Special Issue "The Role of MicroRNA in Cancer"

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (20 October 2021).

Special Issue Editors

Prof. Edoardo Alesse
E-Mail Website
Guest Editor
Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy
Interests: general and molecular pathology, cancer molecular pathogenesis, microRNA, cell cycle, apoptosis, inflammation
Dr. Francesca Zazzeroni
E-Mail Website
Co-Guest Editor
Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy
Interests: cancer molecular pathogenesis; inflammation; NF-kB signaling; apoptosis; preclinical models; new therapeutic targets identification; epatocarcinogenesis; microRNA
Dr. Alessandra Tessitore
E-Mail Website
Co-Guest Editor
Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy
Interests: oncogenes, tumor suppressor genes, cancer molecular diagnostics, personalized medicine, epatocarcinogenesis, microRNA, profiling, bioinformatics

Special Issue Information

Dear Colleagues,

During the last decade, three classes of non-coding RNAs gained great attention. Among them, microRNAs, short (18-22 nucleotide in length) endogenous non-coding RNAs, play a role in regulating the expression of target genes at the post-transcriptional level. MicroRNAs are involved in the control of fundamental cell processes, such as growth, proliferation, differentiation, cell cycle, and programmed death. Dysregulation or aberrant microRNAs’ expression levels and different profiles are described in important pathological conditions, such as cardiovascular, neurological diseases, and cancer. It is known that tumour initiation, progression, and metastasis dissemination are correlated to significant changes in gene expression; for this reason, in the last decade, a large and increasing number of studies has been focused on examining in depth the role of microRNAs in tumorigenesis. Depending on the function of target genes, microRNAs can show tumour promoting (oncomiR) or suppressive (tumor suppressor miRs) properties in cancers, by regulating the expression of entire groups of genes implicated in oncogenesis and metastasis. MicroRNAs are considered as early diagnostic, prognostic, and predictive biomarkers as well. In addition, dysregulated miRNAs produced in the tumour microenvironment can be released into the bloodstream because of passive or active mechanisms. Due to their structure and nature, circulating microRNAs are resistant to endogenous RNase and very stable even in difficult conditions; for this reason, they are considered as suitable and promising non-invasive biomarkers. Novel therapeutic anti-cancer strategies are directed to target dysregulated/aberrantly expressed key microRNAs to re-establish normal physiological conditions, by inhibiting or restoring their normal expression levels. To this aim, the identification of improved and effective delivery systems is of great relevance. Importantly, such new generation- targeted therapies might be considered in combination regimens or as secondary treatment in cancers which are unresponsive to conventional therapeutic schemes.

In this Special Issue, we are interested in recent advances and opinions on the role of non-coding RNAs in oncogenesis. Research papers and reviews will focus on, but are not limited to, the role of microRNAs in tumorigenesis; microRNAs as biomarkers in cancer; therapeutic use of microRNAs in cancer, strategies and delivery systems to restore microRNA expression levels; microRNA preclinical models and bioinformatics approaches for miRNAs/target genes analysis.

Prof. Edoardo Alesse
Guest Editor
Prof. Francesca Zazzeroni
Dr. Alessandra Tessitore
Co-Guest Editors

Manuscript Submission Information

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Keywords

  • non-coding RNAs
  • cancer
  • biomarkers
  • preclinical models
  • targetome
  • microRNA-based therapy

Published Papers (11 papers)

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Research

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Article
NOV/CCN3 Promotes Cell Migration and Invasion in Intrahepatic Cholangiocarcinoma via miR-92a-3p
Genes 2021, 12(11), 1659; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12111659 - 21 Oct 2021
Viewed by 224
Abstract
Intrahepatic cholangiocarcinoma (ICC) is a common type of human cancer with a poor prognosis, and investigating the potential molecular mechanisms that can contribute to gene diagnosis and therapy. Herein, based on the recently concerned vertebrate-specific Cyr61/CTGF/NOV (CCN) gene family because of its important [...] Read more.
Intrahepatic cholangiocarcinoma (ICC) is a common type of human cancer with a poor prognosis, and investigating the potential molecular mechanisms that can contribute to gene diagnosis and therapy. Herein, based on the recently concerned vertebrate-specific Cyr61/CTGF/NOV (CCN) gene family because of its important roles in diverse diseases, we obtained NOV/CCN3 to query for its potential roles in tumorigenesis via bioinformatics analysis. Experimental validations confirmed that both NOV mRNA and protein are up-regulated in two ICC cell lines, suggesting that it may promote cell migration and invasion by promoting EMT. To elucidate the detailed regulatory mechanism, miR-92a-3p is screened and identified as a negative regulatory small RNA targeting NOV, and further experimental validation demonstrates that miR-92a-3p contributes to NOV-mediated migration and invasion of ICC via the Notch signaling pathway. Our study reveals that NOV may be a potential target for diagnosing and treating ICC, which will provide experimental data and molecular theoretical foundation for cancer treatment, particularly for future precision medicine. Full article
(This article belongs to the Special Issue The Role of MicroRNA in Cancer)
Article
Calcineurin Gamma Catalytic Subunit PPP3CC Inhibition by miR-200c-3p Affects Apoptosis in Epithelial Ovarian Cancer
Genes 2021, 12(9), 1400; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12091400 - 10 Sep 2021
Cited by 1 | Viewed by 355
Abstract
Epithelial ovarian cancer (EOC) outpaces all the other forms of the female reproductive system malignancies. MicroRNAs have emerged as promising predictive biomarkers to therapeutic treatments as their expression might characterize the tumor stage or grade. In EOC, miR-200c is considered a master regulator [...] Read more.
Epithelial ovarian cancer (EOC) outpaces all the other forms of the female reproductive system malignancies. MicroRNAs have emerged as promising predictive biomarkers to therapeutic treatments as their expression might characterize the tumor stage or grade. In EOC, miR-200c is considered a master regulator of oncogenes or tumor suppressors. To investigate novel miR-200c-3p target genes involved in EOC tumorigenesis, we evaluated the association between this miRNA and the mRNA expression of several potential target genes by RNA-seq data of both 46 EOC cell lines from Cancer Cell line Encyclopedia (CCLE) and 456 EOC patient bio-specimens from The Cancer Genome Atlas (TCGA). Both analyses showed a significant anticorrelation between miR-200c-3p and the protein phosphatase 3 catalytic subunit γ of calcineurin (PPP3CC) levels involved in the apoptosis pathway. Quantitative mRNA expression analysis in patient biopsies confirmed the inverse correlation between miR-200c-3p and PPP3CC levels. In vitro regulation of PPP3CC expression through miR-200c-3p and RNA interference technology led to a concomitant modulation of BCL2- and p-AKT-related pathways, suggesting the tumor suppressive role of PPP3CC in EOC. Our results suggest that inhibition of high expression of miR-200c-3p in EOC might lead to overexpression of the tumor suppressor PPP3CC and subsequent induction of apoptosis in EOC patients. Full article
(This article belongs to the Special Issue The Role of MicroRNA in Cancer)
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Article
miR-542-3p Contributes to the HK2-Mediated High Glycolytic Phenotype in Human Glioma Cells
Genes 2021, 12(5), 633; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12050633 - 23 Apr 2021
Cited by 1 | Viewed by 681
Abstract
(1) Background: The elevation of glucose metabolism is linked to high-grade gliomas such as glioblastoma multiforme (GBM). The high glycolytic phenotype is associated with cellular proliferation and resistance to treatment with chemotherapeutic agents in GBM. MicroRNA-542-3p (miR-542-3p) has been implicated in several tumors [...] Read more.
(1) Background: The elevation of glucose metabolism is linked to high-grade gliomas such as glioblastoma multiforme (GBM). The high glycolytic phenotype is associated with cellular proliferation and resistance to treatment with chemotherapeutic agents in GBM. MicroRNA-542-3p (miR-542-3p) has been implicated in several tumors including gliomas. However, the role of miR-542-3p in glucose metabolism in human gliomas remains unclear; (2) Methods: We measured the levels of cellular proliferation in human glioma cells. We measured the glycolytic activity in miR-542-3p knockdown and over-expressed human glioma cells. We measured the levels of miR-542-3p and HK2 in glioma tissues from patients with low- and high-grade gliomas using imaging analysis; (3) Results: We show that knockdown of miR-542-3p significantly suppressed cellular proliferation in human glioma cells. Knockdown of miR-542-3p suppressed HK2-induced glycolytic activity in human glioma cells. Consistently, over-expression of miR-542-3p increased HK2-induced glycolytic activity in human glioma cells. The levels of miR-542-3p and HK2 were significantly elevated in glioma tissues of patients with high-grade gliomas relative to that in low-grade gliomas. The elevation of HK2 levels in patients with high-grade gliomas were positively correlated with the high levels of miR-542-3p in GBM and low-grade gliomas (LGG) based on the datasets from the Cancer Genome Atlas (TCGA) database. Moreover, the high levels of miR-542-3p were associated with poor survival rate in the TCGA database; (4) Conclusions: miR-542-3p contributes to the HK2-mediated high glycolytic phenotype in human glioma cells. Full article
(This article belongs to the Special Issue The Role of MicroRNA in Cancer)
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Article
Expression of Estrogen Receptor- and Progesterone Receptor-Regulating MicroRNAs in Breast Cancer
Genes 2021, 12(4), 582; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12040582 - 16 Apr 2021
Cited by 1 | Viewed by 715
Abstract
In ~70% of breast cancer (BC) cases, estrogen and progesterone receptors (ER and PR) are overexpressed, which can change during tumor progression. Expression changes of these receptors during cancer initiation and progression can be caused by alterations in microRNA (miR, miRNA) expression. To [...] Read more.
In ~70% of breast cancer (BC) cases, estrogen and progesterone receptors (ER and PR) are overexpressed, which can change during tumor progression. Expression changes of these receptors during cancer initiation and progression can be caused by alterations in microRNA (miR, miRNA) expression. To assess the association of BC progression with aberrant expression of miRNAs that target ER and PR mRNAs, we quantified miR-19b, -222, -22, -378a, and -181a in BC samples (n = 174) by real-time PCR. Underexpression of miR-222 and miR-378a in stage T2–T4 BC was characteristic for HER2-overexpressing tumors. In addition, the expression of miR-181a and miR-378a was higher in these tumors than in tumors with a HER2 IHC score of 0 or 1+. In tumors with a Ki-67 index ≥ 14%, all tested miRNAs were underexpressed in BC with a high Allred PR score (6–8). In ER-and-PR–negative tumors, miR-22, miR-222, miR-181a, and miR-378a underexpression was associated with Ki-67 index > 35% (median value). MiR-19b and miR-22 underexpression could be a marker of lymph node metastasis in ER- and/or PR-positive tumors with HER2 IHC score 0. Thus, the association of miR-19b, miR-22, miR-222, miR-378a, and miR-181a levels with BC characteristics is influenced by the status of tumor ER, PR, HER2, and Ki-67. Full article
(This article belongs to the Special Issue The Role of MicroRNA in Cancer)
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Article
Clinical Identification of Dysregulated Circulating microRNAs and Their Implication in Drug Response in Triple Negative Breast Cancer (TNBC) by Target Gene Network and Meta-Analysis
Genes 2021, 12(4), 549; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12040549 - 09 Apr 2021
Cited by 2 | Viewed by 1139
Abstract
Resistance to therapy is a persistent problem that leads to mortality in breast cancer, particularly triple-negative breast cancer (TNBC). MiRNAs have become a focus of investigation as tissue-specific regulators of gene networks related to drug resistance. Circulating miRNAs are readily accessible non-invasive potential [...] Read more.
Resistance to therapy is a persistent problem that leads to mortality in breast cancer, particularly triple-negative breast cancer (TNBC). MiRNAs have become a focus of investigation as tissue-specific regulators of gene networks related to drug resistance. Circulating miRNAs are readily accessible non-invasive potential biomarkers for TNBC diagnosis, prognosis, and drug-response. Our aim was to use systems biology, meta-analysis, and network approaches to delineate the drug resistance pathways and clinical outcomes associated with circulating miRNAs in TNBC patients. MiRNA expression analysis was used to investigate differentially regulated circulating miRNAs in TNBC patients, and integrated pathway regulation, gene ontology, and pharmacogenomic network analyses were used to identify target genes, miRNAs, and drug interaction networks. Herein, we identified significant differentially expressed circulating miRNAs in TNBC patients (miR-19a/b-3p, miR-25-3p, miR-22-3p, miR-210-3p, miR-93-5p, and miR-199a-3p) that regulate several molecular pathways (PAM (PI3K/Akt/mTOR), HIF-1, TNF, FoxO, Wnt, and JAK/STAT, PD-1/PD-L1 pathways and EGFR tyrosine kinase inhibitor resistance (TKIs)) involved in drug resistance. Through meta-analysis, we demonstrated an association of upregulated miR-93, miR-210, miR-19a, and miR-19b with poor overall survival outcomes in TNBC patients. These results identify miRNA-regulated mechanisms of drug resistance and potential targets for combination with chemotherapy to overcome drug resistance in TNBC. We demonstrate that integrated analysis of multi-dimensional data can unravel mechanisms of drug-resistance related to circulating miRNAs, particularly in TNBC. These circulating miRNAs may be useful as markers of drug response and resistance in the guidance of personalized medicine for TNBC. Full article
(This article belongs to the Special Issue The Role of MicroRNA in Cancer)
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Review

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Review
Emerging Role of isomiRs in Cancer: State of the Art and Recent Advances
Genes 2021, 12(9), 1447; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12091447 - 20 Sep 2021
Viewed by 425
Abstract
The advent of Next Generation Sequencing technologies brought with it the discovery of several microRNA (miRNA) variants of heterogeneous lengths and/or sequences. Initially ascribed to sequencing errors/artifacts, these isoforms, named isomiRs, are now considered non-canonical variants that originate from physiological processes affecting the [...] Read more.
The advent of Next Generation Sequencing technologies brought with it the discovery of several microRNA (miRNA) variants of heterogeneous lengths and/or sequences. Initially ascribed to sequencing errors/artifacts, these isoforms, named isomiRs, are now considered non-canonical variants that originate from physiological processes affecting the canonical miRNA biogenesis. To date, accurate IsomiRs abundance, biological activity, and functions are not completely understood; however, the study of isomiR biology is an area of great interest due to their high frequency in the human miRNome, their putative functions in cooperating with the canonical miRNAs, and potential for exhibiting novel functional roles. The discovery of isomiRs highlighted the complexity of the small RNA transcriptional landscape in several diseases, including cancer. In this field, the study of isomiRs could provide further insights into the miRNA biology and its implication in oncogenesis, possibly providing putative new cancer diagnostic, prognostic, and predictive biomarkers as well. In this review, a comprehensive overview of the state of research on isomiRs in different cancer types, including the most common tumors such as breast cancer, colorectal cancer, melanoma, and prostate cancer, as well as in the less frequent tumors, as for example brain tumors and hematological malignancies, will be summarized and discussed. Full article
(This article belongs to the Special Issue The Role of MicroRNA in Cancer)
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Review
SALL4 and microRNA: The Role of Let-7
Genes 2021, 12(9), 1301; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12091301 - 24 Aug 2021
Viewed by 517
Abstract
SALL4 is a zinc finger transcription factor that belongs to the spalt-like (SALL) gene family. It plays important roles in the maintenance of self-renewal and pluripotency of embryonic stem cells, and its expression is repressed in most adult organs. SALL4 re-expression has been [...] Read more.
SALL4 is a zinc finger transcription factor that belongs to the spalt-like (SALL) gene family. It plays important roles in the maintenance of self-renewal and pluripotency of embryonic stem cells, and its expression is repressed in most adult organs. SALL4 re-expression has been observed in different types of human cancers, and dysregulation of SALL4 contributes to the pathogenesis, metastasis, and even drug resistance of multiple cancer types. Surprisingly, little is known regarding how SALL4 expression is controlled, but recently microRNAs (miRNAs) have emerged as important regulators of SALL4. Due to the ability of regulating targets differentially in specific tissues, and recent advances in systemic and organ specific miRNA delivery mechanisms, miRNAs have emerged as promising therapeutic targets for cancer treatment. In this review, we summarize current knowledge of the interaction between SALL4 and miRNAs in mammalian development and cancer, paying particular attention to the emerging roles of the Let-7/Lin28 axis. In addition, we discuss the therapeutic prospects of targeting SALL4 using miRNA-based strategies, with a focus on the Let-7/LIN28 axis. Full article
(This article belongs to the Special Issue The Role of MicroRNA in Cancer)
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Review
MiRNAs and Cancer: Key Link in Diagnosis and Therapy
Genes 2021, 12(8), 1289; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12081289 - 23 Aug 2021
Viewed by 982
Abstract
Since the discovery of the first microRNA (miRNA), the exploration of miRNA biology has come to a new era in recent decades. Monumental studies have proven that miRNAs can be dysregulated in different types of cancers and the roles of miRNAs turn out [...] Read more.
Since the discovery of the first microRNA (miRNA), the exploration of miRNA biology has come to a new era in recent decades. Monumental studies have proven that miRNAs can be dysregulated in different types of cancers and the roles of miRNAs turn out to function to either tumor promoters or tumor suppressors. The interplay between miRNAs and the development of cancers has grabbed attention of miRNAs as novel tools and targets for therapeutic attempts. Moreover, the development of miRNA delivery system accelerates miRNA preclinical implications. In this review, we depict recent advances of miRNAs in cancer and discuss the potential diagnostic or therapeutic approaches of miRNAs. Full article
(This article belongs to the Special Issue The Role of MicroRNA in Cancer)
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Review
Association of Exosomal miR-210 with Signaling Pathways Implicated in Lung Cancer
Genes 2021, 12(8), 1248; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12081248 - 16 Aug 2021
Viewed by 524
Abstract
MicroRNA is a class of non-coding RNA involved in post-transcriptional gene regulation. Aberrant expression of miRNAs is well-documented in molecular cancer biology. Extensive research has shown that miR-210 is implicated in the progression of multiple cancers including that of the lung, bladder, colon, [...] Read more.
MicroRNA is a class of non-coding RNA involved in post-transcriptional gene regulation. Aberrant expression of miRNAs is well-documented in molecular cancer biology. Extensive research has shown that miR-210 is implicated in the progression of multiple cancers including that of the lung, bladder, colon, and renal cell carcinoma. In recent years, exosomes have been evidenced to facilitate cell–cell communication and signaling through packaging and transporting active biomolecules such as miRNAs and thereby modify the cellular microenvironment favorable for lung cancers. MiRNAs encapsulated inside the lipid bilayer of exosomes are stabilized and transmitted to target cells to exert alterations in the epigenetic landscape. The currently available literature indicates that exosomal miR-210 is involved in the regulation of various lung cancer-related signaling molecules and pathways, including STAT3, TIMP-1, KRAS/BACH2/GATA-3/RIP3, and PI3K/AKT. Here, we highlight major findings and progress on the roles of exosomal miR-210 in lung cancer. Full article
(This article belongs to the Special Issue The Role of MicroRNA in Cancer)
Review
Circulating microRNAs from the Molecular Mechanisms to Clinical Biomarkers: A Focus on the Clear Cell Renal Cell Carcinoma
Genes 2021, 12(8), 1154; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12081154 - 28 Jul 2021
Cited by 1 | Viewed by 306
Abstract
microRNAs (miRNAs) are emerging as relevant molecules in cancer development and progression. MiRNAs add a post-transcriptional level of control to the regulation of gene expression. The deregulation of miRNA expression results in changing the molecular circuitry in which miRNAs are involved, leading to [...] Read more.
microRNAs (miRNAs) are emerging as relevant molecules in cancer development and progression. MiRNAs add a post-transcriptional level of control to the regulation of gene expression. The deregulation of miRNA expression results in changing the molecular circuitry in which miRNAs are involved, leading to alterations of cell fate determination. In this review, we describe the miRNAs that are emerging as innovative molecular biomarkers from liquid biopsies, not only for diagnosis, but also for post-surgery management in cancer. We focus our attention on renal cell carcinoma, in particular highlighting the crucial role of circulating miRNAs in clear cell renal cell carcinoma (ccRCC) management. In addition, the functional deregulation of miRNA expression in ccRCC is also discussed, to underline the contribution of miRNAs to ccRCC development and progression, which may be relevant for the identification and design of innovative clinical strategies against this tumor. Full article
(This article belongs to the Special Issue The Role of MicroRNA in Cancer)
Review
MicroRNA Changes in Gastric Carcinogenesis: Differential Dysregulation during Helicobacter pylori and EBV Infection
Genes 2021, 12(4), 597; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12040597 - 19 Apr 2021
Viewed by 723
Abstract
Despite medical advances, gastric-cancer (GC) mortality remains high in Europe. Bacterial infection with Helicobacter pylori (H. pylori) and viral infection with the Epstein–Barr virus (EBV) are associated with the development of both distal and proximal gastric cancer. Therefore, the detection of [...] Read more.
Despite medical advances, gastric-cancer (GC) mortality remains high in Europe. Bacterial infection with Helicobacter pylori (H. pylori) and viral infection with the Epstein–Barr virus (EBV) are associated with the development of both distal and proximal gastric cancer. Therefore, the detection of these infections and the prediction of further cancer development could be clinically significant. To this end, microRNAs (miRNAs) could serve as promising new tools. MiRNAs are highly conserved noncoding RNAs that play an important role in gene silencing, mainly acting via translational repression and the degradation of mRNA targets. Recent reports demonstrate the downregulation of numerous miRNAs in GC, especially miR-22, miR-145, miR-206, miR-375, and miR-490, and these changes seem to promote cancer-cell invasion and tumor spreading. The dysregulation of miR-106b, miR-146a, miR-155, and the Let-7b/c complex seems to be of particular importance during H. pylori infection or gastric carcinogenesis. In contrast, many reports describe changes in host miRNA expression and outline the effects of bamHI-A region rightward transcript (BART) miRNA in EBV-infected tissue. The differential regulation of these miRNA, acting alone or in close interaction when both infections coexist, may therefore enable us to detect cancer earlier. In this review, we focus on the two different etiologies of gastric cancer and outline the molecular pathways through which H. pylori- or EBV-induced changes might synergistically act via miR-155 dysregulation to potentiate cancer risk. The three markers, namely, H. pylori presence, EBV infection, and miR-155 expression, may be checked in routine biopsies to evaluate the risk of developing gastric cancer. Full article
(This article belongs to the Special Issue The Role of MicroRNA in Cancer)
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