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Cancers
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MicroRNA and Cancer
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MicroRNA and Cancer

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Biomarkers".

Deadline for manuscript submissions: closed (31 July 2021) | Viewed by 48727

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editor

Dr. Paola Tucci

E-Mail Website
Guest Editor
Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Arcavacata di Rende (CS), Italy
Interests: p53 family; microRNA; tumorigenesis; metabolism; toxicity
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear colleagues,

MicroRNAs (miRs) are small noncoding RNAs that function as post-transcriptional regulators of gene expression and have important roles in almost all biological pathways, including development, differentiation, cell cycle, proliferation, and apoptosis. Deregulated miR expression has been detected in numerous cancers, where miRs act as both oncogene and tumor suppressors. Considering their important roles in tumorigenesis, miRs have been investigated as prognostic and diagnostic biomarkers and as useful targets for therapeutic intervention. From a therapeutic point of view, two modalities can serve to rectify gene networks in cancer cells. For oncomiRs, a rational means is downregulation through antagomirs. Moreover, observation of pathological reduction of tumor-suppressive miRs has inspired the concept of “miR replacement therapy” to enhance the amount of these miRs, thereby restoring them to normal levels. However, the clinical applicability of miR-based therapies is severely limited by the lack of effective delivery systems. Therefore, to understand the role of this new class of regulators, we need to identify the mRNA targets regulated by individual miR as well as to develop specific, efficient, and safe delivery systems of therapeutic miRs.

This Special Issue will focus on the identification and characterization of new miR targets involved in the pathogenesis of cancer and on their role as potential biomarkers for early detection, diagnosis, and for the development of new cancer therapy, including miR delivery systems. Moreover, since p53, p63, and p73 proteins were reported to regulate the expression of several miRs, this Issue will also focus on the regulation of miR and their relationship with the p53 family members during cancer development.

Dr. Paola Tucci
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • microRNA
  • biomarkers
  • cancer
  • p53 family
  • miR delivery system

Published Papers (15 papers)

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Editorial

Jump to: Research, Review

3 pages, 190 KiB  
Editorial
The Role of microRNAs in Cancer: Functions, Biomarkers and Therapeutics
by Paola Tucci
Cancers 2022, 14(4), 872; https://doi.org/10.3390/cancers14040872 - 10 Feb 2022
Cited by 3 | Viewed by 1298
Abstract
MicroRNAs (miRs) are small non-coding RNAs acting as post-transcriptional regulators of gene expression with important roles in almost all biological pathways, including development, differentiation, cell cycle, proliferation, and apoptosis [...] Full article
(This article belongs to the Special Issue MicroRNA and Cancer)

Research

Jump to: Editorial, Review

14 pages, 1176 KiB  
Article
Circulating miRNAs as Novel Non-Invasive Biomarkers to Aid the Early Diagnosis of Suspicious Breast Lesions for Which Biopsy Is Recommended
by Marta Giussani, Chiara Maura Ciniselli, Loris De Cecco, Mara Lecchi, Matteo Dugo, Chiara Gargiuli, Andrea Mariancini, Elisa Mancinelli, Giulia Cosentino, Silvia Veneroni, Biagio Paolini, Rosaria Orlandi, Massimiliano Gennaro, Marilena Valeria Iorio, Catherine Depretto, Claudio Ferranti, Gabriella Sozzi, Marialuisa Sensi, Mario Paolo Colombo, Gianfranco Scaperrotta, Elda Tagliabue and Paolo Verderioadd Show full author list remove Hide full author list
Cancers 2021, 13(16), 4028; https://doi.org/10.3390/cancers13164028 - 10 Aug 2021
Cited by 7 | Viewed by 2274
Abstract
In population-based screens, tissue biopsy remains the standard practice for women with imaging that suggests breast cancer. We examined circulating microRNAs as minimally invasive diagnostic biomarkers to discriminate malignant from benign breast lesions. miRNAs were analyzed by OpenArray in a retrospective cohort of [...] Read more.
In population-based screens, tissue biopsy remains the standard practice for women with imaging that suggests breast cancer. We examined circulating microRNAs as minimally invasive diagnostic biomarkers to discriminate malignant from benign breast lesions. miRNAs were analyzed by OpenArray in a retrospective cohort of plasma samples including 100 patients with malignant (T), 89 benign disease (B), and 99 healthy donors (HD) divided into training and testing sets and a prospective cohort (BABE) of 289 women with suspicious imaging findings who underwent tissue biopsy. miRNAs associated with disease status were identified by univariate analysis and then combined into signatures by multivariate logistic regression models. By combining 16 miRNAs differentially expressed in the T vs. HD comparison, 26 signatures were also able to significantly discriminate T from B disease. Seven of them, involving 5 specific miRNAs (miR-625, miR-423-5p, miR-370-3p, miR-181c, and miR-301b), were statistically validated in the testing set. Among the 7 signatures, the discriminatory performances of 5 were confirmed in the prospective BABE Cohort. This study identified 5 circulating miRNAs that, properly combined, distinguish malignant from benign breast disease in women with a high likelihood of malignancy. Full article
(This article belongs to the Special Issue MicroRNA and Cancer)
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20 pages, 3985 KiB  
Article
The microRNA-210-Stathmin1 Axis Decreases Cell Stiffness to Facilitate the Invasiveness of Colorectal Cancer Stem Cells
by Tsai-Tsen Liao, Wei-Chung Cheng, Chih-Yung Yang, Yin-Quan Chen, Shu-Han Su, Tzu-Yu Yeh, Hsin-Yi Lan, Chih-Chan Lee, Hung-Hsin Lin, Chun-Chi Lin, Ruey-Hwa Lu, Arthur Er-Terg Chiou, Jeng-Kai Jiang and Wei-Lun Hwang
Cancers 2021, 13(8), 1833; https://doi.org/10.3390/cancers13081833 - 12 Apr 2021
Cited by 6 | Viewed by 2319
Abstract
Cell migration is critical for regional dissemination and distal metastasis of cancer cells, which remain the major causes of poor prognosis and death in patients with colorectal cancer (CRC). Although cytoskeletal dynamics and cellular deformability contribute to the migration of cancer cells and [...] Read more.
Cell migration is critical for regional dissemination and distal metastasis of cancer cells, which remain the major causes of poor prognosis and death in patients with colorectal cancer (CRC). Although cytoskeletal dynamics and cellular deformability contribute to the migration of cancer cells and metastasis, the mechanisms governing the migratory ability of cancer stem cells (CSCs), a nongenetic source of tumor heterogeneity, are unclear. Here, we expanded colorectal CSCs (CRCSCs) as colonospheres and showed that CRCSCs exhibited higher cell motility in transwell migration assays and 3D invasion assays and greater deformability in particle tracking microrheology than did their parental CRC cells. Mechanistically, in CRCSCs, microRNA-210-3p (miR-210) targeted stathmin1 (STMN1), which is known for inducing microtubule destabilization, to decrease cell elasticity in order to facilitate cell motility without affecting the epithelial–mesenchymal transition (EMT) status. Clinically, the miR-210-STMN1 axis was activated in CRC patients with liver metastasis and correlated with a worse clinical outcome. This study elucidates a miRNA-oriented mechanism regulating the deformability of CRCSCs beyond the EMT process. Full article
(This article belongs to the Special Issue MicroRNA and Cancer)
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17 pages, 2991 KiB  
Article
Relevance of 2′-O-Methylation and Pseudouridylation for the Malignant Melanoma
by Simon Jasinski-Bergner, Juliane Blümke, Claudia Wickenhauser and Barbara Seliger
Cancers 2021, 13(5), 1167; https://doi.org/10.3390/cancers13051167 - 9 Mar 2021
Cited by 6 | Viewed by 2317
Abstract
The two RNA modifications 2′-O-methylation and pseudouridylation occur on several RNA species including ribosomal RNAs leading to an increased translation as well as cell proliferation associated with distinct functions. Using malignant melanoma (MM) as a model system the proteins mediating these RNA modifications [...] Read more.
The two RNA modifications 2′-O-methylation and pseudouridylation occur on several RNA species including ribosomal RNAs leading to an increased translation as well as cell proliferation associated with distinct functions. Using malignant melanoma (MM) as a model system the proteins mediating these RNA modifications were for the first time analyzed by different bioinformatics tools and public available databases regarding their expression and histological localization. Next to this, the impact of these RNA-modifying factors on prognostic relevant processes and marker genes of malignant melanoma was investigated and correlated to immune surveillance and evasion strategies. The RNA modifying factors exerted statistically significant positive correlations to the expression of genes involved in cell proliferation and were statistically significant negative correlated to the expression of human leukocyte antigen class I genes as well as of components of the antigen processing machinery in malignant melanoma. Upregulation of the RNA modifying proteins was of prognostic relevance in this tumor disease with a negative impact on the overall survival of melanoma patients. Furthermore, the expression of known oncogenic miRs, which are induced in malignant melanoma, directly correlated to the expression of factors involved in these two RNA modifications. Full article
(This article belongs to the Special Issue MicroRNA and Cancer)
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20 pages, 15449 KiB  
Article
Tumor Suppressor miR-584-5p Inhibits Migration and Invasion in Smoking Related Non-Small Cell Lung Cancer Cells by Targeting YKT6
by Saet Byeol Lee, Young Soo Park, Jae Sook Sung, Jong Won Lee, Boyeon Kim and Yeul Hong Kim
Cancers 2021, 13(5), 1159; https://doi.org/10.3390/cancers13051159 - 8 Mar 2021
Cited by 18 | Viewed by 2711
Abstract
Cigarette smoke (CS) affects the expression of microRNAs (miRNAs), which are important regulators of gene expression by inducing DNA methylation. However, the effects of smoking on miRNA expression have not been fully elucidated in smoking-related lung carcinogenesis. Therefore, in this study, to investigate [...] Read more.
Cigarette smoke (CS) affects the expression of microRNAs (miRNAs), which are important regulators of gene expression by inducing DNA methylation. However, the effects of smoking on miRNA expression have not been fully elucidated in smoking-related lung carcinogenesis. Therefore, in this study, to investigate the change of miRNA expression pattern and to identify tumor suppressor miRNAs by smoking in lung carcinogenesis, we used lung carcinogenesis model cell lines that, derived from a murine xenograft model with human bronchial epithelial cells (BEAS-2B), exposed CS or not. The microarray analysis revealed that miR-584-5p expression was downregulated with cancer progression in lung carcinogenesis model cell lines. We confirmed by pyrosequencing that the methylation level of the miR-584-5p promoter increased with cancer progression. In vitro and in vivo experiments showed that miR-584-5p suppressed migration and invasion in non-small cell lung cancer (NSCLC) cells by targeting YKT6. Furthermore, we showed that high level of YKT6 was associated with a poor survival rate in NSCLC patients with a history of smoking. These results suggest that miR-584-5p acts as a tumor suppressor and is a potential molecular biomarker for smoking-related NSCLC. Full article
(This article belongs to the Special Issue MicroRNA and Cancer)
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20 pages, 5407 KiB  
Article
Identification of RCC Subtype-Specific microRNAs–Meta-Analysis of High-Throughput RCC Tumor microRNA Expression Data
by Arkadiusz Kajdasz, Weronika Majer, Katarzyna Kluzek, Jacek Sobkowiak, Tomasz Milecki, Natalia Derebecka, Zbigniew Kwias, Hans A. R. Bluyssen and Joanna Wesoly
Cancers 2021, 13(3), 548; https://doi.org/10.3390/cancers13030548 - 1 Feb 2021
Cited by 18 | Viewed by 2971
Abstract
Renal cell carcinoma (RCC) is one of the most common cancers worldwide with a nearly non-symptomatic course until the advanced stages of the disease. RCC can be distinguished into three subtypes: papillary (pRCC), chromophobe (chRCC) and clear cell renal cell carcinoma (ccRCC) representing [...] Read more.
Renal cell carcinoma (RCC) is one of the most common cancers worldwide with a nearly non-symptomatic course until the advanced stages of the disease. RCC can be distinguished into three subtypes: papillary (pRCC), chromophobe (chRCC) and clear cell renal cell carcinoma (ccRCC) representing up to 75% of all RCC cases. Detection and RCC monitoring tools are limited to standard imaging techniques, in combination with non-RCC specific morphological and biochemical read-outs. RCC subtype identification relays mainly on results of pathological examination of tumor slides. Molecular, clinically applicable and ideally non-invasive tools aiding RCC management are still non-existent, although molecular characterization of RCC is relatively advanced. Hence, many research efforts concentrate on the identification of molecular markers that will assist with RCC sub-classification and monitoring. Due to stability and tissue-specificity miRNAs are promising candidates for such biomarkers. Here, we performed a meta-analysis study, utilized seven NGS and seven microarray RCC studies in order to identify subtype-specific expression of miRNAs. We concentrated on potentially oncocytoma-specific miRNAs (miRNA-424-5p, miRNA-146b-5p, miRNA-183-5p, miRNA-218-5p), pRCC-specific (miRNA-127-3p, miRNA-139-5p) and ccRCC-specific miRNAs (miRNA-200c-3p, miRNA-362-5p, miRNA-363-3p and miRNA-204-5p, 21-5p, miRNA-224-5p, miRNA-155-5p, miRNA-210-3p) and validated their expression in an independent sample set. Additionally, we found ccRCC-specific miRNAs to be differentially expressed in ccRCC tumor according to Fuhrman grades and identified alterations in their isoform composition in tumor tissue. Our results revealed that changes in the expression of selected miRNA might be potentially utilized as a tool aiding ccRCC subclass discrimination and we propose a miRNA panel aiding RCC subtype distinction. Full article
(This article belongs to the Special Issue MicroRNA and Cancer)
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14 pages, 2504 KiB  
Article
Circulating Exosomal MicroRNA-1307-5p as a Predictor for Metastasis in Patients with Hepatocellular Carcinoma
by Jung Woo Eun, Chul Won Seo, Geum Ok Baek, Moon Gyeong Yoon, Hye Ri Ahn, Ju A. Son, Suna Sung, Do Wan Kim, Soon Sun Kim, Hyo Jung Cho and Jae Youn Cheong
Cancers 2020, 12(12), 3819; https://doi.org/10.3390/cancers12123819 - 18 Dec 2020
Cited by 18 | Viewed by 2707
Abstract
Exosomal microRNAs (exo-miRs) contribute to cancer metastasis. To identify pro-metastatic circulating exo-miRs in hepatocellular carcinoma (HCC), next-generation sequencing-based plasma exo-miR profiles of 14 patients with HCC (eight non-metastatic and six with metastasis within 1 year of follow-up) were analyzed. Sixty-one miRs were significantly [...] Read more.
Exosomal microRNAs (exo-miRs) contribute to cancer metastasis. To identify pro-metastatic circulating exo-miRs in hepatocellular carcinoma (HCC), next-generation sequencing-based plasma exo-miR profiles of 14 patients with HCC (eight non-metastatic and six with metastasis within 1 year of follow-up) were analyzed. Sixty-one miRs were significantly overexpressed among patients with metastatic HCC. Candidate miRs were selected through integrative analyses of two different public expression datasets, GSE67140 and The Cancer Genome Atlas liver hepatocellular carcinoma (TCGA_LIHC). Integrative analyses revealed 3 of 61 miRs (miR-106b-5p, miR-1307-5p, and miR-340-5p) commonly overexpressed both in metastasis and vascular invasion groups, with prognostic implications. Validation was performed using stored blood samples of 150 patients with HCC. Validation analysis showed that circulating exo-miR-1307-5p was significantly overexpressed in the metastasis group (p = 0.04), as well as in the vascular invasion and tumor recurrence groups. Circulating exo-miR-1307-5p expression was significantly correlated with tumor stage progression (p < 0.0001). Downstream signaling pathways of miR-1307 were predicted using TargetScan and Ingenuity Pathway Analysis. On comprehensive bioinformatics analysis, the downstream pathway of miR-1307-5p, promoting epithelial–mesenchymal transition (EMT), showed SEC14L2 and ENG downregulation. Our results show that circulating exo-miR-1307-5p promotes metastasis and helps predict metastasis in HCC, and SEC14L2 and ENG are target tumor suppressor genes of miR-1307 that promote EMT. Full article
(This article belongs to the Special Issue MicroRNA and Cancer)
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18 pages, 2060 KiB  
Article
A Pilot Study Comparing the Efficacy of Lactate Dehydrogenase Levels Versus Circulating Cell-Free microRNAs in Monitoring Responses to Checkpoint Inhibitor Immunotherapy in Metastatic Melanoma Patients
by Matias A. Bustos, Rebecca Gross, Negin Rahimzadeh, Hunter Cole, Linh T. Tran, Kevin D. Tran, Ling Takeshima, Stacey L. Stern, Steven O’Day and Dave S. B. Hoon
Cancers 2020, 12(11), 3361; https://doi.org/10.3390/cancers12113361 - 13 Nov 2020
Cited by 25 | Viewed by 2444
Abstract
Serum lactate dehydrogenase (LDH) is a standard prognostic biomarker for stage IV melanoma patients. Often, LDH levels do not provide real-time information about the metastatic melanoma patients’ disease status and treatment response. Therefore, there is a need to find reliable blood biomarkers for [...] Read more.
Serum lactate dehydrogenase (LDH) is a standard prognostic biomarker for stage IV melanoma patients. Often, LDH levels do not provide real-time information about the metastatic melanoma patients’ disease status and treatment response. Therefore, there is a need to find reliable blood biomarkers for improved monitoring of metastatic melanoma patients who are undergoing checkpoint inhibitor immunotherapy (CII). The objective in this prospective pilot study was to discover circulating cell-free microRNA (cfmiR) signatures in the plasma that could assess melanoma patients’ responses during CII. The cfmiRs were evaluated by the next-generation sequencing (NGS) HTG EdgeSeq microRNA (miR) Whole Transcriptome Assay (WTA; 2083 miRs) in 158 plasma samples obtained before and during the course of CII from 47 AJCC stage III/IV melanoma patients’ and 73 normal donors’ plasma samples. Initially, cfmiR profiles for pre- and post-treatment plasma samples of stage IV non-responder melanoma patients were compared to normal donors’ plasma samples. Using machine learning, we identified a 9 cfmiR signature that was associated with stage IV melanoma patients being non-responsive to CII. These cfmiRs were compared in pre- and post-treatment plasma samples from stage IV melanoma patients that showed good responses. Circulating miR-4649-3p, miR-615-3p, and miR-1234-3p demonstrated potential prognostic utility in assessing CII responses. Compared to LDH levels during CII, circulating miR-615-3p levels were consistently more efficient in detecting melanoma patients undergoing CII who developed progressive disease. By combining stage III/IV patients, 92 and 17 differentially expressed cfmiRs were identified in pre-treatment plasma samples from responder and non-responder patients, respectively. In conclusion, this pilot study demonstrated cfmiRs that identified treatment responses and could allow for real-time monitoring of patients receiving CII. Full article
(This article belongs to the Special Issue MicroRNA and Cancer)
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Graphical abstract

15 pages, 2228 KiB  
Article
MiRNA-103/107 in Primary High-Grade Serous Ovarian Cancer and Its Clinical Significance
by Milosz Wilczynski, Michal Kielbik, Daria Senderowska, Tomasz Krawczyk, Bozena Szymanska, Magdalena Klink, Jan Bieńkiewicz, Hanna Romanowicz, Filip Frühauf and Andrzej Malinowski
Cancers 2020, 12(9), 2680; https://doi.org/10.3390/cancers12092680 - 19 Sep 2020
Cited by 3 | Viewed by 2266
Abstract
High levels of miRNA-103/107 are associated with poor outcomes in the case of breast cancer patients. MiRNA-103/107-DICER axis may be one of the key regulators of cancer aggressiveness. MiRNA-103/107 expression levels have never been related to patients’ clinicopathological data in epithelial ovarian cancer. [...] Read more.
High levels of miRNA-103/107 are associated with poor outcomes in the case of breast cancer patients. MiRNA-103/107-DICER axis may be one of the key regulators of cancer aggressiveness. MiRNA-103/107 expression levels have never been related to patients’ clinicopathological data in epithelial ovarian cancer. We aimed to assess miRNA-103/107 expression levels in high grade serous ovarian cancer tissues. Expression levels of both miRNAs were related to the clinicopathological features and survival. We also evaluated expression levels of miRNA-103/107 and DICER in selected ovarian cancer cell lines (A2780, A2780cis, SK-OV-3, OVCAR3). We assessed the relative expression of miRNA-103/107 (quantitative reverse transcription-polymerase chain reaction) in fifty archival formalin-fixed paraffin-embedded tissue samples of primary high grade serous ovarian cancer. Then, miRNA-103/107 and DICER expression levels were evaluated in selected ovarian cancer cell lines. Additionally, DICER, N-/E-cadherin protein levels were assessed with the use of western blot. We identified miRNA-107 up-regulation in ovarian cancer in comparison to healthy tissues (p = 0.0005). In the case of miRNA-103, we did not observe statistically significant differences between cancerous and healthy tissues (p = 0.07). We did not find any correlations between miRNA-103/107 expression levels and clinicopathological features. Kaplan–Meier survival (disease-free and overall survival) analysis revealed that both miRNAs could not be considered as prognostic factors. SK-OV-3 cancer cell lines were characterized by high expression of miRNA-103/107, relatively low expression of DICER (western-blot), and relatively high N-cadherin levels in comparison to other ovarian cancer cell lines. Clinical and prognostic significance of miRNA-103/107 was not confirmed in our study. Full article
(This article belongs to the Special Issue MicroRNA and Cancer)
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36 pages, 7199 KiB  
Article
Chemically Induced Hypoxia Enhances miRNA Functions in Breast Cancer
by Emma Gervin, Bonita Shin, Reid Opperman, Mackenzie Cullen, Riley Feser, Sujit Maiti and Mousumi Majumder
Cancers 2020, 12(8), 2008; https://doi.org/10.3390/cancers12082008 - 22 Jul 2020
Cited by 24 | Viewed by 5068
Abstract
In aggressively growing tumors, hypoxia induces HIF-1α expression promoting angiogenesis. Previously, we have shown that overexpression of oncogenic microRNAs (miRNAs, miRs) miR526b/miR655 in poorly metastatic breast cancer cell lines promotes aggressive cancer phenotypes in vitro and in vivo. Additionally, miR526b/miR655 expression is significantly [...] Read more.
In aggressively growing tumors, hypoxia induces HIF-1α expression promoting angiogenesis. Previously, we have shown that overexpression of oncogenic microRNAs (miRNAs, miRs) miR526b/miR655 in poorly metastatic breast cancer cell lines promotes aggressive cancer phenotypes in vitro and in vivo. Additionally, miR526b/miR655 expression is significantly higher in human breast tumors, and high miR526b/miR655 expression is associated with poor prognosis. However, the roles of miR526b/miR655 in hypoxia are unknown. To test the relationship between miR526b/miR655 and hypoxia, we used various in vitro, in silico, and in situ assays. In normoxia, miRNA-high aggressive breast cancer cell lines show higher HIF-1α expression than miRNA-low poorly metastatic breast cancer cell lines. To test direct involvement of miR526b/miR655 in hypoxia, we analyzed miRNA-high cell lines (MCF7-miR526b, MCF7-miR655, MCF7-COX2, and SKBR3-miR526b) compared to controls (MCF7 and SKBR3). CoCl2-induced hypoxia in breast cancer further promotes HIF-1α mRNA and protein expression while reducing VHL expression (a negative HIF-1α regulator), especially in miRNA-high cell lines. Hypoxia enhances oxidative stress, epithelial to mesenchymal transition, cell migration, and vascular mimicry more prominently in MCF7-miR526b/MCF7-miR655 cell lines compared to MCF7 cells. Hypoxia promotes inflammatory and angiogenesis marker (COX-2, EP4, NFκB1, VEGFA) expression in all miRNA-high cells. Hypoxia upregulates miR526b/miR655 expression in MCF7 cells, thus observed enhancement of hypoxia-induced functions in MCF7 could be attributed to miR526b/miR655 upregulation. In silico bioinformatics analysis shows miR526b/miR655 regulate PTEN (a negative regulator of HIF-1α) and NFκB1 (positive regulator of COX-2 and EP4) expression by downregulation of transcription factors NR2C2, SALL4, and ZNF207. Hypoxia-enhanced functions in miRNA-high cells are inhibited by COX-2 inhibitor (Celecoxib), EP4 antagonist (ONO-AE3-208), and irreversible PI3K/Akt inhibitor (Wortmannin). This establishes that hypoxia enhances miRNA functions following the COX-2/EP4/PI3K/Akt pathways and this pathway can serve as a therapeutic target to abrogate hypoxia and miRNA induced functions in breast cancer. In situ, HIF-1α expression is significantly higher in human breast tumors (n = 96) compared to non-cancerous control tissues (n = 20) and is positively correlated with miR526b/miR655 expression. In stratified tumor samples, HIF-1α expression was significantly higher in ER-positive, PR-positive, and HER2-negative breast tumors. Data extracted from the TCGA database also show a strong correlation between HIF-1α and miRNA-cluster expression in breast tumors. This study, for the first time, establishes the dynamic roles of miR526b/miR655 in hypoxia. Full article
(This article belongs to the Special Issue MicroRNA and Cancer)
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Graphical abstract

Review

Jump to: Editorial, Research

18 pages, 767 KiB  
Review
Role of MicroRNAs in the Development and Progression of the Four Medulloblastoma Subgroups
by Emilia Bevacqua, Jasmin Farshchi, Maria Victoria Niklison-Chirou and Paola Tucci
Cancers 2021, 13(24), 6323; https://doi.org/10.3390/cancers13246323 - 16 Dec 2021
Cited by 3 | Viewed by 2537
Abstract
Medulloblastoma is the most frequent malignant brain tumour in children. Medulloblastoma originate during the embryonic stage. They are located in the cerebellum, which is the area of the central nervous system (CNS) responsible for controlling equilibrium and coordination of movements. In 2012, medulloblastoma [...] Read more.
Medulloblastoma is the most frequent malignant brain tumour in children. Medulloblastoma originate during the embryonic stage. They are located in the cerebellum, which is the area of the central nervous system (CNS) responsible for controlling equilibrium and coordination of movements. In 2012, medulloblastoma were divided into four subgroups based on a genome-wide analysis of RNA expression. These subgroups are named Wingless, Sonic Hedgehog, Group 3 and Group 4. Each subgroup has a different cell of origin, prognosis, and response to therapies. Wingless and Sonic Hedgehog medulloblastoma are so named based on the main mutation originating these tumours. Group 3 and Group 4 have generic names because we do not know the key mutation driving these tumours. Gene expression at the post-transcriptional level is regulated by a group of small single-stranded non-coding RNAs. These microRNA (miRNAs or miRs) play a central role in several cellular functions such as cell differentiation and, therefore, any malfunction in this regulatory system leads to a variety of disorders such as cancer. The role of miRNAs in medulloblastoma is still a topic of intense clinical research; previous studies have mostly concentrated on the clinical entity of the single disease rather than in the four molecular subgroups. In this review, we summarize the latest discoveries on miRNAs in the four medulloblastoma subgroups. Full article
(This article belongs to the Special Issue MicroRNA and Cancer)
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22 pages, 2530 KiB  
Review
Current Implications of microRNAs in Genome Stability and Stress Responses of Ovarian Cancer
by Arkadiusz Gajek, Patrycja Gralewska, Agnieszka Marczak and Aneta Rogalska
Cancers 2021, 13(11), 2690; https://doi.org/10.3390/cancers13112690 - 29 May 2021
Cited by 6 | Viewed by 3268
Abstract
Genomic alterations and aberrant DNA damage signaling are hallmarks of ovarian cancer (OC), the leading cause of mortality among gynecological cancers worldwide. Owing to the lack of specific symptoms and late-stage diagnosis, survival chances of patients are significantly reduced. Poly (ADP-ribose) polymerase (PARP) [...] Read more.
Genomic alterations and aberrant DNA damage signaling are hallmarks of ovarian cancer (OC), the leading cause of mortality among gynecological cancers worldwide. Owing to the lack of specific symptoms and late-stage diagnosis, survival chances of patients are significantly reduced. Poly (ADP-ribose) polymerase (PARP) inhibitors and replication stress response inhibitors present attractive therapeutic strategies for OC. Recent research has focused on ovarian cancer-associated microRNAs (miRNAs) that play significant regulatory roles in various cellular processes. While miRNAs have been shown to participate in regulation of tumorigenesis and drug responses through modulating the DNA damage response (DDR), little is known about their potential influence on sensitivity to chemotherapy. The main objective of this review is to summarize recent findings on the utility of miRNAs as cancer biomarkers, in particular, ovarian cancer, and their regulation of DDR or modified replication stress response proteins. We further discuss the suppressive and promotional effects of various miRNAs on ovarian cancer and their participation in cell cycle disturbance, response to DNA damage, and therapeutic functions in multiple cancer types, with particular focus on ovarian cancer. Improved understanding of the mechanisms by which miRNAs regulate drug resistance should facilitate the development of effective combination therapies for ovarian cancer. Full article
(This article belongs to the Special Issue MicroRNA and Cancer)
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23 pages, 729 KiB  
Review
Roles of microRNAs in Regulating Cancer Stemness in Head and Neck Cancers
by Melysa Fitriana, Wei-Lun Hwang, Pak-Yue Chan, Tai-Yuan Hsueh and Tsai-Tsen Liao
Cancers 2021, 13(7), 1742; https://doi.org/10.3390/cancers13071742 - 6 Apr 2021
Cited by 9 | Viewed by 3929
Abstract
Head and neck squamous cell carcinomas (HNSCCs) are epithelial malignancies with 5-year overall survival rates of approximately 40–50%. Emerging evidence indicates that a small population of cells in HNSCC patients, named cancer stem cells (CSCs), play vital roles in the processes of tumor [...] Read more.
Head and neck squamous cell carcinomas (HNSCCs) are epithelial malignancies with 5-year overall survival rates of approximately 40–50%. Emerging evidence indicates that a small population of cells in HNSCC patients, named cancer stem cells (CSCs), play vital roles in the processes of tumor initiation, progression, metastasis, immune evasion, chemo-/radioresistance, and recurrence. The acquisition of stem-like properties of cancer cells further provides cellular plasticity for stress adaptation and contributes to therapeutic resistance, resulting in a worse clinical outcome. Thus, targeting cancer stemness is fundamental for cancer treatment. MicroRNAs (miRNAs) are known to regulate stem cell features in the development and tissue regeneration through a miRNA–target interactive network. In HNSCCs, miRNAs act as tumor suppressors and/or oncogenes to modulate cancer stemness and therapeutic efficacy by regulating the CSC-specific tumor microenvironment (TME) and signaling pathways, such as epithelial-to-mesenchymal transition (EMT), Wnt/β-catenin signaling, and epidermal growth factor receptor (EGFR) or insulin-like growth factor 1 receptor (IGF1R) signaling pathways. Owing to a deeper understanding of disease-relevant miRNAs and advances in in vivo delivery systems, the administration of miRNA-based therapeutics is feasible and safe in humans, with encouraging efficacy results in early-phase clinical trials. In this review, we summarize the present findings to better understand the mechanical actions of miRNAs in maintaining CSCs and acquiring the stem-like features of cancer cells during HNSCC pathogenesis. Full article
(This article belongs to the Special Issue MicroRNA and Cancer)
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20 pages, 1208 KiB  
Review
MicroRNAs: Tiny Regulators of Gene Expression with Pivotal Roles in Normal B-Cell Development and B-Cell Chronic Lymphocytic Leukemia
by Katerina Katsaraki, Paraskevi Karousi, Pinelopi I. Artemaki, Andreas Scorilas, Vasiliki Pappa, Christos K. Kontos and Sotirios G. Papageorgiou
Cancers 2021, 13(4), 593; https://doi.org/10.3390/cancers13040593 - 3 Feb 2021
Cited by 30 | Viewed by 3180
Abstract
MicroRNAs (miRNAs) represent a class of small non-coding RNAs bearing regulatory potency. The implication of miRNAs in physiological cellular processes has been well documented so far. A typical process orchestrated by miRNAs is the normal B-cell development. A stage-specific expression pattern of miRNAs [...] Read more.
MicroRNAs (miRNAs) represent a class of small non-coding RNAs bearing regulatory potency. The implication of miRNAs in physiological cellular processes has been well documented so far. A typical process orchestrated by miRNAs is the normal B-cell development. A stage-specific expression pattern of miRNAs has been reported in the developmental procedure, as well as interactions with transcription factors that dictate B-cell development. Besides their involvement in normal hematopoiesis, miRNAs are severally implicated in hematological malignancies, a typical paradigm of which is B-cell chronic lymphocytic leukemia (B-CLL). B-CLL is a highly heterogeneous disease characterized by the accumulation of abnormal B cells in blood, bone marrow, lymph nodes, and spleen. Therefore, timely, specific, and sensitive assessment of the malignancy is vital. Several studies have attempted to highlight the remarkable significance of miRNAs as regulators of gene expression, biomarkers for diagnosis, prognosis, progression, and therapy response prediction, as well as molecules with potential therapeutic utility. This review seeks to outline the linkage between miRNA function in normal and malignant hematopoiesis by demonstrating the main benchmarks of the implication of miRNAs in the regulation of normal B-cell development, and to summarize the key findings about their value as regulators, biomarkers, or therapeutic targets in B-CLL. Full article
(This article belongs to the Special Issue MicroRNA and Cancer)
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25 pages, 718 KiB  
Review
Insulin Resistance and Endometrial Cancer: Emerging Role for microRNA
by Iwona Sidorkiewicz, Maciej Jóźwik, Magdalena Niemira and Adam Krętowski
Cancers 2020, 12(9), 2559; https://doi.org/10.3390/cancers12092559 - 8 Sep 2020
Cited by 16 | Viewed by 7315
Abstract
Endometrial cancer (EC) remains one of the most common cancers of the female reproductive system. Epidemiological and clinical data implicate insulin resistance (IR) and its accompanying hyperinsulinemia as key factors in the development of EC. MicroRNAs (miRNAs) are short molecules of non-coding endogenous [...] Read more.
Endometrial cancer (EC) remains one of the most common cancers of the female reproductive system. Epidemiological and clinical data implicate insulin resistance (IR) and its accompanying hyperinsulinemia as key factors in the development of EC. MicroRNAs (miRNAs) are short molecules of non-coding endogenous RNA that function as post-transcriptional regulators. Accumulating evidence has shown that the miRNA expression pattern is also likely to be associated with EC risk factors. The aim of this work was the verification of the relationships between IR, EC, and miRNA, and, as based on the literature data, elucidation of miRNA’s potential utility for EC prevention in IR patients. The pathways affected in IR relate to the insulin receptors, insulin-like growth factors and their receptors, insulin-like growth factor binding proteins, sex hormone-binding globulin, and estrogens. Herein, we present and discuss arguments for miRNAs as a plausible molecular link between IR and EC development. Specifically, our careful literature search indicated that dysregulation of at least 13 miRNAs has been ascribed to both conditions. We conclude that there is a reasonable possibility for miRNAs to become a predictive factor of future EC in IR patients. Full article
(This article belongs to the Special Issue MicroRNA and Cancer)
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