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16 pages, 14335 KiB

Open AccessArticle

High Expression of a tRNA^Pro Derivative Associates with Poor Survival and Independently Predicts Colorectal Cancer Recurrence

by Panagiotis Tsiakanikas, Panagiotis G. Adamopoulos, Dimitra Tsirba, Pinelopi I. Artemaki, Iordanis N. Papadopoulos, Christos K. Kontos and Andreas Scorilas

Biomedicines 2022, 10(5), 1120; https://doi.org/10.3390/biomedicines10051120 - 12 May 2022

Cited by 13 | Viewed by 2219

Abstract

Colorectal cancer (CRC) is the second most lethal cause of cancer-related deaths in Europe. Fragments of tRNA^Pro are conserved among vertebrates, characterized by pleiotropic regulatory functions and have been found to discriminate colorectal tumors from normal colorectal mucosa. In the current study, [...] Read more.

Colorectal cancer (CRC) is the second most lethal cause of cancer-related deaths in Europe. Fragments of tRNA^Pro are conserved among vertebrates, characterized by pleiotropic regulatory functions and have been found to discriminate colorectal tumors from normal colorectal mucosa. In the current study, we investigated the prognostic utility of 5′-tiRNA-Pro^TGG levels in CRC. For this purpose, total RNA was extracted from 155 malignant colorectal tumors and 74 adjacent non-cancerous tissue specimens, polyadenylated and reverse-transcribed using an oligo-dT adapter as primer. Real-time quantitative PCR (qPCR) was used to assess the levels of 5′-tiRNA-Pro^TGG. Kaplan-Meier survival analysis demonstrated that high 5′-tiRNA-Pro^TGG levels predict both poor disease-free survival (DFS) and overall survival (OS) of CRC patients. Of note, high 5′-tiRNA-Pro^TGG levels retain their unfavorable prognostic value in patients with rectal cancer and/or moderately differentiated CRC (grade II). More importantly, multivariate cox regression analysis highlighted that the overexpression of 5′-tiRNA-Pro^TGG constitutes an adverse prognostic factor predicting short-term relapse of CRC patients independently of the established prognosticators in CRC. Finally, bioinformatics analysis unveiled a potentially critical role of 5′-tiRNA-Pro^TGG regarding the maintenance of cellular homeostasis, signaling, cell communication, and cellular motility. Full article

(This article belongs to the Special Issue MicroRNAs, tRNA Fragments, and Circular RNAs: Pivotal Regulators of Gene Expression and Their Roles in Human Diseases)

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14 pages, 1665 KiB

Open AccessArticle

The lncRNAs/miR-30e/CHI3L1 Axis Is Dysregulated in Systemic Sclerosis

by Valentin Dichev, Nikolay Mehterov, Maria Kazakova, Rositsa Karalilova, Anastas Batalov and Victoria Sarafian

Biomedicines 2022, 10(2), 496; https://doi.org/10.3390/biomedicines10020496 - 19 Feb 2022

Cited by 8 | Viewed by 2132

Abstract

Systemic sclerosis (SSc) is an autoimmune disease with completely undefined etiology and treatment difficulties. The expression of both protein coding and non-coding RNAs is dysregulated during disease development. We aimed to examine a possible regulatory axis implemented in the control of chitinase-3 like [...] Read more.

Systemic sclerosis (SSc) is an autoimmune disease with completely undefined etiology and treatment difficulties. The expression of both protein coding and non-coding RNAs is dysregulated during disease development. We aimed to examine a possible regulatory axis implemented in the control of chitinase-3 like protein 1 (CHI3L1) or YKL-40, an inflammation-associated glycoprotein, shown to be elevated in SSc. A panel of seven miRNAs and three lncRNAs potentially involved in the control of CHI3L1 were selected on the basis of in silico analysis. TagMan assay was used to evaluate the expression levels of miRNAs and RT-qPCR for lncRNAs in white blood cells (WBCs) and plasma from SSc patients and healthy controls. Among the eight screened miRNAs, miR-30e-5p (p = 0.04) and miR-30a-5p (p = 0.01) were significantly downregulated in WBCs and plasma of SSc patients, respectively. On the contrary, the expression of the metastasis associated lung adenocarcinoma transcript 1 (MALAT1) (p = 0.044) and the Nuclear enriched abundant transcript 1 (NEAT1) (p = 0.008) in WBCs was upregulated compared to the controls. Increased levels of MALAT1 and NEAT1 could be associated with the downregulation of miR-30e-5p and miR-30a-5p expression in WBCs and plasma. We present novel data on the involvement of a possible regulatory axis lncRNAs/miR-30e/CHI3L1 in SSc and hypothesize that MALAT1 and NEAT1 could act as miR-30e-5p and miR-30a-5p decoys. This may be a reason for the increased serum levels of CHI3L1 in SSc patients. Full article

(This article belongs to the Special Issue MicroRNAs, tRNA Fragments, and Circular RNAs: Pivotal Regulators of Gene Expression and Their Roles in Human Diseases)

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20 pages, 6011 KiB

Open AccessArticle

miR-6315 Attenuates Methotrexate Treatment-Induced Decreased Osteogenesis and Increased Adipogenesis Potentially through Modulating TGF-β/Smad2 Signalling

by Ya-Li Zhang, Liang Liu, Yu-Wen Su and Cory J. Xian

Biomedicines 2021, 9(12), 1926; https://doi.org/10.3390/biomedicines9121926 - 16 Dec 2021

Cited by 3 | Viewed by 2188

Abstract

Methotrexate (MTX) treatment for childhood malignancies has shown decreased osteogenesis and increased adipogenesis in bone marrow stromal cells (BMSCs), leading to bone loss and bone marrow adiposity, for which the molecular mechanisms are not fully understood. Currently, microRNAs (miRNAs) are emerging as vital [...] Read more.

Methotrexate (MTX) treatment for childhood malignancies has shown decreased osteogenesis and increased adipogenesis in bone marrow stromal cells (BMSCs), leading to bone loss and bone marrow adiposity, for which the molecular mechanisms are not fully understood. Currently, microRNAs (miRNAs) are emerging as vital mediators involved in bone/bone marrow fat homeostasis and our previous studies have demonstrated that miR-6315 was upregulated in bones of MTX-treated rats, which might be associated with bone/fat imbalance by directly targeting Smad2. However, the underlying mechanisms by which miR-6315 regulates osteogenic and adipogenic differentiation require more investigations. Herein, we further explored and elucidated the regulatory roles of miR-6315 in osteogenesis and adipogenesis using in vitro cell models. We found that miR-6315 promotes osteogenic differentiation and it alleviates MTX-induced increased adipogenesis. Furthermore, our results suggest that the involvement of miR-6315 in osteogenesis/adipogenesis regulation might be partially through modulating the TGF-β/Smad2 signalling pathway. Our findings indicated that miR-6315 may be important in regulating osteogenesis and adipogenesis and might be a therapeutic target for preventing/attenuating MTX treatment-associated bone loss and marrow adiposity. Full article

(This article belongs to the Special Issue MicroRNAs, tRNA Fragments, and Circular RNAs: Pivotal Regulators of Gene Expression and Their Roles in Human Diseases)

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19 pages, 5393 KiB

Open AccessArticle

tRNA Derivatives in Multiple Myeloma: Investigation of the Potential Value of a tRNA-Derived Molecular Signature

by Paraskevi Karousi, Aristea-Maria Papanota, Pinelopi I. Artemaki, Christine-Ivy Liacos, Dimitrios Patseas, Nefeli Mavrianou-Koutsoukou, Aikaterini-Anna Liosi, Maria-Anna Kalioraki, Ioannis Ntanasis-Stathopoulos, Maria Gavriatopoulou, Efstathios Kastritis, Meletios-Athanasios Dimopoulos, Andreas Scorilas, Evangelos Terpos and Christos K. Kontos

Biomedicines 2021, 9(12), 1811; https://doi.org/10.3390/biomedicines9121811 - 01 Dec 2021

Cited by 9 | Viewed by 1903

Abstract

Multiple myeloma (MM) is a hematologic malignancy arising from the clonal proliferation of malignant plasma cells. tRNA-derived RNA fragments (tRFs) constitute a class of small non-coding RNAs, deriving from specific enzymatic cleavage of tRNAs. To the best of our knowledge, this is one [...] Read more.

Multiple myeloma (MM) is a hematologic malignancy arising from the clonal proliferation of malignant plasma cells. tRNA-derived RNA fragments (tRFs) constitute a class of small non-coding RNAs, deriving from specific enzymatic cleavage of tRNAs. To the best of our knowledge, this is one of few studies to uncover the potential clinical significance of tRFs in MM. Total RNA was extracted from CD138+ plasma cells of MM and smoldering MM patients, and in vitro polyadenylated. First-strand cDNA synthesis was performed, priming from an oligo-dT-adaptor sequence. Next, real-time quantitative PCR (qPCR) assays were developed for the quantification of six tRFs. Biostatistical analysis was performed to assess the results and in silico analysis was conducted to predict the function of one of the tRFs. Our results showed that elevated levels of five out of six tRFs are indicators of favorable prognosis in MM, predicting prolonged overall survival (OS), while two of them constitute potential molecular biomarkers of favorable prognosis in terms of disease progression. Moreover, three tRFs could be used as surrogate prognostic biomarkers along with the R-ISS staging system to predict OS. In conclusion, tRFs show molecular biomarker utility in MM, while their mechanisms of function merit further investigation. Full article

(This article belongs to the Special Issue MicroRNAs, tRNA Fragments, and Circular RNAs: Pivotal Regulators of Gene Expression and Their Roles in Human Diseases)

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19 pages, 2150 KiB

Open AccessArticle

Platelet miRNA Biosignature Discriminates between Dementia with Lewy Bodies and Alzheimer’s Disease

by Ana Gámez-Valero, Jaume Campdelacreu, Dolores Vilas, Lourdes Ispierto, Jordi Gascón-Bayarri, Ramón Reñé, Ramiro Álvarez, Maria P. Armengol, Francesc E. Borràs and Katrin Beyer

Biomedicines 2021, 9(9), 1272; https://doi.org/10.3390/biomedicines9091272 - 20 Sep 2021

Cited by 9 | Viewed by 2880

Abstract

Dementia with Lewy bodies (DLB) is one of the most common causes of degenerative dementia, after Alzheimer’s disease (AD), and presents pathological and clinical overlap with both AD and Parkinson’s disease (PD). Consequently, only one in three DLB cases is diagnosed correctly. Platelets, [...] Read more.

Dementia with Lewy bodies (DLB) is one of the most common causes of degenerative dementia, after Alzheimer’s disease (AD), and presents pathological and clinical overlap with both AD and Parkinson’s disease (PD). Consequently, only one in three DLB cases is diagnosed correctly. Platelets, previously related to neurodegeneration, contain microRNAs (miRNAs) whose analysis may provide disease biomarkers. Here, we profiled the whole platelet miRNA transcriptome from DLB patients and healthy controls. Differentially expressed miRNAs were further validated in three consecutive studies from 2017 to 2019 enrolling 162 individuals, including DLB, AD, and PD patients, and healthy controls. Results comprised a seven-miRNA biosignature, showing the highest diagnostic potential for the differentiation between DLB and AD. Additionally, compared to controls, two miRNAs were down-regulated in DLB, four miRNAs were up-regulated in AD, and two miRNAs were down-regulated in PD. Predictive target analysis identified three disease-specific clusters of pathways as a result of platelet-miRNA deregulation. Our cross-sectional study assesses the identification of a novel, highly specific and sensitive platelet-associated miRNA-based biosignature, which distinguishes DLB from AD. Full article

(This article belongs to the Special Issue MicroRNAs, tRNA Fragments, and Circular RNAs: Pivotal Regulators of Gene Expression and Their Roles in Human Diseases)

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14 pages, 2067 KiB

Open AccessArticle

Salivary miR-30c-5p as Potential Biomarker for Detection of Oral Squamous Cell Carcinoma

by Nikolay Mehterov, Boyan Vladimirov, Andrea Sacconi, Claudio Pulito, Marcin Rucinski, Giovanni Blandino and Victoria Sarafian

Biomedicines 2021, 9(9), 1079; https://doi.org/10.3390/biomedicines9091079 - 24 Aug 2021

Cited by 13 | Viewed by 2725

Abstract

The levels of different classes of extracellular RNAs (exRNAs) remain stable in bodily fluids. The detection of either enriched or depleted specific subsets of salivary microRNAs (miRNAs) has the potential to serve as a non-invasive approach for biomarker development. Thus, salivary miRNAs have [...] Read more.

The levels of different classes of extracellular RNAs (exRNAs) remain stable in bodily fluids. The detection of either enriched or depleted specific subsets of salivary microRNAs (miRNAs) has the potential to serve as a non-invasive approach for biomarker development. Thus, salivary miRNAs have emerged as a promising molecular tool for early diagnosis and screening of oral squamous cell carcinoma (OSCC). Total RNA was extracted from saliva supernatant of 33 OSCC patients and 12 controls (discovery set), and the differential expression of 8 cancer-related miRNAs was detected by TaqMan assay. Among the screened miRNAs, miR-30c-5p (p < 0.04) was significantly decreased in OSCC saliva. The same transcriptional behavior of miR30c-5p was observed in an additional validation set. miR-30c-5p showed a significant statistical difference between cases and controls with areas under the curve (AUC) of 0.82 (95% CI: 0.71–0.89). The sensitivity and the specificity of miR-30c-5p were 86% and 74%, respectively. The target identification analysis revealed enrichment of miR-30c-5p targets in p53 and Wnt signaling pathways in OSCC. Additionally, the miR-30c-5p targets had clinical significance related to overall survival. In conclusion, these findings show that downregulated miR-30c-5p has the potential to serve as a novel, non-invasive biomarker for early OSCC detection. Full article

(This article belongs to the Special Issue MicroRNAs, tRNA Fragments, and Circular RNAs: Pivotal Regulators of Gene Expression and Their Roles in Human Diseases)

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18 pages, 1539 KiB

Open AccessArticle

Childhood Obesity-Related Mechanisms: MicroRNome and Transcriptome Changes in a Nested Case-Control Study

by Jin Hee Kim, Da Hae Kim, Youn-Hee Lim, Choong Ho Shin, Young Ah Lee, Bung-Nyun Kim, Johanna Inhyang Kim and Yun-Chul Hong

Biomedicines 2021, 9(8), 878; https://doi.org/10.3390/biomedicines9080878 - 23 Jul 2021

Cited by 2 | Viewed by 2321

Abstract

Childhood obesity could contribute to adulthood obesity, leading to adverse health outcomes in adults. However, the mechanisms for how obesity is developed are still unclear. To determine the epigenome-wide and genome-wide expression changes related with childhood obesity, we compared microRNome and transcriptome levels [...] Read more.

Childhood obesity could contribute to adulthood obesity, leading to adverse health outcomes in adults. However, the mechanisms for how obesity is developed are still unclear. To determine the epigenome-wide and genome-wide expression changes related with childhood obesity, we compared microRNome and transcriptome levels as well as leptin protein levels in whole bloods of 12 obese and 24 normal children aged 6 years. miR-328-3p, miR-1301-3p, miR-4685-3p, and miR-6803-3p were negatively associated with all obesity indicators. The four miRNAs were also associated with 3948 mRNAs, and separate 475 mRNAs (185 among 3948 mRNAs) were associated with all obesity indicators. The 2533 mRNAs (64.2%) among the 3948 mRNAs and 286 mRNAs (60.2%) among the 475 mRNAs were confirmed as targets of the four miRNAs in public databases through miRWalk 2.0. Leptin protein was associated with miR-6803-3p negatively and all obesity indicators positively. Using DAVID bioinformatics resources 6.8, top three pathways for obesity-related gene set were metabolic pathways, pathways in cancer, and PI3K-Akt signaling pathway. The top three obesity-related disease classes were metabolic, cardiovascular, and chemdependency. Our results support that childhood obesity could be developed through miRNAs-related epigenetic mechanism and, further, these obesity-related epigenetic changes could control the pathways related with the development of various diseases. Full article

(This article belongs to the Special Issue MicroRNAs, tRNA Fragments, and Circular RNAs: Pivotal Regulators of Gene Expression and Their Roles in Human Diseases)

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12 pages, 1992 KiB

Open AccessArticle

Highly Magnetized Encoded Hydrogel Microparticles with Enhanced Rinsing Capabilities for Efficient microRNA Detection

by Wookyoung Jang, Jiwoo Kim, Seok Joon Mun, Sun Min Kim and Ki Wan Bong

Biomedicines 2021, 9(7), 848; https://doi.org/10.3390/biomedicines9070848 - 20 Jul 2021

Cited by 4 | Viewed by 2992

Abstract

Encoded hydrogel microparticles mounting DNA probes are powerful tools for high-performance microRNA (miRNA) detection in terms of sensitivity, specificity, and multiplex detection capability. However, several particle rinsing steps in the assay procedure present challenges for rapid and efficient detection. To overcome this limitation, [...] Read more.

Encoded hydrogel microparticles mounting DNA probes are powerful tools for high-performance microRNA (miRNA) detection in terms of sensitivity, specificity, and multiplex detection capability. However, several particle rinsing steps in the assay procedure present challenges for rapid and efficient detection. To overcome this limitation, we encapsulated dense magnetic nanoparticles to reduce the rinsing steps and duration via magnetic separation. A large number of magnetic nanoparticles were encapsulated into hydrogel microparticles based on a discontinuous dewetting technique combined with degassed micromolding lithography. In addition, we attached DNA probes targeting three types of miRNAs related to preeclampsia to magnetically encoded hydrogel microparticles by post-synthesis conjugation and achieved sensitivity comparable to that of conventional nonmagnetic encoded hydrogel microparticles. To demonstrate the multiplex capability of magnetically encoded hydrogel microparticles while maintaining the advantages of the simplified rinsing process when addressing multiple samples, we conducted a triplex detection of preeclampsia-related miRNAs. In conclusion, the introduction of magnetically encoded hydrogel microparticles not only allowed efficient miRNA detection but also provided comparable sensitivity and multiplexed detectability to conventional nonmagnetic encoded hydrogel microparticles. Full article

(This article belongs to the Special Issue MicroRNAs, tRNA Fragments, and Circular RNAs: Pivotal Regulators of Gene Expression and Their Roles in Human Diseases)

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12 pages, 1786 KiB

Open AccessArticle

Longitudinal Circulating Levels of miR-23b-3p, miR-126-3p and lncRNA GAS5 in HCC Patients Treated with Sorafenib

by Michele Manganelli, Ilaria Grossi, Manuela Ferracin, Paola Guerriero, Massimo Negrini, Michele Ghidini, Chiara Senti, Margherita Ratti, Claudio Pizzo, Rodolfo Passalacqua, Sarah Molfino, Gianluca Baiocchi, Nazario Portolani, Eleonora Marchina, Giuseppina De Petro and Alessandro Salvi

Biomedicines 2021, 9(7), 813; https://doi.org/10.3390/biomedicines9070813 - 13 Jul 2021

Cited by 13 | Viewed by 2428

Abstract

Human hepatocellular carcinoma (HCC) is the most frequent primary tumor of the liver and the third cause of cancer-related deaths. The multikinase inhibitor sorafenib is a systemic drug for unresectable HCC. The identification of molecular biomarkers for the early diagnosis of HCC and [...] Read more.

Human hepatocellular carcinoma (HCC) is the most frequent primary tumor of the liver and the third cause of cancer-related deaths. The multikinase inhibitor sorafenib is a systemic drug for unresectable HCC. The identification of molecular biomarkers for the early diagnosis of HCC and responsiveness to treatment are needed. In this work, we performed an exploratory study to investigate the longitudinal levels of cell-free long ncRNA GAS5 and microRNAs miR-126-3p and -23b-3p in a cohort of 7 patients during the period of treatment with sorafenib. We used qPCR to measure the amounts of GAS5 and miR-126-3p and droplet digital PCR (ddPCR) to measure the levels of miR-23b-3p. Patients treated with sorafenib displayed variable levels of GAS5, miR-126-3p and miR-23b-3p at different time-points of follow-up. miR-23b-3p was further measured by ddPCR in 37 healthy individuals and 25 untreated HCC patients. The amount of miR-23b-3p in the plasma of untreated HCC patients was significantly downregulated if compared to healthy individuals. The ROC curve analysis underlined its diagnostic relevance. In conclusion, our results highlight a potential clinical significance of circulating miR-23b-3p and an exploratory observation on the longitudinal plasmatic levels of GAS5, miR-126-3p and miR-23b-3p during sorafenib treatment. Full article

(This article belongs to the Special Issue MicroRNAs, tRNA Fragments, and Circular RNAs: Pivotal Regulators of Gene Expression and Their Roles in Human Diseases)

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14 pages, 1580 KiB

Open AccessArticle

miR-208b Reduces the Expression of Kcnj5 in a Cardiomyocyte Cell Line

by Julia Hupfeld, Maximilian Ernst, Maria Knyrim, Stephanie Binas, Udo Kloeckner, Sindy Rabe, Katja Quarch, Danny Misiak, Matthew Fuszard, Claudia Grossmann, Michael Gekle and Barbara Schreier

Biomedicines 2021, 9(7), 719; https://doi.org/10.3390/biomedicines9070719 - 23 Jun 2021

Cited by 4 | Viewed by 2139

Abstract

MicroRNAs (miRs) contribute to different aspects of cardiovascular pathology, among them cardiac hypertrophy and atrial fibrillation. Cardiac miR expression was analyzed in a mouse model with structural and electrical remodeling. Next-generation sequencing revealed that miR-208b-3p was ~25-fold upregulated. Therefore, the aim of our [...] Read more.

MicroRNAs (miRs) contribute to different aspects of cardiovascular pathology, among them cardiac hypertrophy and atrial fibrillation. Cardiac miR expression was analyzed in a mouse model with structural and electrical remodeling. Next-generation sequencing revealed that miR-208b-3p was ~25-fold upregulated. Therefore, the aim of our study was to evaluate the impact of miR-208b on cardiac protein expression. First, an undirected approach comparing whole RNA sequencing data to miR-walk 2.0 miR-208b 3′-UTR targets revealed 58 potential targets of miR-208b being regulated. We were able to show that miR-208b mimics bind to the 3′ untranslated region (UTR) of voltage-gated calcium channel subunit alpha1 C and Kcnj5, two predicted targets of miR-208b. Additionally, we demonstrated that miR-208b mimics reduce GIRK1/4 channel-dependent thallium ion flux in HL-1 cells. In a second undirected approach we performed mass spectrometry to identify the potential targets of miR-208b. We identified 40 potential targets by comparison to miR-walk 2.0 3′-UTR, 5′-UTR and CDS targets. Among those targets, Rock2 and Ran were upregulated in Western blots of HL-1 cells by miR-208b mimics. In summary, miR-208b targets the mRNAs of proteins involved in the generation of cardiac excitation and propagation, as well as of proteins involved in RNA translocation (Ran) and cardiac hypertrophic response (Rock2). Full article

(This article belongs to the Special Issue MicroRNAs, tRNA Fragments, and Circular RNAs: Pivotal Regulators of Gene Expression and Their Roles in Human Diseases)

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20 pages, 3483 KiB

Open AccessArticle

An Integrative Transcriptomic and Methylation Approach for Identifying Differentially Expressed Circular RNAs Associated with DNA Methylation Change

by Tianyi Xu, LiPing Wang, Peilin Jia, Xiaofeng Song and Zhongming Zhao

Biomedicines 2021, 9(6), 657; https://doi.org/10.3390/biomedicines9060657 - 08 Jun 2021

Cited by 6 | Viewed by 2873

Abstract

Recently, accumulating evidence has supported that circular RNA (circRNA) plays important roles in tumorigenesis by regulating gene expression at transcriptional and post-transcriptional levels. Expression of circRNAs can be epigenetically silenced by DNA methylation; however, the underlying regulatory mechanisms of circRNAs by DNA methylation [...] Read more.

Recently, accumulating evidence has supported that circular RNA (circRNA) plays important roles in tumorigenesis by regulating gene expression at transcriptional and post-transcriptional levels. Expression of circRNAs can be epigenetically silenced by DNA methylation; however, the underlying regulatory mechanisms of circRNAs by DNA methylation remains largely unknown. We explored this regulation in hepatocellular carcinoma (HCC) using genome-wide DNA methylation and RNA sequencing data of the primary tumor and matched adjacent normal tissues from 20 HCC patients. Our pipeline identified 1012 upregulated and 747 downregulated circRNAs (collectively referred to as differentially expressed circRNAs, or DE circRNAs) from HCC RNA-seq data. Among them, 329 DE circRNAs covered differentially methylated sites (adjusted p-value < 0.05, |ΔM| > 0.5) in circRNAs’ interior and/or flanking regions. Interestingly, the corresponding parental genes of 46 upregulated and 31 downregulated circRNAs did not show significant expression change in the HCC tumor versus normal samples. Importantly, 34 of the 77 DE circRNAs (44.2%) had significant correlation with DNA methylation change in HCC (Spearman’s rank-order correlation, p-value < 0.05), suggesting that aberrant DNA methylation might regulate circular RNA expression in HCC. Our study revealed genome-wide differential circRNA expression in HCC. The significant correlation with DNA methylation change suggested that epigenetic regulation might act on both mRNA and circRNA expression. The specific regulation in HCC and general view in other cancer or disease requires further investigation. Full article

(This article belongs to the Special Issue MicroRNAs, tRNA Fragments, and Circular RNAs: Pivotal Regulators of Gene Expression and Their Roles in Human Diseases)

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13 pages, 3107 KiB

Open AccessArticle

Regulation of MRP4 Expression by circHIPK3 via Sponging miR-124-3p/miR-4524-5p in Hepatocellular Carcinoma

by Haihong Hu, Yu Wang, Zhiyuan Qin, Wen Sun, Yanhong Chen, Jiaqi Wang, Yingying Wang, Jing Nie, Lu Chen, Sheng Cai, Lushan Yu and Su Zeng

Biomedicines 2021, 9(5), 497; https://doi.org/10.3390/biomedicines9050497 - 30 Apr 2021

Cited by 10 | Viewed by 2262

Abstract

Multidrug resistance-associated protein 4 (MRP4), a member of the adenosine triphosphate (ATP) binding cassette transporter family, pumps various molecules out of the cell and is involved in cell communication and drug distribution. Several studies have reported the role of miRNAs in downregulating the [...] Read more.

Multidrug resistance-associated protein 4 (MRP4), a member of the adenosine triphosphate (ATP) binding cassette transporter family, pumps various molecules out of the cell and is involved in cell communication and drug distribution. Several studies have reported the role of miRNAs in downregulating the expression of MRP4. However, regulation of MRP4 by circular RNA (circRNA) is yet to be elucidated. In this study, MRP4 was significantly upregulated in hepatocellular carcinoma (HCC) tissues compared to the adjacent noncancerous tissues. Computational prediction, luciferase reporter assay and miRNA transfection were used to investigate the interaction between miRNAs and MRP4. miR-124-3p and miR-4524-5p reduced the expression of MRP4 at the protein but not mRNA level. Circular RNA in vivo precipitation and luciferase reporter assays demonstrated that circHIPK3, as a competitive endogenous RNA, binds with miR-124-3p and miR-4524-5p. Further, knockdown of circHIPK3 resulted in downregulation of MRP4 protein, whereas cotransfection of circHIPK3-siRNA and miR-124-3p or miR-4524-5p inhibitors restored its expression. In conclusion, we report that miR-4524-5p downregulates the expression of MRP4 and circHIPK3 regulates MRP4 expression by sponging miR-124-3p and miR-4524-5p for the first time. Our results may provide novel insights into the prevention of MRP4-related proliferation and multiple drug resistance in HCC. Full article

(This article belongs to the Special Issue MicroRNAs, tRNA Fragments, and Circular RNAs: Pivotal Regulators of Gene Expression and Their Roles in Human Diseases)

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14 pages, 1142 KiB

Open AccessArticle

Circulating microRNAs Related to Bone Metabolism in HIV-Associated Bone Loss

by Maria P. Yavropoulou, Artemis Kolynou, Polyzois Makras, Maria Pikilidou, Sideris Nanoudis, Lemonia Skoura, Olga Tsachouridou, Georgios Ntritsos, Alexandros Tzallas, Dimitrios G. Tsalikakis, Olga Tsave, Simeon Metallidis and Dimitrios Chatzidimitriou

Biomedicines 2021, 9(4), 443; https://doi.org/10.3390/biomedicines9040443 - 20 Apr 2021

Cited by 2 | Viewed by 2098

Abstract

The pathophysiology of human immunodeficiency virus (HIV)-associated bone loss is complex and to date largely unknown. In this study, we investigated serum expression of microRNAS (miRNAs) linked to bone metabolism in HIV-associated bone loss. This was a case-control study. Thirty male individuals with [...] Read more.

The pathophysiology of human immunodeficiency virus (HIV)-associated bone loss is complex and to date largely unknown. In this study, we investigated serum expression of microRNAS (miRNAs) linked to bone metabolism in HIV-associated bone loss. This was a case-control study. Thirty male individuals with HIV infection (HIV+) and osteoporosis/osteopenia (HIV+/OP+) (cases) and 30 age-matched male HIV+ individuals with normal bone mass (HIV+/OP−) (controls) were included in the analysis. Thirty male individuals matched for age without HIV infection (HIV−), were also included as second controls. The selected panel of miRNAs was as follows: hsa-miRNA-21-5p; hsa-miRNA-23a-3p; hsa-miRNA-24-2-5p; hsa-miRNA-26a-5p; hsa-miRNA-29a-3p; hsa-miRNA-124-3p; hsa-miRNA-33a-5p; and hsa-miRNA-133a-3p. Within the cohort of HIV+ individuals, relative serum expression of miRNA-21-5p and miRNA-23a-3p was significantly lower (p < 0.001) while the expression of miRNA-24-2-5p was significantly higher (p = 0.030) in HIV+/OP+ compared to HIV+/OP−. Expression of miRNA-21-5p demonstrated a sensitivity of 84.6% and a specificity of 66.7 in distinguishing HIV+/OP+ individuals. Expression of circulating miRNAs related to bone metabolism; miRNA-23a-3p, miRNA-24-2-5p, and miRNA-21-5p is significantly altered in HIV+OP+ individuals, in line with data on other causes of osteoporosis, suggesting a common pattern of circulating miRNAs independent of the underlying cause. Full article

(This article belongs to the Special Issue MicroRNAs, tRNA Fragments, and Circular RNAs: Pivotal Regulators of Gene Expression and Their Roles in Human Diseases)

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16 pages, 3073 KiB

Open AccessArticle

MicroRNAs Regulating Tumor and Immune Cell Interactions in the Prediction of Relapse in Early Stage Breast Cancer

by Chara Papadaki, Konstantina Thomopoulou, Alexia Monastirioti, George Koronakis, Maria A. Papadaki, Konstantinos Rounis, Lambros Vamvakas, Christoforos Nikolaou, Dimitrios Mavroudis and Sofia Agelaki

Biomedicines 2021, 9(4), 421; https://doi.org/10.3390/biomedicines9040421 - 13 Apr 2021

Cited by 2 | Viewed by 2247

Abstract

MicroRNAs (miRNAs) are involved in the regulation of immune response and hold an important role in tumor immune escape. We investigated the differential expression of the immunomodulatory miR-10b, miR-19a, miR-20a, miR-126, and miR-155 in the plasma of healthy women and patients with early [...] Read more.

MicroRNAs (miRNAs) are involved in the regulation of immune response and hold an important role in tumor immune escape. We investigated the differential expression of the immunomodulatory miR-10b, miR-19a, miR-20a, miR-126, and miR-155 in the plasma of healthy women and patients with early stage breast cancer and interrogated their role in the prediction of patients’ relapse. Blood samples were obtained from healthy women (n = 20) and patients with early stage breast cancer (n = 140) before adjuvant chemotherapy. Plasma miRNA expression levels were assessed by RT-qPCR. Relapse predicting models were developed using binary logistic regression and receiver operating curves (ROC) were constructed to determine miRNA sensitivity and specificity. Only miR-155 expression was lower in patients compared with healthy women (p = 0.023), whereas miR-155 and miR-10b were lower in patients who relapsed compared with healthy women (p = 0.039 and p = 0.002, respectively). MiR-155 expression combined with axillary lymph node infiltration and tumor grade demonstrated increased capability in distinguishing relapsed from non-relapsed patients [(area under the curve, (AUC = 0.861; p < 0.001)]. Combined miR-19a and miR-20a expression had the highest performance in discriminating patients with early relapse (AUC = 0.816; p < 0.001). Finally, miR-10b in combination with lymph node status and grade had the highest accuracy to discriminate patients with late relapse (AUC = 0.971; p < 0.001). The robustness of the relapse predicting models was further confirmed in a 10-fold cross validation. Deregulation of circulating miRNAs involved in tumor-immune interactions may predict relapse in early stage breast cancer. Their successful clinical integration could potentially address the significance challenge of treatment escalation or de-escalation according to the risk of recurrence. Full article

(This article belongs to the Special Issue MicroRNAs, tRNA Fragments, and Circular RNAs: Pivotal Regulators of Gene Expression and Their Roles in Human Diseases)

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12 pages, 684 KiB

Open AccessReview

MicroRNAs: Novel Targets in Hepatic Ischemia–Reperfusion Injury

by Holly Ingram, Murat Dogan, James D. Eason, Cem Kuscu and Canan Kuscu

Biomedicines 2022, 10(4), 791; https://doi.org/10.3390/biomedicines10040791 - 29 Mar 2022

Cited by 9 | Viewed by 2489

Abstract

Hepatic ischemia–reperfusion injury (IRI) is one of the main factors for early allograft dysfunction (EAD), which may lead to graft rejection, graft loss, or shortened graft life in liver transplantation. Hepatic IRI appears to be inevitable during the majority of liver procurement and [...] Read more.

Hepatic ischemia–reperfusion injury (IRI) is one of the main factors for early allograft dysfunction (EAD), which may lead to graft rejection, graft loss, or shortened graft life in liver transplantation. Hepatic IRI appears to be inevitable during the majority of liver procurement and transportation of donor organs, resulting in a cascade of biological changes. The activation of signaling pathways during IRI results in the up- and downregulation of genes and microRNAs (miRNAs). miRNAs are ~21 nucleotides in length and well-characterized for their role in gene regulations; they have recently been used for therapeutic approaches in addition to their role as biomarkers for many diseases. miRNAs that are associated with hepatic IRI in in vitro and in vivo animal models are comprehensively summarized in this review. In those studies, the manipulation of miRNAs has been shown for the inhibition of aggravated immune response, reduction of apoptosis, stimulation of tissue repair, and enhancement of cell recovery to attenuate liver damage. Therefore, the utilization of liver-specific miRNA holds great potential as a therapeutic agent to improve early allograft dysfunction, hepatic injury, and patient outcome. Full article

(This article belongs to the Special Issue MicroRNAs, tRNA Fragments, and Circular RNAs: Pivotal Regulators of Gene Expression and Their Roles in Human Diseases)

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23 pages, 797 KiB

Open AccessReview

Circular RNAs as Potential Biomarkers in Breast Cancer

by Fatima Domenica Elisa De Palma, Francesco Salvatore, Jonathan G. Pol, Guido Kroemer and Maria Chiara Maiuri

Biomedicines 2022, 10(3), 725; https://doi.org/10.3390/biomedicines10030725 - 21 Mar 2022

Cited by 26 | Viewed by 4381

Abstract

Due to the high heterogeneity and initially asymptomatic nature of breast cancer (BC), the management of this disease depends on imaging together with immunohistochemical and molecular evaluations. These tests allow early detection of BC and patient stratification as they guide clinicians in prognostication [...] Read more.

Due to the high heterogeneity and initially asymptomatic nature of breast cancer (BC), the management of this disease depends on imaging together with immunohistochemical and molecular evaluations. These tests allow early detection of BC and patient stratification as they guide clinicians in prognostication and treatment decision-making. Circular RNAs (circRNAs) represent a class of newly identified long non-coding RNAs. These molecules have been described as key regulators of breast carcinogenesis and progression. Moreover, circRNAs play a role in drug resistance and are associated with clinicopathological features in BC. Accumulating evidence reveals a clinical interest in deregulated circRNAs as diagnostic, prognostic and predictive biomarkers. Furthermore, due to their covalently closed structure, circRNAs are highly stable and easily detectable in body fluids, making them ideal candidates for use as non-invasive biomarkers. Herein, we provide an overview of the biogenesis and pleiotropic functions of circRNAs, and report on their clinical relevance in BC. Full article

(This article belongs to the Special Issue MicroRNAs, tRNA Fragments, and Circular RNAs: Pivotal Regulators of Gene Expression and Their Roles in Human Diseases)

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19 pages, 2481 KiB

Open AccessReview

A Non-Canonical Link between Non-Coding RNAs and Cardiovascular Diseases

by Lucia Natarelli and Christian Weber

Biomedicines 2022, 10(2), 445; https://doi.org/10.3390/biomedicines10020445 - 14 Feb 2022

Cited by 10 | Viewed by 2482

Abstract

Cardiovascular diseases (CVDs) are among the top leading causes of mortality worldwide. Besides canonical environmental and genetic changes reported so far for CVDs, non-coding RNAs (ncRNAs) have emerged as key regulators of genetic and epigenetic mechanisms involved in CVD progression. High-throughput and sequencing [...] Read more.

Cardiovascular diseases (CVDs) are among the top leading causes of mortality worldwide. Besides canonical environmental and genetic changes reported so far for CVDs, non-coding RNAs (ncRNAs) have emerged as key regulators of genetic and epigenetic mechanisms involved in CVD progression. High-throughput and sequencing data revealed that almost 80% of the total genome not only encodes for canonical ncRNAs, such as micro and long ncRNAs (miRNAs and lncRNAs), but also generates novel non-canonical sub-classes of ncRNAs, such as isomiRs and miRNA- and lncRNA-like RNAs. Moreover, recent studies reveal that canonical ncRNA sequences can influence the onset and evolution of CVD through novel “non-canonical” mechanisms. However, a debate exists over the real existence of these non-canonical ncRNAs and their concrete biochemical functions, with most of the dark genome being considered as “junk RNA”. In this review, we report on the ncRNAs with a scientifically validated canonical and non-canonical biogenesis. Moreover, we report on canonical ncRNAs that play a role in CVD through non-canonical mechanisms of action. Full article

(This article belongs to the Special Issue MicroRNAs, tRNA Fragments, and Circular RNAs: Pivotal Regulators of Gene Expression and Their Roles in Human Diseases)

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20 pages, 6408 KiB

Open AccessReview

The Role of Mitochondrial miRNAs in the Development of Radon-Induced Lung Cancer

by Assiya Kussainova, Olga Bulgakova, Akmaral Aripova, Zumama Khalid, Rakhmetkazhi Bersimbaev and Alberto Izzotti

Biomedicines 2022, 10(2), 428; https://doi.org/10.3390/biomedicines10020428 - 11 Feb 2022

Cited by 6 | Viewed by 2630

Abstract

MicroRNAs are short, non-coding RNA molecules regulating gene expression by inhibiting the translation of messenger RNA (mRNA) or leading to degradation. The miRNAs are encoded in the nuclear genome and exported to the cytosol. However, miRNAs have been found in mitochondria and are [...] Read more.

MicroRNAs are short, non-coding RNA molecules regulating gene expression by inhibiting the translation of messenger RNA (mRNA) or leading to degradation. The miRNAs are encoded in the nuclear genome and exported to the cytosol. However, miRNAs have been found in mitochondria and are probably derived from mitochondrial DNA. These miRNAs are able to directly regulate mitochondrial genes and mitochondrial activity. Mitochondrial dysfunction is the cause of many diseases, including cancer. In this review, we consider the role of mitochondrial miRNAs in the pathogenesis of lung cancer with particular reference to radon exposure. Full article

(This article belongs to the Special Issue MicroRNAs, tRNA Fragments, and Circular RNAs: Pivotal Regulators of Gene Expression and Their Roles in Human Diseases)

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24 pages, 713 KiB

Open AccessReview

Single Nucleotide Polymorphisms in microRNA Genes and Colorectal Cancer Risk and Prognosis

by Maria Radanova, Mariya Levkova, Galya Mihaylova, Rostislav Manev, Margarita Maneva, Rossen Hadgiev, Nikolay Conev and Ivan Donev

Biomedicines 2022, 10(1), 156; https://doi.org/10.3390/biomedicines10010156 - 12 Jan 2022

Cited by 11 | Viewed by 2559

Abstract

There is growing interest in single nucleotide polymorphisms (SNPs) in the genes of microRNAs (miRNAs), which could be associated with susceptibility to colorectal cancer (CRC) and therefore for prognosis of the disease and/or treatment response. Moreover, these miRNAs-SNPs could serve as new, low-invasive [...] Read more.

There is growing interest in single nucleotide polymorphisms (SNPs) in the genes of microRNAs (miRNAs), which could be associated with susceptibility to colorectal cancer (CRC) and therefore for prognosis of the disease and/or treatment response. Moreover, these miRNAs-SNPs could serve as new, low-invasive biomarkers for early detection of CRC. In the present article, we performed a thorough review of different SNPs, which were investigated for a correlation with the CRC risk, prognosis, and treatment response. We also analyzed the results from different meta-analyses and the possible reasons for reported contradictory findings, especially when different research groups investigated the same SNP in a gene for a particular miRNA. This illustrates the need for more case-control studies involving participants with different ethnic backgrounds. According to our review, three miRNAs-SNPs—miR-146a rs2910164, miR-27a rs895819 and miR-608 rs4919510—appear as promising prognostic, diagnostic and predictive biomarkers for CRC, respectively. Full article

(This article belongs to the Special Issue MicroRNAs, tRNA Fragments, and Circular RNAs: Pivotal Regulators of Gene Expression and Their Roles in Human Diseases)

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32 pages, 1452 KiB

Open AccessReview

MicroRNA and Alternative mRNA Splicing Events in Cancer Drug Response/Resistance: Potent Therapeutic Targets

by Rahaba Marima, Flavia Zita Francies, Rodney Hull, Thulo Molefi, Meryl Oyomno, Richard Khanyile, Sikhumbuzo Mbatha, Mzubanzi Mabongo, David Owen Bates and Zodwa Dlamini

Biomedicines 2021, 9(12), 1818; https://doi.org/10.3390/biomedicines9121818 - 02 Dec 2021

Cited by 19 | Viewed by 5117

Abstract

Cancer is a multifaceted disease that involves several molecular mechanisms including changes in gene expression. Two important processes altered in cancer that lead to changes in gene expression include altered microRNA (miRNA) expression and aberrant splicing events. MiRNAs are short non-coding RNAs that [...] Read more.

Cancer is a multifaceted disease that involves several molecular mechanisms including changes in gene expression. Two important processes altered in cancer that lead to changes in gene expression include altered microRNA (miRNA) expression and aberrant splicing events. MiRNAs are short non-coding RNAs that play a central role in regulating RNA silencing and gene expression. Alternative splicing increases the diversity of the proteome by producing several different spliced mRNAs from a single gene for translation. MiRNA expression and alternative splicing events are rigorously regulated processes. Dysregulation of miRNA and splicing events promote carcinogenesis and drug resistance in cancers including breast, cervical, prostate, colorectal, ovarian and leukemia. Alternative splicing may change the target mRNA 3′UTR binding site. This alteration can affect the produced protein and may ultimately affect the drug affinity of target proteins, eventually leading to drug resistance. Drug resistance can be caused by intrinsic and extrinsic factors. The interplay between miRNA and alternative splicing is largely due to splicing resulting in altered 3′UTR targeted binding of miRNAs. This can result in the altered targeting of these isoforms and altered drug targets and drug resistance. Furthermore, the increasing prevalence of cancer drug resistance poses a substantial challenge in the management of the disease. Henceforth, molecular alterations have become highly attractive drug targets to reverse the aberrant effects of miRNAs and splicing events that promote malignancy and drug resistance. While the miRNA–mRNA splicing interplay in cancer drug resistance remains largely to be elucidated, this review focuses on miRNA and alternative mRNA splicing (AS) events in breast, cervical, prostate, colorectal and ovarian cancer, as well as leukemia, and the role these events play in drug resistance. MiRNA induced cancer drug resistance; alternative mRNA splicing (AS) in cancer drug resistance; the interplay between AS and miRNA in chemoresistance will be discussed. Despite this great potential, the interplay between aberrant splicing events and miRNA is understudied but holds great potential in deciphering miRNA-mediated drug resistance. Full article

(This article belongs to the Special Issue MicroRNAs, tRNA Fragments, and Circular RNAs: Pivotal Regulators of Gene Expression and Their Roles in Human Diseases)

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15 pages, 1136 KiB

Open AccessReview

MiRNAs as New Tools in Lesion Vitality Evaluation: A Systematic Review and Their Forensic Applications

by Alice Chiara Manetti, Aniello Maiese, Arianna Baronti, Eleonora Mezzetti, Paola Frati, Vittorio Fineschi and Emanuela Turillazzi

Biomedicines 2021, 9(11), 1731; https://doi.org/10.3390/biomedicines9111731 - 20 Nov 2021

Cited by 15 | Viewed by 1717

Abstract

Wound vitality demonstration is one of the most challenging fields in forensic pathology. In recent years, researchers focused on the application of histological and immunohistochemical staining in this sphere of study. It is based on the detection of inflammation, red cell infiltration, and [...] Read more.

Wound vitality demonstration is one of the most challenging fields in forensic pathology. In recent years, researchers focused on the application of histological and immunohistochemical staining in this sphere of study. It is based on the detection of inflammation, red cell infiltration, and tissue alterations at the histological examination, all of which are supposedly present in antemortem rather than post-mortem wounds. Nevertheless, some doubts about the reliability of those markers have arisen. Furthermore, the lack of a standardized protocol and the operator dependency of this approach make the proper interpretation of its results difficult. Moreover, a differential miRNAs expression has been demonstrated in antemortem and post-mortem wounds. Herein, a systematic review concerning the current knowledge about the use of miRNAs in lesion vitality evaluation is carried out, to encourage researchers to deepen this peculiar study area. A compendium about the potential miRNAs that may be further investigated as vitality markers is also provided. The aim is to collect all available data about this topic to direct further studies on this field and highlight the future applications of miRNAs in forensic pathology. We found 20 articles and a total of 51 miRNAs that are involved in inflammation and wound healing. Further studies are certainly needed to deepen the role of miRNAs in inflammatory processes in lesioned skin and to evaluate their reliability in distinguishing between antemortem and post-mortem lesions. Full article

(This article belongs to the Special Issue MicroRNAs, tRNA Fragments, and Circular RNAs: Pivotal Regulators of Gene Expression and Their Roles in Human Diseases)

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38 pages, 938 KiB

Open AccessReview

MicroRNAs as Critical Biomarkers of Major Depressive Disorder: A Comprehensive Perspective

by Miguel A. Ortega, Miguel Angel Alvarez-Mon, Cielo García-Montero, Oscar Fraile-Martinez, Guillermo Lahera, Jorge Monserrat, Luis Muñoz-Merida, Fernando Mora, Roberto Rodríguez-Jiménez, Sonia Fernandez-Rojo, Javier Quintero and Melchor Álvarez-Mon

Biomedicines 2021, 9(11), 1659; https://doi.org/10.3390/biomedicines9111659 - 10 Nov 2021

Cited by 21 | Viewed by 4897

Abstract

Major Depressive Disorder (MDD) represents a major global health concern, a body-mind malady of rising prevalence worldwide nowadays. The complex network of mechanisms involved in MDD pathophysiology is subjected to epigenetic changes modulated by microRNAs (miRNAs). Serum free or vesicles loaded miRNAs have [...] Read more.

Major Depressive Disorder (MDD) represents a major global health concern, a body-mind malady of rising prevalence worldwide nowadays. The complex network of mechanisms involved in MDD pathophysiology is subjected to epigenetic changes modulated by microRNAs (miRNAs). Serum free or vesicles loaded miRNAs have starred numerous publications, denoting a key role in cell-cell communication, systematically and in brain structure and neuronal morphogenesis, activity and plasticity. Upregulated or downregulated expression of these signaling molecules may imply the impairment of genes implicated in pathways of MDD etiopathogenesis (neuroinflammation, brain-derived neurotrophic factor (BDNF), neurotransmitters, hypothalamic-pituitary-adrenal (HPA) axis, oxidative stress, circadian rhythms...). In addition, these miRNAs could serve as potential biomarkers with diagnostic, prognostic and predictive value, allowing to classify severity of the disease or to make decisions in clinical management. They have been considered as promising therapy targets as well and may interfere with available antidepressant treatments. As epigenetic malleable regulators, we also conclude emphasizing lifestyle interventions with physical activity, mindfulness and diet, opening the door to new clinical management considerations. Full article

(This article belongs to the Special Issue MicroRNAs, tRNA Fragments, and Circular RNAs: Pivotal Regulators of Gene Expression and Their Roles in Human Diseases)

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32 pages, 11165 KiB

Open AccessReview

Dissecting the Role of Circular RNAs in Sarcomas with Emphasis on Osteosarcomas

by Eleftheria Lakiotaki, Dimitrios S. Kanakoglou, Andromachi Pampalou, Eleni A. Karatrasoglou, Christina Piperi and Penelope Korkolopoulou

Biomedicines 2021, 9(11), 1642; https://doi.org/10.3390/biomedicines9111642 - 08 Nov 2021

Cited by 5 | Viewed by 2544

Abstract

Circular RNAs (circRNAs) are single-stranded RNAs generated from exons back-splicing from a single pre-mRNA, forming covalently closed loop structures which lack 5′-3′-polarity or polyadenylated tail. Ongoing research depicts that circRNAs play a pivotal role in tumorigenesis, tumor progression, metastatic potential and chemoresistance by [...] Read more.

Circular RNAs (circRNAs) are single-stranded RNAs generated from exons back-splicing from a single pre-mRNA, forming covalently closed loop structures which lack 5′-3′-polarity or polyadenylated tail. Ongoing research depicts that circRNAs play a pivotal role in tumorigenesis, tumor progression, metastatic potential and chemoresistance by regulating transcription, microRNA (miRNA) sponging, RNA-binding protein interactions, alternative splicing and to a lesser degree, protein coding. Sarcomas are rare malignant tumors stemming from mesenchymal cells. Due to their clinically insidious onset, they often present at advanced stage and their treatment may require aggressive chemotherapeutic or surgical options. This review is mainly focused on the regulatory functions of circRNAs on osteosarcoma progression and their potential role as biomarkers, an area which has prompted lately extensive research. The attributed oncogenic role of circRNAs on other mesenchymal tumors such as Kaposi Sarcoma (KS), Rhabdomyosarcoma (RMS) or Gastrointestinal Stromal Tumors (GISTs) is also described. The involvement of circRNAs on sarcoma oncogenesis and relevant emerging diagnostic, prognostic and therapeutic applications are expected to gain more research interest in the future. Full article

(This article belongs to the Special Issue MicroRNAs, tRNA Fragments, and Circular RNAs: Pivotal Regulators of Gene Expression and Their Roles in Human Diseases)

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20 pages, 1331 KiB

Open AccessReview

The Dual Role of Circular RNAs as miRNA Sponges in Breast Cancer and Colon Cancer

by Jiashu Huang, Shenghao Yu, Lei Ding, Lingyuan Ma, Hongjian Chen, Hui Zhou, Yayan Zou, Min Yu, Jie Lin and Qinghua Cui

Biomedicines 2021, 9(11), 1590; https://doi.org/10.3390/biomedicines9111590 - 31 Oct 2021

Cited by 16 | Viewed by 2600

Abstract

Breast cancer (BC) and colon cancer (CRC) are the two most deadly cancers in the world. These cancers partly share the same genetic background and are partially regulated by the same genes. The outcomes of traditional chemoradiotherapy and surgery remain suboptimal, with high [...] Read more.

Breast cancer (BC) and colon cancer (CRC) are the two most deadly cancers in the world. These cancers partly share the same genetic background and are partially regulated by the same genes. The outcomes of traditional chemoradiotherapy and surgery remain suboptimal, with high postoperative recurrence and a low survival rate. It is, therefore, urgent to innovate and improve the existing treatment measures. Many studies primarily reported that the microRNA (miRNA) sponge functions of circular RNA (circRNA) in BC and CRC have an indirect relationship between the circRNA–miRNA axis and malignant behaviors. With a covalent ring structure, circRNAs can regulate the expression of target genes in multiple ways, especially by acting as miRNA sponges. Therefore, this review mainly focuses on the roles of circRNAs as miRNA sponges in BC and CRC based on studies over the last three years, thus providing a theoretical reference for finding new therapeutic targets in the future. Full article

(This article belongs to the Special Issue MicroRNAs, tRNA Fragments, and Circular RNAs: Pivotal Regulators of Gene Expression and Their Roles in Human Diseases)

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17 pages, 979 KiB

Open AccessReview

The Role of Circulating MicroRNAs in Patients with Early-Stage Pancreatic Adenocarcinoma

by Michal Eid, Paraskevi Karousi, Lumír Kunovský, Štěpán Tuček, Dagmar Brančíková, Zdeněk Kala, Ondřej Slabý, Jiří Mayer, Christos K. Kontos and Jan Trna

Biomedicines 2021, 9(10), 1468; https://doi.org/10.3390/biomedicines9101468 - 14 Oct 2021

Cited by 12 | Viewed by 2466

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is increasing in incidence and is still associated with a high rate of mortality. Only a minority of patients are diagnosed in the early stage. Radical surgery is the only potential curative procedure. However, radicality is reached in 20% [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is increasing in incidence and is still associated with a high rate of mortality. Only a minority of patients are diagnosed in the early stage. Radical surgery is the only potential curative procedure. However, radicality is reached in 20% of patients operated on. Despite the multidisciplinary approach in resectable tumors, early tumor recurrences are common. Options on how to select optimal candidates for resection remain limited. Nevertheless, accumulating evidence shows an important role of circulating non-coding plasma and serum microRNAs (miRNAs), which physiologically regulate the function of a target protein. miRNAs also play a crucial role in carcinogenesis. In PDAC patients, the expression levels of certain miRNAs vary and may modulate the function of oncogenes or tumor suppressor genes. As they can be detected in a patient’s blood, they have the potential to become promising non-invasive diagnostic and prognostic biomarkers. Moreover, they may also serve as markers of chemoresistance. Thus, miRNAs could be useful for early and accurate diagnosis, prognostic stratification, and individual treatment planning. In this review, we summarize the latest findings on miRNAs in PDAC patients, focusing on their potential use in the early stage of the disease. Full article

(This article belongs to the Special Issue MicroRNAs, tRNA Fragments, and Circular RNAs: Pivotal Regulators of Gene Expression and Their Roles in Human Diseases)

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24 pages, 1249 KiB

Open AccessReview

Exosomes and Micro-RNAs in Aging Process

by Yousra Hamdan, Loubna Mazini and Gabriel Malka

Biomedicines 2021, 9(8), 968; https://doi.org/10.3390/biomedicines9080968 - 06 Aug 2021

Cited by 12 | Viewed by 4421

Abstract

Exosomes are the main actors of intercellular communications and have gained great interest in the new cell-free regenerative medicine. These nanoparticles are secreted by almost all cell types and contain lipids, cytokines, growth factors, messenger RNA, and different non-coding RNA, especially micro-RNAs (mi-RNAs). [...] Read more.

Exosomes are the main actors of intercellular communications and have gained great interest in the new cell-free regenerative medicine. These nanoparticles are secreted by almost all cell types and contain lipids, cytokines, growth factors, messenger RNA, and different non-coding RNA, especially micro-RNAs (mi-RNAs). Exosomes’ cargo is released in the neighboring microenvironment but is also expected to act on distant tissues or organs. Different biological processes such as cell development, growth and repair, senescence, migration, immunomodulation, and aging, among others, are mediated by exosomes and principally exosome-derived mi-RNAs. Moreover, their therapeutic potential has been proved and reinforced by their use as biomarkers for disease diagnostics and progression. Evidence has increasingly shown that exosome-derived mi-RNAs are key regulators of age-related diseases, and their involvement in longevity is becoming a promising issue. For instance, mi-RNAs such as mi-RNA-21, mi-RNA-29, and mi-RNA-34 modulate tissue functionality and regeneration by targeting different tissues and involving different pathways but might also interfere with long life expectancy. Human mi-RNAs profiling is effectively related to the biological fluids that are reported differently between young and old individuals. However, their underlying mechanisms modulating cell senescence and aging are still not fully understood, and little was reported on the involvement of mi-RNAs in cell or tissue longevity. In this review, we summarize exosome biogenesis and mi-RNA synthesis and loading mechanism into exosomes’ cargo. Additionally, we highlight the molecular mechanisms of exosomes and exosome-derived mi-RNA regulation in the different aging processes. Full article

(This article belongs to the Special Issue MicroRNAs, tRNA Fragments, and Circular RNAs: Pivotal Regulators of Gene Expression and Their Roles in Human Diseases)

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17 pages, 1729 KiB

Open AccessReview

Intrauterine Hypoxia and Epigenetic Programming in Lung Development and Disease

by Yajie Tong, Shuqing Zhang, Suzette Riddle, Lubo Zhang, Rui Song and Dongmei Yue

Biomedicines 2021, 9(8), 944; https://doi.org/10.3390/biomedicines9080944 - 02 Aug 2021

Cited by 9 | Viewed by 3150

Abstract

Clinically, intrauterine hypoxia is the foremost cause of perinatal morbidity and developmental plasticity in the fetus and newborn infant. Under hypoxia, deviations occur in the lung cell epigenome. Epigenetic mechanisms (e.g., DNA methylation, histone modification, and miRNA expression) control phenotypic programming and are [...] Read more.

Clinically, intrauterine hypoxia is the foremost cause of perinatal morbidity and developmental plasticity in the fetus and newborn infant. Under hypoxia, deviations occur in the lung cell epigenome. Epigenetic mechanisms (e.g., DNA methylation, histone modification, and miRNA expression) control phenotypic programming and are associated with physiological responses and the risk of developmental disorders, such as bronchopulmonary dysplasia. This developmental disorder is the most frequent chronic pulmonary complication in preterm labor. The pathogenesis of this disease involves many factors, including aberrant oxygen conditions and mechanical ventilation-mediated lung injury, infection/inflammation, and epigenetic/genetic risk factors. This review is focused on various aspects related to intrauterine hypoxia and epigenetic programming in lung development and disease, summarizes our current knowledge of hypoxia-induced epigenetic programming and discusses potential therapeutic interventions for lung disease. Full article

(This article belongs to the Special Issue MicroRNAs, tRNA Fragments, and Circular RNAs: Pivotal Regulators of Gene Expression and Their Roles in Human Diseases)

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15 pages, 842 KiB

Open AccessReview

The Landscape of Regulatory Noncoding RNAs in Ewing’s Sarcoma

by Connor Barrett, Anuj Budhiraja, Vijay Parashar and Mona Batish

Biomedicines 2021, 9(8), 933; https://doi.org/10.3390/biomedicines9080933 - 31 Jul 2021

Cited by 8 | Viewed by 3432

Abstract

Ewing’s sarcoma (ES) is a pediatric sarcoma caused by a chromosomal translocation. Unlike in most cancers, the genomes of ES patients are very stable. The translocation product of the EWS-FLI1 fusion is most often the predominant genetic driver of oncogenesis, and it is [...] Read more.

Ewing’s sarcoma (ES) is a pediatric sarcoma caused by a chromosomal translocation. Unlike in most cancers, the genomes of ES patients are very stable. The translocation product of the EWS-FLI1 fusion is most often the predominant genetic driver of oncogenesis, and it is pertinent to explore the role of epigenetic alterations in the onset and progression of ES. Several types of noncoding RNAs, primarily microRNAs and long noncoding RNAs, are key epigenetic regulators that have been shown to play critical roles in various cancers. The functions of these epigenetic regulators are just beginning to be appreciated in ES. Here, we performed a comprehensive literature review to identify these noncoding RNAs. We identified clinically relevant tumor suppressor microRNAs, tumor promoter microRNAs and long noncoding RNAs. We then explored the known interplay between different classes of noncoding RNAs and described the currently unmet need for expanding the noncoding RNA repertoire of ES. We concluded the review with a discussion of epigenetic regulation of ES via regulatory noncoding RNAs. These noncoding RNAs provide new avenues of exploration to develop better therapeutics and identify novel biomarkers. Full article

(This article belongs to the Special Issue MicroRNAs, tRNA Fragments, and Circular RNAs: Pivotal Regulators of Gene Expression and Their Roles in Human Diseases)

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14 pages, 742 KiB

Open AccessReview

MicroRNA 320, an Anti-Oncogene Target miRNA for Cancer Therapy

by Yuanyuan Liang, Shun Li and Liling Tang

Biomedicines 2021, 9(6), 591; https://doi.org/10.3390/biomedicines9060591 - 23 May 2021

Cited by 29 | Viewed by 4069

Abstract

MicroRNAs are a set of highly conserved non-coding RNAs that control gene expression at the post-transcriptional/translational levels by binding to the 3′-UTR of diverse target genes. Increasing evidence indicates that miRNAs not only play a vital role in many biological processes, but they [...] Read more.

MicroRNAs are a set of highly conserved non-coding RNAs that control gene expression at the post-transcriptional/translational levels by binding to the 3′-UTR of diverse target genes. Increasing evidence indicates that miRNAs not only play a vital role in many biological processes, but they are also frequently deregulated in pathological conditions, including cancer. The miR-320 family is one of many tumor suppressor families and is composed of five members, which has been demonstrated to be related to the repression of epithelial-mesenchymal transition (EMT) inhibition, cell proliferation, and apoptosis. Moreover, this family has been shown to regulate drug resistance, and act as a potential biomarker for the diagnosis, prognosis, and prediction of cancer. In this review, we summarized recent research with reference to the tumor suppressor function of miR-320 and the regulation mechanisms of miR-320 expression. The collected evidence shown here supports that miR-320 may act as a novel biomarker for cancer prognosis and therapeutic response to cancer treatment. Full article

(This article belongs to the Special Issue MicroRNAs, tRNA Fragments, and Circular RNAs: Pivotal Regulators of Gene Expression and Their Roles in Human Diseases)

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16 pages, 974 KiB

Open AccessReview

Role of MicroRNAs in Human Osteosarcoma: Future Perspectives

by Lola Llobat and Olivia Gourbault

Biomedicines 2021, 9(5), 463; https://doi.org/10.3390/biomedicines9050463 - 23 Apr 2021

Cited by 21 | Viewed by 2895

Abstract

Osteosarcoma (OS) is a rare form of cancer with high death rate but is one of the most frequent forms of bone cancer in children and adolescents. MiRNAs are small endogenous RNAs that regulate gene expression post-transcriptionally. The discovery of miRNAs could allow [...] Read more.

Osteosarcoma (OS) is a rare form of cancer with high death rate but is one of the most frequent forms of bone cancer in children and adolescents. MiRNAs are small endogenous RNAs that regulate gene expression post-transcriptionally. The discovery of miRNAs could allow us to obtain an earlier diagnosis, predict prognosis and chemoresistance, and lead to the discovery of new treatments in different types of tumors, including OS. Despite the fact that there is currently only one clinical trial being carried out on a single miRNA for solid tumors, it is very probable that the number of clinical trials including miRNAs as prognostic and diagnostic biomarkers, as well as potential therapeutic targets, will increase in the near future. This review summarizes the different miRNAs related to OS and their possible therapeutic application. Full article

(This article belongs to the Special Issue MicroRNAs, tRNA Fragments, and Circular RNAs: Pivotal Regulators of Gene Expression and Their Roles in Human Diseases)

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