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Special Issue "Crosstalk between MicroRNA and Oxidative Stress in Physiology and Pathology"

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

Deadline for manuscript submissions: 30 September 2019.

Special Issue Editors

Guest Editor
Dr. Antonella Fioravanti Website E-Mail
Rheumatology Unit, Azienda Ospedaliera Universitaria Senese, Siena, Italy
Phone: ++39 0577 233345
Guest Editor
Prof. Dr. Francesco Dotta Website E-Mail
Diabetes Unit, Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy.
Guest Editor
Prof. Dr. Antonio Giordano Website E-Mail
1. Department of Biology, College of Science and Technology, Temple University, PA, USA
2. Department of Medical Biotechnologies, University of Siena, Italy
Guest Editor
Prof. Dr. Luigi Pirtoli Website E-Mail
1. Department of Biology, College of Science and Technology, Temple University, PA, USA
2. Radiation Oncology Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Italy (Retired)

Special Issue Information

Dear Colleagues,

MicroRNAs (miRNAs)—small non-coding RNAs 19–24 nucleotides long—have emerged as important post-transcriptional regulators of gene expression, by binding specific sequences within target messenger RNA (mRNA). The importance of miRNA epigenetic regulation in cellular function is becoming increasingly clear as novel targets are discovered. They have been associated with controlling important cellular processes, such as lipid metabolism, apoptosis, differentiation, and organ development. Importantly, miRNAs have recently been addressed as novel mediators of cell–cell communication being cell secreted, and are found in many different biological fluids. Such characteristics also make miRNA potential disease biomarkers.

An altered miRNA expression has been linked to pathological features, such as inflammatory, degenerative, or autoimmune processes, and is involved in several disease outcomes, including cancer, cardiovascular diseases, diabetes mellitus, and rheumatic and neurological disorders.

Although they have been extensively studied, their detailed mechanisms are not yet fully understood.

Reactive oxygen species (ROS) are free radicals containing oxygen molecules derived from cellular oxidative metabolism, including enzyme activities and mitochondrial respiration, and play a pivotal role in many cellular functions. Whereas ROS are essential for normal cellular processes, the aberrant production of ROS, or the failure of the capacity to scavenge excessive ROS, determines an altered redox status with an excessive synthesis of free radicals, leading to an imbalance in the redox environment of the cell.

The loss of normal ROS levels can cause the damage of lipids, proteins, and DNA, all of which contribute to the development of various pathologies such as neurological disorders, rheumatic and cardiovascular diseases, diabetes, and cancer.

Recent research highlights conditions where there is a cross-talk between miRNA and oxidative stress, even if this complex and mutual interaction needs to be amply elucidated.

In this regard, we invite investigators to contribute original research articles and review articles that will stimulate the continuing efforts to understand the mechanisms underlying the interaction between miRNA and oxidative stress under normal and diseased processes, to develop strategies to treat these pathological conditions and to identify novel biomarkers of disease.

Dr. Antonella Fioravanti
Prof. Dr. Francesco Dotta
Prof. Dr. Antonio Giordano
Prof. Dr. Luigi Pirtoli
Guest Editors

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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

  • microRNA
  • oxidative stress
  • cardiovascular diseases
  • rheumatic diseases
  • cancer
  • diabetes
  • neurological disorders
  • multiple sclerosis

Published Papers (4 papers)

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Research

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Open AccessArticle
miR526b and miR655 Induce Oxidative Stress in Breast Cancer
Int. J. Mol. Sci. 2019, 20(16), 4039; https://doi.org/10.3390/ijms20164039 - 19 Aug 2019
Abstract
In eukaryotes, overproduction of reactive oxygen species (ROS) causes oxidative stress, which contributes to chronic inflammation and cancer. MicroRNAs (miRNAs) are small, endogenously produced RNAs that play a major role in cancer progression. We established that overexpression of miR526b/miR655 promotes aggressive breast cancer [...] Read more.
In eukaryotes, overproduction of reactive oxygen species (ROS) causes oxidative stress, which contributes to chronic inflammation and cancer. MicroRNAs (miRNAs) are small, endogenously produced RNAs that play a major role in cancer progression. We established that overexpression of miR526b/miR655 promotes aggressive breast cancer phenotypes. Here, we investigated the roles of miR526b/miR655 in oxidative stress in breast cancer using in vitro and in silico assays. miRNA-overexpression in MCF7 cells directly enhances ROS and superoxide (SO) production, detected with fluorescence assays. We found that cell-free conditioned media contain extracellular miR526b/miR655 and treatment with these miRNA-conditioned media causes overproduction of ROS/SO in MCF7 and primary cells (HUVECs). Thioredoxin Reductase 1 (TXNRD1) is an oxidoreductase that maintains ROS/SO concentration. Overexpression of TXNRD1 is associated with breast cancer progression. We observed that miR526b/miR655 overexpression upregulates TXNRD1 expression in MCF7 cells, and treatment with miRNA-conditioned media upregulates TXNRD1 in both MCF7 and HUVECs. Bioinformatic analysis identifies two negative regulators of TXNRD1, TCF21 and PBRM1, as direct targets of miR526b/miR655. We validated that TCF21 and PBRM1 were significantly downregulated with miRNA upregulation, establishing a link between miR526b/miR655 and TXNRD1. Finally, treatments with oxidative stress inducers such as H2O2 or miRNA-conditioned media showed an upregulation of miR526b/miR655 expression in MCF7 cells, indicating that oxidative stress also induces miRNA overexpression. This study establishes the dynamic functions of miR526b/miR655 in oxidative stress induction in breast cancer. Full article
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Open AccessArticle
miR-27a-5p Attenuates Hypoxia-induced Rat Cardiomyocyte Injury by Inhibiting Atg7
Int. J. Mol. Sci. 2019, 20(10), 2418; https://doi.org/10.3390/ijms20102418 - 16 May 2019
Abstract
Acute myocardial infarction (AMI) is an ischemic heart disease with high mortality worldwide. AMI triggers a hypoxic microenvironment and induces extensive myocardial injury, including autophagy and apoptosis. MiRNAs, which are a class of posttranscriptional regulators, have been shown to be involved in the [...] Read more.
Acute myocardial infarction (AMI) is an ischemic heart disease with high mortality worldwide. AMI triggers a hypoxic microenvironment and induces extensive myocardial injury, including autophagy and apoptosis. MiRNAs, which are a class of posttranscriptional regulators, have been shown to be involved in the development of ischemic heart diseases. We have previously reported that hypoxia significantly alters the miRNA transcriptome in rat cardiomyoblast cells (H9c2), including miR-27a-5p. In the present study, we further investigated the potential function of miR-27a-5p in the cardiomyocyte response to hypoxia, and showed that miR-27a-5p expression was downregulated in the H9c2 cells at different hypoxia-exposed timepoints and the myocardium of a rat AMI model. Follow-up experiments revealed that miR-27a-5p attenuated hypoxia-induced cardiomyocyte injury by regulating autophagy and apoptosis via Atg7, which partly elucidated the anti-hypoxic injury effects of miR-27a-5p. Taken together, this study shows that miR-27a-5p has a cardioprotective effect on hypoxia-induced H9c2 cell injury, suggesting it may be a novel target for the treatment of hypoxia-related heart diseases. Full article
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Review

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Open AccessReview
MicroRNA Networks Modulate Oxidative Stress in Cancer
Int. J. Mol. Sci. 2019, 20(18), 4497; https://doi.org/10.3390/ijms20184497 - 11 Sep 2019
Abstract
Imbalanced regulation of reactive oxygen species (ROS) and antioxidant factors in cells is known as “oxidative stress (OS)”. OS regulates key cellular physiological responses through signal transduction, transcription factors and noncoding RNAs (ncRNAs). Increasing evidence indicates that continued OS can cause chronic inflammation, [...] Read more.
Imbalanced regulation of reactive oxygen species (ROS) and antioxidant factors in cells is known as “oxidative stress (OS)”. OS regulates key cellular physiological responses through signal transduction, transcription factors and noncoding RNAs (ncRNAs). Increasing evidence indicates that continued OS can cause chronic inflammation, which in turn contributes to cardiovascular and neurological diseases and cancer development. MicroRNAs (miRNAs) are small ncRNAs that produce functional 18-25-nucleotide RNA molecules that play critical roles in the regulation of target gene expression by binding to complementary regions of the mRNA and regulating mRNA degradation or inhibiting translation. Furthermore, miRNAs function as either tumor suppressors or oncogenes in cancer. Dysregulated miRNAs reportedly modulate cancer hallmarks such as metastasis, angiogenesis, apoptosis and tumor growth. Notably, miRNAs are involved in ROS production or ROS-mediated function. Accordingly, investigating the interaction between ROS and miRNAs has become an important endeavor that is expected to aid in the development of effective treatment/prevention strategies for cancer. This review provides a summary of the essential properties and functional roles of known miRNAs associated with OS in cancers. Full article
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Open AccessReview
Development and Clinical Trials of Nucleic Acid Medicines for Pancreatic Cancer Treatment
Int. J. Mol. Sci. 2019, 20(17), 4224; https://doi.org/10.3390/ijms20174224 - 29 Aug 2019
Abstract
Approximately 30% of pancreatic cancer patients harbor targetable mutations. However, there has been no therapy targeting these molecules clinically. Nucleic acid medicines show high specificity and can target RNAs. Nucleic acid medicine is expected to be the next-generation treatment next to small molecules [...] Read more.
Approximately 30% of pancreatic cancer patients harbor targetable mutations. However, there has been no therapy targeting these molecules clinically. Nucleic acid medicines show high specificity and can target RNAs. Nucleic acid medicine is expected to be the next-generation treatment next to small molecules and antibodies. There are several kinds of nucleic acid drugs, including antisense oligonucleotides, small interfering RNAs, microRNAs, aptamers, decoys, and CpG oligodeoxynucleotides. In this review, we provide an update on current research of nucleic acid-based therapies. Despite the challenging obstacles, we hope that nucleic acid drugs will have a significant impact on the treatment of pancreatic cancer. The combination of genetic diagnosis using next generation sequencing and targeted therapy may provide effective precision medicine for pancreatic cancer patients. Full article
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Figure 1

Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Title: Crosstalk Between Oxidative Stress Signaling and MicroRNA Regulatory Systems in Cancer; Focused on Gastrointestinal Carcinogenesis

Author: Abolfazl Akbari

Abstract: Molecular mechanisms underlying development and progression of gastrointestinal cancers are mediated by both oxidative stress (OS) and microRNAs (miRNAs). Notably, OS signaling may regulate expression of miRNAs, and miRNAs function as imperative players in OS-related tumors. In view of the defined biological roles of both OS systems and miRNAs in gastrointestinal carcinogenesis, a possible interplay between these two key cellular networks is considered. Based on overgrowing evidence, a reciprocal connection between oxidative stress signaling pathways and miRNA regulatory machines is to be expected in gastrointestinal cancer development and progression. Illumination of the molecular crosstalking between miRNAs and OS would improve our pathophysiological insight into cancers. As well, understanding the molecular mechanisms in which these systems reciprocally be regulated may have an implication in future medical practice mainly cancer therapeutic response. Today, therapeutic strategies focusing on miRNA and OS in cancer treatment is increasingly delineated. Since the use of antioxidants is limited owing to the contrasting consequences of OS signaling in cancer, the discovery of OS-responsive miRNAs may provide a potential new strategy to overcome OS-mediated carcinogenesis.

Given the possible interaction between OS and miRNAs in gastrointestinal cancers, this review aims to elucidate the existing evidence on the interaction between OS and miRNA regulatory machinery and its role in gastrointestinal carcinogenesis. In this regard, we illustrate the function of miRNAs which target OS systems during homeostasis and tumorigenesis. We also will discuss the biological crosstalk between OS systems and miRNA machinery and corresponding cell signaling pathways.

 

Title:Interplay between microRNAs and oxidative stress in ovarian conditions: focus on ovarian cancer and endometriosis

Author: Josep Marí Alexandre; Gilabert-Estellés

Abstract: Ovarian cancer and endometriosis are two distinct gynaecological conditions that, however, share many biological aspects in which miRNAs have been involved (i.e. the ability to implant at distance, proliferate and invade the surrounding tissue, inflammation, reduction of apoptosis and deregulation of angiogenesis). Besides, a growing body of evidence supports the role of oxidative stress in both the development and the resistance to treatment in these gyneacological diseases. Therefore, this review aims to address the need for a better understanding of the dialogue between these two molecular players in the pathophysiology of ovarian conditions: endometriosis, ovarian cancer and endometriosis-associated ovarian cancer.    

Title: Role of microRNAs in diabetes related oxidative stress

Author: Mirza Muhammad Fahd Qadir, Dagmar Klein, Juan Domínguez-Bendala and Ricardo L. Pastori

Abstract: Cellular oxidative stress generates excessive production of Reactive Oxygen Species (ROS) which oxidizes and damages different components of the cell machinery. Damaging ROS is induced by misfunction of the mitochondrial oxidative phosphorylation cellular process. The association of anomalous production of ROS with many diseases, including both Type 1 and type 2 diabetes and their complications, has been well established. In the last few years, many studies suggest a strong link between oxidative stress and microRNAs (miRNAs). miRNAs are small non-coding RNAs that mainly suppress gene expression by interaction with the 3’UTR of specific mRNA of target genes. Here, we review progress of studies focusing on the association of miRNAs with oxidative stress in the development of diabetes, including that induced by autoimmnunity in pancreatic islets in T1D and also metabolic syndrome and insulin resistance in T2D.

 Title: The yin-yang regulation of miRNAs and ROS in cancer

Authors: Kamesh R. Babu; Yvonne Tay

Abstract: Reactive oxygen species (ROS) are highly reactive oxygen containing chemical species formed as by-product of normal aerobic respiration and also from a number of other cellular enzymatic reactions. Elevated and sustained ROS production promotes tumor initiation by inducing DNA damage or mutation, and activates oncogenic signaling pathways to promote cancer progression. Recent studies have showed that ROS can facilitate carcinogenesis by controlling microRNA (miRNA) expression through regulating miRNA biogenesis, transcription factors and epigenetic modification. Likewise, miRNAs are shown to control cellular ROS homeostasis by regulating the expression of proteins involved in ROS production and elimination. In this review, we summarized the significance of ROS in cancer initiation, progression, and the crosstalk between ROS signaling and miRNA pathway in cancer.    

 

Title: MicroRNA and Oxidative Stress interplay in the context of breast cancer pathogenesis

Authors: Iorio Marilena Valeria;Tagliabue Elda;Cosentino Giulia; Plantamura Ilaria; Cataldo Alessandra

Abstract: Oxidative stress is a pathological condition determined by a disturbance in reactive oxygen species (ROS) homeostasis. Depending on the entity of the perturbation, normal cells can either restore equilibrium or activate pathways of cell death. On the contrary, cancer cells exploit this phenomenon to sustain a proliferative and aggressive phenotype. In fact, ROS overproduction or their reduced disposal influence all hallmarks of cancer, from genome instability to cell metabolism, angiogenesis, invasion and metastasis. A persistent state of oxidative stress can even initiate tumorigenesis.

MicroRNAs (miRNAs) are small non coding RNAs with regulatory functions, which expression has been extensively proven to be dysregulated in cancer. Intuitively, miRNA transcription and biogenesis are affected by the oxidative status of the cell and, in some instances, they participate in defining it. Indeed, it is widely reported the role of miRNAs in regulating numerous factors involved in the ROS signaling pathways.

Given that miRNA function and modulation relies on cell type or tumors, in order to delineate a clearer and more exhaustive picture, in this review we present a comprehensive overview of the literature concerning how miRNAs and ROS signaling interplay affects breast cancer progression.

Title: Interplay between microRNAs and oxidative stress in neurodegeneration diseases: focus on Parkinson’s disease

Authors: Julia Konovalova, Dmytro Gerasymchuk, Ilmari Parkkinen, Piotr Chmielarz, Andrii Domanskyi

Abstract: MicroRNAs are important post-transcriptional regulators of gene expression playing important roles in neuronal differentiation, survival, and activity. Age-related dysregulation of microRNA biogenesis increases cellular stress and vulnerability in neurodegenerative diseases, including Parkinson’s disease (PD). Several microRNAs regulate neurodegeneration-associated genes suggesting that changes in microRNA expression may contribute to the development of the neurodegenerative phenotype. Indeed, we and others have directly demonstrated that a functional Dicer-dependent microRNA network is necessary for neuronal maintenance, brain microRNA levels are affected in patients suffering from neurodegeneration, and that individual microRNAs may affect neuronal survival and activity.

The factors affecting neuronal survival in neurodegenerative diseases include mitochondrial dysfunction, deregulation of proteostasis and accumulation of insoluble protein aggregates, decreased neurotrophic signalling, and increased oxidative stress. However, despite many years of intensive research, no efficient treatments that could slow down or stop neuronal degeneration are currently available.

Here we review the current advances in the studies addressing the role of individual microRNAs and microRNAs biogenesis in neuronal maintenance and protection from cellular stressors, including oxidative stress. We also discuss the possibility of using advanced gene therapy and genome editing systems targeting microRNA biogenesis and/or utilizing individual microRNAs to develop novel treatments for PD and other neurodegenerative diseases.

Title:The crosstalk between microRNAs and ROS in neurodegenerative diseases

Authors: Moslem Jafari Sani

Abstract: Neurodegenerative diseases (NDDs) are included more than six hundred disease entities and progressively lead to nervous system dysfunction, loss of neurons, causing irreversible damage to patients, disability and death for more than thirty million individuals worldwide. Also we can call them as a type of RNA disorder in which miRNAs play a pivotal role.  MicroRNAs (miRNAs) play a major role in the fine-tuning of gene expression and they have recently emerged as novel biomarkers and therapeutic tools in many diseases such as NDDs. more evidence suggests that oxidative stress (OS) significantly contributes to deregulated miRNA pathways during the progression of the NDDs.Recent evidence suggested that microRNAs (miRNA)s like mi-R9, mi-R128 and mi-R 125b in Alzheimer disease (AD) or mi-R 133b in Parkinson disease(PD) can be used for diagnosis. We found that there is a relationship between TDP-43 and the reactive oxygen species (ROS) which causes some defects in amyotrophic lateral sclerosis (ALS).

Inflammation and oxidative stress are thought to promote damage in multiple sclerosis (MS). Also a number of studies reported that reactive oxygen species (ROS) play a key role in myelin phagocytosis, contributing to several of the processes underlying MS pathogenesis

oxidative stress can change the rate of miRNA expression in NDs by affecting on apoptosis or other signaling pathways that alter the miRNA expression. That’s why it can have crosstalk with miRNA expression. In this review, we decided to overview and discuss the crosstalk between microRNAs and ROS in common NDDs and explain how oxidative stress can effect on the dose of miRNA as biomarker of NDs and finally enlighted this unknown road a little more.

Title: Development and Clinical Trials of Nucleic Acid Medicines for Pancreatic Cancer Treatment

Authors: Keiko Yamakawa, Yuko Narusawa, Nozomi Hashimoto, Masanao Yokohira, Yoko Matsuda,

Abstract: Approximately 30% of pancreatic cancer patients hurbor drugable mutations. However, there has been no targeting therapy to these molecules clinically. Nucleic acid medicines show high specificity and can target RNAs. Nucleic acid medicine is expected to be the next generation treatment next to small molecules and antibodies. There are several kinds of nucleic acid drugs, including antisense oligonucleotides, small interfering RNAs, microRNA, aptamers, and decoys. In this review, we provide an update on current researches of nucleic acid-based therapies. Despite the challenging obstacles, we hope that a significant impact on the treatment of pancreatic cancer by nucleic acid drugs will come. The combination of genetic diagnosis using next generation sequence and targeting therapy may provide effective precision medicine for pancreatic cancer patients.

Title: MicroRNA mediate visfatin and resistin induction of oxidative stress in human osteoarthritic synovial fibroblasts via NF-κB pathway

Authors: Stefano Giannotti

Abstract: Synovial membrane inflammation actively participate to structural damage during osteoarthritis (OA). MicroRNA (miRNA), adipokines and oxidative stress contribute to cartilage destruction and synovitis in OA. We investigated the relationship between visfatin, resistin and some miRNA in oxidative stress regulation, in human OA synovial fibroblasts. Cultured cells were treated with visfatin and resistin, after 24 hrs we evaluated various pro-inflammatory cytokines, metalloproteinases (MMPs), type II collagen (Col2a1), miR-34a, miR-146a, miR-181a, antioxidant enzymes and B-cell lymphoma (BCL)2 by qRT-PCR, apoptosis and mitochondrial superoxide production by cytometry and p50 NF-κB by immunofluorescence. Synoviocytes were transfected with miRNA inhibitors and oxidative stress evaluation after adipokines stimulus was performed. The implication of nuclear factor (NF)-κB pathway was assessed by a NF-κB inhibitor (BAY-11-7082). Visfatin and resistin significantly up-regulated gene expression of interleukin (IL)-1β, IL-6, IL-17, tumor necrosis factor (TNF)-α, MMP-1, MMP-13 and reduced Col2a1. Furthermore, adipokines induced apoptosis and superoxide production, the transcriptional levels of BCL2, superoxide dismutase (SOD)-2, catalase (CAT), NRF2, miR-34a, miR-146a and miR-181a. MiRNA inhibitors counteracted adipokines modulation of oxidative stress. Visfatin and resistin effects were suppressed by BAY-11-7082. Our data suggest that miRNA may represent possible mediators of oxidative stress induced by visfatin and resistin via NF-κB pathway in human OA synoviocytes.

Title: MicroRNA networks modulate oxidative stress in cancer

Authors: Yang-Hsiang Lin, Meng-Han Wu and Chau-Ting Yeh

Abstract: Imbalance regulation of reactive oxygen species (ROS) and antioxidant factors in cells are known as “oxidative stress (OS)”. OS regulates key cellular physiological response through signaling transduction, transcriptional factors and non-coding RNAs (ncRNAs). Increasing evidences indicate that continued OS can cause chronic inflammation, which in turn contribute to cardiovascular, neurological diseases and cancer development. MicroRNAs (miRNAs) are a small ncRNA producing 18-25-nucleotide functional RNA molecules that play critical roles in the regulation of target genes expression via binding to complementary regions of mRNA and regulate mRNA degradation or repress their translation. Furthermore, miRNAs function as either tumor suppressor or oncogenes in cancers. The dysregulated miRNAs have been reported to modulate the hallmarks of cancer such as metastasis, angiogenesis, apoptosis and tumor growth. Notably, miRNAs are involved in ROS production or ROS-mediated function. Accordingly, investigating interaction between ROS and miRNAs has become important issues and should aid in the development of effective treatment/prevent strategies in cancer. The current review provides a summary of the essential properties and functional roles of known miRNAs associated with the oxidative stress in cancers.

Keywords: Oxidative stress; MicroRNA; Signal transduction; Therapeutic target

Title: miR-34a is involved in oxidative stress response induced by radiotherapy through NRF2 modulation in different cancer cell lines.

Authors: Paolo Tini

Abstract: MicroRNAs (miRNA) regulate processes as development, apoptosis or oxidative stress, or multiple diseases including cancer. However, their involvement in redox balance as radiation response is not fully elucidated. Here, we investigated the role of miR-34a in regulating apoptosis and oxidative stress induced by radiation therapy (RT) in human HeLa, rhabdomyosarcoma (RD) and glioblastoma (T98G) lines.Cells were transfected with miR-34a inhibitor, radiations were delivered using x-6 MV photon linear accelerator (0.5, 2, 4 Gy) and their effects assessed by clonogenic assay. Apoptosis and superoxide anion were detected by cytometry. MiR-34a, silencing information regulator (SIRT)1, B-cell lymphoma (BCL)2, superoxide dismutase (SOD)-2, catalase (CAT) and nuclear factor erythroid (NRF)2 expression was analyzed by qRT-PCR. NRF2 activation was assessed by immunofluorescence. Doses of RT significantly affected cell clonogenic ability, induced apoptosis and superoxide anion production, increased miR-34a, SIRT-1, BCL2, SOD-2, CAT and NRF2 gene expression in cancer lines compared to baseline. Transfection with miR-34a inhibitor suppressed the increase of apoptosis and oxidative stress caused by RT. RT significantly induced NRF2 activation and nuclear translocation, which was counteracted by silencing of miR-34a. Our data suggest the role of miR-34a in regulating apoptosis and oxidative stress induced by RT probably through the modulation of NRF2 activity. MiR-34a could represent a novel radiosensitizing therapeutic strategy for cancer clinical management.

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