was used for target gene and pathway analysis. A total of three miRNAs from EOC serum (hsa-miR-1909-5p, hsa-miR-885-5p and hsa-let-7d-3p) and one microRNA from tissue samples (hsa-miR-200c-3p) were validated as significant to distinguish patients with EOC from HIs. KEGG pathway enrichment analysis showed seven significant pathways, which included 'prion diseases', 'proteoglycans in cancer', 'oxytocin signaling pathway', 'hippo signaling pathway', 'adrenergic signaling in cardiomyocytes', 'oocyte meiosis' and 'thyroid hormone signaling pathway', in which the validated miRNAs served a role. This supports the hypothesis that four validated miRNAs, have the potential to be a biomarker of EOC diagnosis and target for treatment.
Evaluation Analysis of miRNAs Overexpression in Liquid-Based Cytology Endometrial Samples
Journal of Cancer
Background: miRNAs have an important role as their deregulation is linked to endometrial cancer. Methods: A custom miScript® miRNA PCR Array was used to investigate for the first time the expression of eight miRNAs in forty-nine histologically confirmed Liquid Based cytology endometrial samples. The expression profile of the same miRNAs was also examined in sixty formalin-fixed tissue samples. Results: Expression of seven miRNAs was significantly higher in malignant samples with three of them (mir-182, mir-141 and mir-205) performing optimally. Conclusion: These results suggest the potential use of this non-invasive method of sampling for miRNA expression studies. Furthermore miRNA overexpression could serve as an ancillary or reflex test for optimal identification of malignant samples especially in morphologically inadequate samples.