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MicroRNA as Biomarkers in Cancer Diagnostics and Therapy

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 November 2018) | Viewed by 52203

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Special Issue Editor


E-Mail Website1 Website2
Guest Editor
1. Department of Radiology, Michigan State University, Interdisciplinary Science and Technology Building, East Lansing, MI 48824, USA
2. Precision Health Program, Michigan State University, Interdisciplinary Science and Technology Building, East Lansing, MI 48824, USA
Interests: tissue slide-based microRNA diagnostics; microRNA biology and evolution; cell type-specific activities of microRNAs in oncology with a focus on breast and pancreatic cancer; nanoparticle-based delivery of microRNA activity modulators
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

MicroRNAs (miRNAs) are small non-coding RNA molecules that function predominantly as post-transcriptional regulators of gene expression. miRNAs play important roles in development, cellular differentiation and homeostasis, and host-virus interactions. miRNA expression and function are dysregulated in cancer. Specific miRNAs have been shown to exert tumor-promoting or tumor-suppressive functions depending of the expressing cell type and cancer site. Within cancer cells, miRNA can modulate growth and chemoresistance, stem cell, epithelial-to-mesenchymal transition and/or metastatic programs. Within other cell types of the tumor microenvironment, miRNAs can promote angiogenic and immune suppressive programs.

Most miRNAs act in a cell-autonomous fashion within the expressing cell, yet miRNAs are an important cargo in extracellular vesicles that can affect specific biological program or pathways in recipient cells. There are several examples of miRNA-mediated cell-to-cell communication that imparts a favorable microenvironment for cancer cell growth and metastasis. Circulating miRNAs either in extracellular vesicles, multi-protein complexes, or in other forms are readily found and often altered in blood and other bio-fluids of cancer patients.

This Special Issue will provide a comprehensive update on the latest findings of cancer-associated miRNAs, with a focus on the clinical application of miRNAs as biomarkers for cancer diagnosis and prognosis, and treatment prediction, as well as miRNA-based therapeutic strategies.

Original papers and review articles that describe advances in detection methodology, bioinformatics approaches, and statistical analysis with an impact on clinical application of miRNAs as cancer biomarkers are welcomed.

Dr. William Chi-shing Cho
Dr. Lorenzo F. Sempere
Guest Editors

Manuscript Submission Information

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Keywords

  • MicroRNA (miRNA, miR)
  • Tissue analysis
  • Circulating biomarkers (blood, bio-fluids)
  • Extracellular vesicle, exosomes
  • Cancer diagnosis
  • Treatment prediction
  • Therapeutics
  • Pre-clinical models and clinical trials

Published Papers (9 papers)

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Editorial

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5 pages, 178 KiB  
Editorial
Celebrating 25 Years of MicroRNA Research: From Discovery to Clinical Application
by Lorenzo F. Sempere
Int. J. Mol. Sci. 2019, 20(8), 1987; https://doi.org/10.3390/ijms20081987 - 23 Apr 2019
Cited by 10 | Viewed by 2203
Abstract
In 1993, the Ambros lab reported the cloning and developmental function of lin-4, the first microRNA [...] Full article
(This article belongs to the Special Issue MicroRNA as Biomarkers in Cancer Diagnostics and Therapy)

Research

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14 pages, 20073 KiB  
Article
Co-Detection of miR-21 and TNF-α mRNA in Budding Cancer Cells in Colorectal Cancer
by Trine Møller, Jaslin P James, Kim Holmstrøm, Flemming B Sørensen, Jan Lindebjerg and Boye S Nielsen
Int. J. Mol. Sci. 2019, 20(8), 1907; https://doi.org/10.3390/ijms20081907 - 17 Apr 2019
Cited by 28 | Viewed by 5686
Abstract
MicroRNA-21 (miR-21) is upregulated in many cancers including colon cancers and is a prognostic indicator of recurrence and poor prognosis. In colon cancers, miR-21 is highly expressed in stromal fibroblastic cells and more weakly in a subset of cancer cells, particularly budding cancer [...] Read more.
MicroRNA-21 (miR-21) is upregulated in many cancers including colon cancers and is a prognostic indicator of recurrence and poor prognosis. In colon cancers, miR-21 is highly expressed in stromal fibroblastic cells and more weakly in a subset of cancer cells, particularly budding cancer cells. Exploration of the expression of inflammatory markers in colon cancers revealed tumor necrosis factor alpha (TNF-α) mRNA expression at the invasive front of colon cancers. Surprisingly, a majority of the TNF-α mRNA expressing cells were found to be cancer cells and not inflammatory cells. Because miR-21 is positively involved in cell survival and TNF-α promotes necrosis, we found it interesting to analyze the presence of miR-21 in areas of TNF-α mRNA expression at the invasive front of colon cancers. For this purpose, we developed an automated procedure for the co-staining of miR-21, TNF-α mRNA and the cancer cell marker cytokeratin based on analysis of frozen colon cancer tissue samples (n = 4) with evident cancer cell budding. In all four cases, TNF-α mRNA was seen in a small subset of cancer cells at the invasive front. Evaluation of miR-21 and TNF-α mRNA expression was performed on digital slides obtained by confocal slide scanning microscopy. Both co-expression and lack of co-expression with miR-21 in the budding cancer cells was noted, suggesting non-correlated expression. miR-21 was more often seen in cancer cells than TNF-α mRNA. In conclusion, we report that miR-21 is not linked to expression of the pro-inflammatory cytokine TNF-α mRNA, but that miR-21 and TNF-α both take part in the cancer expansion at the invasive front of colon cancers. We hypothesize that miR-21 may protect both fibroblasts and cancer cells from cell death directed by TNF-α paracrine and autocrine activity. Full article
(This article belongs to the Special Issue MicroRNA as Biomarkers in Cancer Diagnostics and Therapy)
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17 pages, 1621 KiB  
Article
Identification of Endogenous Control miRNAs for RT-qPCR in T-Cell Acute Lymphoblastic Leukemia
by Monika Drobna, Bronisława Szarzyńska-Zawadzka, Patrycja Daca-Roszak, Maria Kosmalska, Roman Jaksik, Michał Witt and Małgorzata Dawidowska
Int. J. Mol. Sci. 2018, 19(10), 2858; https://doi.org/10.3390/ijms19102858 - 20 Sep 2018
Cited by 27 | Viewed by 7045
Abstract
Optimal endogenous controls enable reliable normalization of microRNA (miRNA) expression in reverse-transcription quantitative PCR (RT-qPCR). This is particularly important when miRNAs are considered as candidate diagnostic or prognostic biomarkers. Universal endogenous controls are lacking, thus candidate normalizers must be evaluated individually for each [...] Read more.
Optimal endogenous controls enable reliable normalization of microRNA (miRNA) expression in reverse-transcription quantitative PCR (RT-qPCR). This is particularly important when miRNAs are considered as candidate diagnostic or prognostic biomarkers. Universal endogenous controls are lacking, thus candidate normalizers must be evaluated individually for each experiment. Here we present a strategy that we applied to the identification of optimal control miRNAs for RT-qPCR profiling of miRNA expression in T-cell acute lymphoblastic leukemia (T-ALL) and in normal cells of T-lineage. First, using NormFinder for an iterative analysis of miRNA stability in our miRNA-seq data, we established the number of control miRNAs to be used in RT-qPCR. Then, we identified optimal control miRNAs by a comprehensive analysis of miRNA stability in miRNA-seq data and in RT-qPCR by analysis of RT-qPCR amplification efficiency and expression across a variety of T-lineage samples and T-ALL cell line culture conditions. We then showed the utility of the combination of three miRNAs as endogenous normalizers (hsa-miR-16-5p, hsa-miR-25-3p, and hsa-let-7a-5p). These miRNAs might serve as first-line candidate endogenous controls for RT-qPCR analysis of miRNAs in different types of T-lineage samples: T-ALL patient samples, T-ALL cell lines, normal immature thymocytes, and mature T-lymphocytes. The strategy we present is universal and can be transferred to other RT-qPCR experiments. Full article
(This article belongs to the Special Issue MicroRNA as Biomarkers in Cancer Diagnostics and Therapy)
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17 pages, 7704 KiB  
Article
A Three–MicroRNA Signature as a Potential Biomarker for the Early Detection of Oral Cancer
by Yi-An Chang, Shun-Long Weng, Shun-Fa Yang, Chih-Hung Chou, Wei-Chih Huang, Siang-Jyun Tu, Tzu-Hao Chang, Chien-Ning Huang, Yuh-Jyh Jong and Hsien-Da Huang
Int. J. Mol. Sci. 2018, 19(3), 758; https://doi.org/10.3390/ijms19030758 - 7 Mar 2018
Cited by 73 | Viewed by 5909
Abstract
Oral squamous cell carcinoma (OSCC) is often diagnosed at a late stage and may be malignantly transformed from oral leukoplakia (OL). This study aimed to identify potential plasma microRNAs (miRNAs) for the early detection of oral cancer. Plasma from normal, OL, and OSCC [...] Read more.
Oral squamous cell carcinoma (OSCC) is often diagnosed at a late stage and may be malignantly transformed from oral leukoplakia (OL). This study aimed to identify potential plasma microRNAs (miRNAs) for the early detection of oral cancer. Plasma from normal, OL, and OSCC patients were evaluated. Small RNA sequencing was used to screen the differently expressed miRNAs among the groups. Next, these miRNAs were validated with individual samples by quantitative real-time polymerase chain reaction (qRT-PCR) assays in the training phase (n = 72) and validation phase (n = 178). The possible physiological roles of the identified miRNAs were further investigated using bioinformatics analysis. Three miRNAs (miR-222-3p, miR-150-5p, and miR-423-5p) were identified as differentially expressed among groups; miR-222-3p and miR-423-5p negatively correlated with T stage, lymph node metastasis status, and clinical stage. A high diagnostic accuracy (Area under curve = 0.88) was demonstrated for discriminating OL from OSCC. Bioinformatics analysis reveals that miR-423-5p and miR-222-3p are significantly over-expressed in oral cancer tissues and involved in various cancer pathways. The three-plasma miRNA panel may be useful to monitor malignant progression from OL to OSCC and as potential biomarkers for early detection of oral cancer. Full article
(This article belongs to the Special Issue MicroRNA as Biomarkers in Cancer Diagnostics and Therapy)
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12 pages, 628 KiB  
Article
Circulating Plasma Levels of miR-20b, miR-29b and miR-155 as Predictors of Bevacizumab Efficacy in Patients with Metastatic Colorectal Cancer
by Paola Ulivi, Matteo Canale, Alessandro Passardi, Giorgia Marisi, Martina Valgiusti, Giovanni Luca Frassineti, Daniele Calistri, Dino Amadori and Emanuela Scarpi
Int. J. Mol. Sci. 2018, 19(1), 307; https://doi.org/10.3390/ijms19010307 - 20 Jan 2018
Cited by 63 | Viewed by 5496
Abstract
Targeting angiogenesis in the treatment of colorectal cancer (CRC) is a common strategy, for which potential predictive biomarkers have been studied. miRNAs are small non-coding RNAs involved in several processes including the angiogenic pathway. They are very stable in biological fluids, which turns [...] Read more.
Targeting angiogenesis in the treatment of colorectal cancer (CRC) is a common strategy, for which potential predictive biomarkers have been studied. miRNAs are small non-coding RNAs involved in several processes including the angiogenic pathway. They are very stable in biological fluids, which turns them into potential circulating biomarkers. In this study, we considered a case series of patients with metastatic (m) CRC treated with a bevacizumab (B)-based treatment, enrolled in the prospective multicentric Italian Trial in Advanced Colorectal Cancer (ITACa). We then analyzed a panel of circulating miRNAs in relation to the patient outcome. In multivariate analysis, circulating basal levels of hsa-miR-20b-5p, hsa-miR-29b-3p and hsa-miR-155-5p resulted in being significantly associated with progression-free survival (PFS) (p = 0.027, p = 0.034 and p = 0.039, respectively) and overall survival (OS) (p = 0.044, p = 0.024 and p = 0.032, respectively). We also observed that an increase in hsa-miR-155-5p at the first clinical evaluation was significantly associated with shorter PFS (HR 3.03 (95% CI 1.06–9.09), p = 0.040) and OS (HR 3.45 (95% CI 1.18–10.00), p = 0.024), with PFS and OS of 9.5 (95% CI 6.8–18.7) and 15.9 (95% CI 8.4–not reached), respectively, in patients with an increase ≥30% of hsa-miR-155-5p and 22.3 (95% CI 10.2–25.5) and 42.9 (24.8–not reached) months, respectively, in patients without such increase. In conclusion, our results highlight the potential usefulness of circulating basal levels of hsa-miR-20b-5p, hsa-miR-29b-3p and hsa-miR-155-5p in predicting the outcome of patients with mCRC treated with B. In addition, the variation of circulating hsa-miR-155-5p could also be indicative of the patient survival. Full article
(This article belongs to the Special Issue MicroRNA as Biomarkers in Cancer Diagnostics and Therapy)
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Review

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26 pages, 738 KiB  
Review
Relevance of MicroRNAs as Potential Diagnostic and Prognostic Markers in Colorectal Cancer
by Grzegorz Hibner, Małgorzata Kimsa-Furdzik and Tomasz Francuz
Int. J. Mol. Sci. 2018, 19(10), 2944; https://doi.org/10.3390/ijms19102944 - 27 Sep 2018
Cited by 55 | Viewed by 4952
Abstract
Colorectal cancer (CRC) is currently the third and the second most common cancer in men and in women, respectively. Every year, more than one million new CRC cases and more than half a million deaths are reported worldwide. The majority of new cases [...] Read more.
Colorectal cancer (CRC) is currently the third and the second most common cancer in men and in women, respectively. Every year, more than one million new CRC cases and more than half a million deaths are reported worldwide. The majority of new cases occur in developed countries. Current screening methods have significant limitations. Therefore, a lot of scientific effort is put into the development of new diagnostic biomarkers of CRC. Currently used prognostic markers are also limited in assessing the effectiveness of CRC therapy. MicroRNAs (miRNAs) are a promising subject of research especially since single miRNA can recognize a variety of different mRNA transcripts. MiRNAs have important roles in epigenetic regulation of basic cellular processes, such as proliferation, apoptosis, differentiation, and migration, and may serve as potential oncogenes or tumor suppressors during cancer development. Indeed, in a large variety of human tumors, including CRC, significant distortions in miRNA expression profiles have been observed. Thus, the use of miRNAs as diagnostic and prognostic biomarkers in cancer, particularly in CRC, appears to be an inevitable consequence of the advancement in oncology and gastroenterology. Here, we review the literature to discuss the potential usefulness of selected miRNAs as diagnostic and prognostic biomarkers in CRC. Full article
(This article belongs to the Special Issue MicroRNA as Biomarkers in Cancer Diagnostics and Therapy)
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30 pages, 2013 KiB  
Review
MiRNA Dysregulation in Childhood Hematological Cancer
by Jaqueline Carvalho de Oliveira, Gabriela Molinari Roberto, Mirella Baroni, Karina Bezerra Salomão, Julia Alejandra Pezuk and María Sol Brassesco
Int. J. Mol. Sci. 2018, 19(9), 2688; https://doi.org/10.3390/ijms19092688 - 10 Sep 2018
Cited by 25 | Viewed by 5652
Abstract
For decades, cancer biology focused largely on the protein-encoding genes that have clear roles in tumor development or progression: cell-cycle control, apoptotic evasion, genome instability, drug resistance, or signaling pathways that stimulate growth, angiogenesis, or metastasis. MicroRNAs (miRNAs), however, represent one of the [...] Read more.
For decades, cancer biology focused largely on the protein-encoding genes that have clear roles in tumor development or progression: cell-cycle control, apoptotic evasion, genome instability, drug resistance, or signaling pathways that stimulate growth, angiogenesis, or metastasis. MicroRNAs (miRNAs), however, represent one of the more abundant classes of cell modulators in multicellular organisms and largely contribute to regulating gene expression. Many of the ~2500 miRNAs discovered to date in humans regulate vital biological processes, and their aberrant expression results in pathological and malignant outcomes. In this review, we highlight what has been learned about the roles of miRNAs in some of the most common human pediatric leukemias and lymphomas, along with their value as diagnostic/prognostic factors. Full article
(This article belongs to the Special Issue MicroRNA as Biomarkers in Cancer Diagnostics and Therapy)
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17 pages, 1254 KiB  
Review
MicroRNAs as Potential Biomarkers in Merkel Cell Carcinoma
by Aelita Konstantinell, Dag H. Coucheron, Baldur Sveinbjørnsson and Ugo Moens
Int. J. Mol. Sci. 2018, 19(7), 1873; https://doi.org/10.3390/ijms19071873 - 26 Jun 2018
Cited by 22 | Viewed by 4709
Abstract
Merkel cell carcinoma (MCC) is a rare and aggressive type of skin cancer associated with a poor prognosis. This carcinoma was named after its presumed cell of origin, the Merkel cell, which is a mechanoreceptor cell located in the basal epidermal layer of [...] Read more.
Merkel cell carcinoma (MCC) is a rare and aggressive type of skin cancer associated with a poor prognosis. This carcinoma was named after its presumed cell of origin, the Merkel cell, which is a mechanoreceptor cell located in the basal epidermal layer of the skin. Merkel cell polyomavirus seems to be the major causal factor for MCC because approximately 80% of all MCCs are positive for viral DNAs. UV exposure is the predominant etiological factor for virus-negative MCCs. Intracellular microRNA analysis between virus-positive and virus-negative MCC cell lines and tumor samples have identified differentially expressed microRNAs. Comparative microRNA profiling has also been performed between MCCs and other non-MCC tumors, but not between normal Merkel cells and malignant Merkel cells. Finally, Merkel cell polyomavirus encodes one microRNA, but its expression in virus-positive MCCs is low, or non-detectable or absent, jeopardizing its biological relevance in tumorigenesis. Here, we review the results of microRNA studies in MCCs and discuss the potential application of microRNAs as biomarkers for the diagnosis, progression and prognosis, and treatment of MCC. Full article
(This article belongs to the Special Issue MicroRNA as Biomarkers in Cancer Diagnostics and Therapy)
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17 pages, 3375 KiB  
Review
The Role of Circulating Free DNA and MicroRNA in Non-Invasive Diagnosis of HBV- and HCV-Related Hepatocellular Carcinoma
by Francesca Pezzuto, Luigi Buonaguro, Franco Maria Buonaguro and Maria Lina Tornesello
Int. J. Mol. Sci. 2018, 19(4), 1007; https://doi.org/10.3390/ijms19041007 - 28 Mar 2018
Cited by 52 | Viewed by 9468
Abstract
Hepatocellular carcinoma (HCC) is the third and the fifth leading cause of cancer related death worldwide in men and in women, respectively. HCC generally has a poor prognosis, with a very low 5-year overall survival, due to delayed diagnosis and treatment. Early tumour [...] Read more.
Hepatocellular carcinoma (HCC) is the third and the fifth leading cause of cancer related death worldwide in men and in women, respectively. HCC generally has a poor prognosis, with a very low 5-year overall survival, due to delayed diagnosis and treatment. Early tumour detection and timely intervention are the best strategies to reduce morbidity and mortality in HCC patients. Histological evaluation of liver biopsies is the gold standard for cancer diagnosis, although it is an invasive, time-consuming and expensive procedure. Recently, the analysis of circulating free DNA (cfDNA) and RNA molecules released by tumour cells in body fluids, such as blood serum, saliva and urine, has attracted great interest for development of diagnostic assays based on circulating liver cancer molecular biomarkers. Such “liquid biopsies” have shown to be useful for the identification of specific molecular signatures in nucleic acids released by cancer cells, such as gene mutations and altered methylation of DNA as well as variations in the levels of circulating microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). Body fluids analysis may represent a valuable strategy to monitor liver disease progression in subjects chronically infected with hepatitis viruses or cancer relapse in HCC treated patients. Several studies showed that qualitative and quantitative assays evaluating molecular profiles of circulating cell-free nucleic acids could be successfully employed for early diagnosis and therapeutic management of HCC patients. This review describes the state of art on the use of liquid biopsy for cancer driver gene mutations, deregulated DNA methylation as well as miRNA levels in HCC diagnosis. Full article
(This article belongs to the Special Issue MicroRNA as Biomarkers in Cancer Diagnostics and Therapy)
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