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1
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Ali E, Ahmed MA, Shawki MA, El Arab LRE, Khalifa MK, Swellam M. Expression of some circulating microRNAs as predictive biomarkers for prognosis and treatment response in glioblastoma. Sci Rep 2025; 15:1933. [PMID: 39809835 PMCID: PMC11733229 DOI: 10.1038/s41598-024-83800-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Accepted: 12/17/2024] [Indexed: 01/16/2025] Open
Abstract
Glioblastoma multiforme (GBM) is the most prevalent, treatment-resistant, and fatal form of brain malignancy. It is characterized by genetic heterogeneity, and an infiltrative nature, and GBM treatment is highly challenging. Despite multimodal therapies, clinicians lack efficient prognostic and predictive markers. Therefore, new insights into GBM management are urgently needed to increase the chance of therapeutic success. Circulating miRNAs (miRs) are important regulators of cancer progression and are potentially useful for GBM diagnosis and treatment. This study investigated how miR-29a, miR-106a, and miR-200a affect the prognosis of GBM patients. This study was conducted on 25 GBM patients and 20 healthy volunteers as a control group. The expression levels of target miRs were analyzed pre- and post-treatment using qRT-PCR and evaluated in relation to both clinical GBM criteria and the patient's survival modes. The diagnostic efficacy of target miRs was assessed using the receiver operating characteristic (ROC) curve. MiRs levels showed significant differences among the enrolled participants. All investigated miRs were significantly elevated in GBM patients with non-frontal lesions. Only miR-200a showed a significant difference in GBM patients older than 60 years with a tumor size ≥ 5 mm. Regarding miR-106a, a significant difference was detected based on the surgical strategy and use of an Eastern Cooperative Oncology Group (ECOG) performance status equal to 2. For miR-29a, a significant upregulation was detected according to the surgical strategy. All post-treatment miRs levels in GBM patients were significantly downregulated. In conclusion, circulating miRs revealed a significant role in predicting GBM patient treatment outcomes providing valuable insights for personalized therapeutic strategies.
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Affiliation(s)
- Elham Ali
- Molecular Biology, Zoology and Entomology Department, Faculty of Science (for Girls), Al-Azhar University, Nasr City, Cairo, 11754, Egypt.
| | - Marwa Adel Ahmed
- Clinical Pharmacy Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - May A Shawki
- Clinical Pharmacy Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Lobna R Ezz El Arab
- Clinical Oncology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Mohamed K Khalifa
- CSO at Omicsense, Cairo, Egypt
- Molecular Pathology Laboratory Children Cancer Hospital, Cairo, 57357, Egypt
| | - Menha Swellam
- Biochemistry Department, Biotechnology Research Institute, National Research Centre, Dokki, Giza, Egypt
- High Throughput Molecular and Genetic Laboratory, Central Laboratories Network and the Centers of Excellence, National Research Centre, Dokki, Giza, Egypt
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2
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Kesheh MM, Bayat M, Kobravi S, Lotfalizadeh MH, Heydari A, Memar MY, Baghi HB, Kermanshahi AZ, Ravaei F, Taghavi SP, Zarepour F, Nahand JS, Hashemian SMR, Mirzaei H. MicroRNAs and human viral diseases: A focus on the role of microRNA-29. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167500. [PMID: 39260679 DOI: 10.1016/j.bbadis.2024.167500] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Revised: 06/01/2024] [Accepted: 08/01/2024] [Indexed: 09/13/2024]
Abstract
The viral replication can impress through cellular miRNAs. Indeed, either the antiviral responses or the viral infection changes through cellular miRNAs resulting in affecting many regulatory signaling pathways. One of the microRNA families that is effective in human cancers, diseases, and viral infections is the miR-29 family. Members of miR-29 family are effective in different viral infections as their roles have appeared in regulation of immunity pathways either in innate immunity including interferon and inflammatory pathways or in adaptive immunity including activation of T-cells and antibodies production. Although miR-29a affects viral replication by suppressing antiviral responses, it can inhibit the expression of viral mRNAs via binding to their 3'UTR. In the present work, we discuss the evidence related to miR-29a and viral infection through host immunity regulation. We also review roles of other miR-29 family members by focusing on their role as biomarkers for diagnosing and targets for viral diseases management.
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Affiliation(s)
- Mina Mobini Kesheh
- Department of Virology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mobina Bayat
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sepehr Kobravi
- Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Tehran Azad University, Tehran, Iran
| | | | - Azhdar Heydari
- Physiology Research Center, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran; Department of Physiology, School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Mohammad Yousef Memar
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hossein Bannazadeh Baghi
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Virology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Atefeh Zamani Kermanshahi
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Virology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Fatemeh Ravaei
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran; Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Seyed Pouya Taghavi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran; Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Fatemeh Zarepour
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran; Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Javid Sadri Nahand
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Seyed Mohammad Reza Hashemian
- Chronic Respiratory Diseases Research Center (CRDRC), National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Islamic Republic of Iran
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
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3
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Gupta I, Gaykalova DA. Unveiling the role of PIK3R1 in cancer: A comprehensive review of regulatory signaling and therapeutic implications. Semin Cancer Biol 2024; 106-107:58-86. [PMID: 39197810 DOI: 10.1016/j.semcancer.2024.08.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 07/11/2024] [Accepted: 08/20/2024] [Indexed: 09/01/2024]
Abstract
Phosphoinositide 3-kinase (PI3K) is responsible for phosphorylating phosphoinositides to generate secondary signaling molecules crucial for regulating various cellular processes, including cell growth, survival, and metabolism. The PI3K is a heterodimeric enzyme complex comprising of a catalytic subunit (p110α, p110β, or p110δ) and a regulatory subunit (p85). The binding of the regulatory subunit, p85, with the catalytic subunit, p110, forms an integral component of the PI3K enzyme. PIK3R1 (phosphoinositide-3-kinase regulatory subunit 1) belongs to class IA of the PI3K family. PIK3R1 exhibits structural complexity due to alternative splicing, giving rise to distinct isoforms, prominently p85α and p55α. While the primary p85α isoform comprises multiple domains, including Src homology 3 (SH3) domains, a Breakpoint Cluster Region Homology (BH) domain, and Src homology 2 (SH2) domains (iSH2 and nSH2), the shorter isoform, p55α, lacks certain domains present in p85α. In this review, we will highlight the intricate regulatory mechanisms governing PI3K signaling along with the impact of PIK3R1 alterations on cellular processes. We will further delve into the clinical significance of PIK3R1 mutations in various cancer types and their implications for prognosis and treatment outcomes. Additionally, we will discuss the evolving landscape of targeted therapies aimed at modulating PI3K-associated pathways. Overall, this review will provide insights into the dynamic interplay of PIK3R1 in cancer, fostering advancements in precision medicine and the development of targeted interventions.
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Affiliation(s)
- Ishita Gupta
- Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, USA; Department of Otorhinolaryngology-Head and Neck Surgery, Marlene & Stewart Greenebaum Comprehensive Cancer Center, University of Maryland Medical Center, Baltimore, MD, USA
| | - Daria A Gaykalova
- Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, USA; Department of Otorhinolaryngology-Head and Neck Surgery, Marlene & Stewart Greenebaum Comprehensive Cancer Center, University of Maryland Medical Center, Baltimore, MD, USA; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
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4
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Doghish YA, Doghish AS, Mageed SSA, Mohammed OA, Hamza TA, Abdelaziz AA, Moustafa YM, Abdel-Reheim MA, Abbass SO, Abbass SO, Abbass MO, Noureldin S, Amin SA, Elimam H, Doghish SA. Natural compounds targeting miRNAs: a novel approach in oral cancer therapy. Funct Integr Genomics 2024; 24:202. [PMID: 39455476 DOI: 10.1007/s10142-024-01473-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2024] [Revised: 10/05/2024] [Accepted: 10/08/2024] [Indexed: 10/28/2024]
Abstract
Oral cancer (OC) is a significant global health issue, with high rates of both mortality and morbidity. Conventional treatments, including surgery, radiation, and chemotherapy, are commonly used, but they often come with serious side effects and may not fully eliminate cancer cells, resulting in recurrence and resistance to treatment. In recent years, natural products derived from plants and other biological sources have gained attention for their potential anticancer properties. These compounds offer advantages such as lower toxicity compared to traditional chemotherapy. Notable natural compounds like quercetin, berberine, curcumin, andrographolide, nimbolide, ovatodiolide, and cucurbitacin B have demonstrated effectiveness in inhibiting OC cell growth by targeting various signaling pathways involved in cancer progression. Recent breakthroughs in molecular biology have highlighted the crucial role of microRNAs (miRNAs) in the development of OC. Targeting dysregulated miRNAs with natural products offers a promising strategy for treating the disease. Natural compounds exert anticancer effects by influencing both altered cellular signaling pathways and miRNA expression profiles. This study aims to explore the role of miRNAs as potential molecular targets in OC and to investigate how natural products may regulate these miRNAs. Additionally, this review will shed light on the therapeutic potential of phytochemicals in modulating miRNA expression and their significance in OC treatment.
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Affiliation(s)
- Youssef A Doghish
- Faculty of Dentistry, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt
| | - Ahmed S Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt.
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, 11231, Cairo, Egypt.
| | - Sherif S Abdel Mageed
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt
| | - Osama A Mohammed
- Department of Pharmacology, College of Medicine, University of Bisha, 61922, Bisha, Saudi Arabia
| | - Tamer A Hamza
- Faculty of Dentistry, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt
| | - Ahmed Adel Abdelaziz
- Faculty of Dentistry, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt
| | - Yasser M Moustafa
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt
| | | | | | - Sara O Abbass
- Faculty of Dentistry, Modern University for Technology & Information, Cairo, Egypt
| | | | - Salma Noureldin
- Faculty of Dentistry, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt
| | - Salma Ahmed Amin
- Faculty of Dentistry, Misr International University (MIU), Cairo, Egypt
| | - Hanan Elimam
- Department of Biochemistry, Faculty of Pharmacy, University of Sadat City, Sadat City, 32897, Egypt
| | - Sama A Doghish
- Faculty of Computer and Information Sciences, Ain Shams University, Cairo, 11566, Egypt
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5
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Morando N, Rosenzvit MC, Pando MA, Allmer J. The Role of MicroRNAs in HIV Infection. Genes (Basel) 2024; 15:574. [PMID: 38790203 PMCID: PMC11120859 DOI: 10.3390/genes15050574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2024] [Revised: 04/17/2024] [Accepted: 04/23/2024] [Indexed: 05/26/2024] Open
Abstract
MicroRNAs (miRNAs), a class of small, non-coding RNAs, play a pivotal role in regulating gene expression at the post-transcriptional level. These regulatory molecules are integral to many biological processes and have been implicated in the pathogenesis of various diseases, including Human Immunodeficiency Virus (HIV) infection. This review aims to cover the current understanding of the multifaceted roles miRNAs assume in the context of HIV infection and pathogenesis. The discourse is structured around three primary focal points: (i) elucidation of the mechanisms through which miRNAs regulate HIV replication, encompassing both direct targeting of viral transcripts and indirect modulation of host factors critical for viral replication; (ii) examination of the modulation of miRNA expression by HIV, mediated through either viral proteins or the activation of cellular pathways consequent to viral infection; and (iii) assessment of the impact of miRNAs on the immune response and the progression of disease in HIV-infected individuals. Further, this review delves into the potential utility of miRNAs as biomarkers and therapeutic agents in HIV infection, underscoring the challenges and prospects inherent to this line of inquiry. The synthesis of current evidence positions miRNAs as significant modulators of the host-virus interplay, offering promising avenues for enhancing the diagnosis, treatment, and prevention of HIV infection.
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Affiliation(s)
- Nicolas Morando
- Instituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)-Universidad de Buenos Aires, Buenos Aires 1121, Argentina; (N.M.); (M.A.P.)
| | - Mara Cecilia Rosenzvit
- Departamento de Microbiología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires 1121, Argentina;
- Instituto de Investigaciones en Microbiología y Parasitología Médica (IMPaM, UBA-CONICET), Universidad de Buenos Aires, Buenos Aires 1121, Argentina
| | - Maria A. Pando
- Instituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)-Universidad de Buenos Aires, Buenos Aires 1121, Argentina; (N.M.); (M.A.P.)
| | - Jens Allmer
- Medical Informatics and Bioinformatics, Institute for Measurement Engineering and Sensor Technology, Hochschule Ruhr West, University of Applied Sciences, 45479 Mülheim an der Ruhr, Germany
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6
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Wazahat R, Zaidi R, Kumar P. Epigenetic regulations in Mycobacterium tuberculosis infection. Indian J Tuberc 2024; 71:204-212. [PMID: 38589125 DOI: 10.1016/j.ijtb.2023.06.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 06/02/2023] [Accepted: 06/22/2023] [Indexed: 04/10/2024]
Abstract
Mycobacterium tuberculosis (Mtb) employs several sophisticated strategies to evade host immunity and facilitate its intracellular survival. One of them is the epigenetic manipulation of host chromatin by three strategies i.e., DNA methylation, histone modifications and miRNA involvement. A host-directed therapeutic can be an attractive approach that targets these host epigenetics or gene regulations and circumvent manipulation of host cell machinery by Mtb. Given the complexity of the nature of intracellular infection by Mtb, there are challenges in identifying the important host proteins, non-coding RNA or the secretory proteins of Mtb itself that directly or indirectly bring upon the epigenetic modifications in the host chromatin. Equally challenging is developing the methods of targeting these epigenetic factors through chemical or non-chemical approaches as host-directed therapeutics. The current review article briefly summarizes several of the epigenetic factors that serve to bring upon potential changes in the host transcriptional machinery and targets the immune system for immunosuppression and disease progression in Mtb infection.
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Affiliation(s)
- Rushna Wazahat
- Department of Biochemistry, Jamia Hamdard, New Delhi 110062, India.
| | - Rana Zaidi
- Department of Biochemistry, Jamia Hamdard, New Delhi 110062, India
| | - Pankaj Kumar
- Department of Biochemistry, Jamia Hamdard, New Delhi 110062, India.
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7
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Guo S, Guo Y, Chen Y, Cui S, Zhang C, Chen D. The role of CEMIP in cancers and its transcriptional and post-transcriptional regulation. PeerJ 2024; 12:e16930. [PMID: 38390387 PMCID: PMC10883155 DOI: 10.7717/peerj.16930] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Accepted: 01/22/2024] [Indexed: 02/24/2024] Open
Abstract
CEMIP is a protein known for inducing cell migration and binding to hyaluronic acid. Functioning as a hyaluronidase, CEMIP primarily facilitates the breakdown of the extracellular matrix component, hyaluronic acid, thereby regulating various signaling pathways. Recent evidence has highlighted the significant role of CEMIP in different cancers, associating it with diverse pathological states. While identified as a biomarker for several diseases, CEMIP's mechanism in cancer seems distinct. Accumulating data suggests that CEMIP expression is triggered by chemical modifications to itself and other influencing factors. Transcriptionally, chemical alterations to the CEMIP promoter and involvement of transcription factors such as AP-1, HIF, and NF-κB regulate CEMIP levels. Similarly, specific miRNAs have been found to post-transcriptionally regulate CEMIP. This review provides a comprehensive summary of CEMIP's role in various cancers and explores how both transcriptional and post-transcriptional mechanisms control its expression.
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Affiliation(s)
- Song Guo
- Shandong University of Technology, School of Life Sciences and Medicine, Zibo, Shandong, China
| | - Yunfei Guo
- Shandong University of Technology, School of Life Sciences and Medicine, Zibo, Shandong, China
| | - Yuanyuan Chen
- Shandong University of Technology, School of Life Sciences and Medicine, Zibo, Shandong, China
| | - Shuaishuai Cui
- Shandong University of Technology, School of Life Sciences and Medicine, Zibo, Shandong, China
| | - Chunmei Zhang
- Shandong University of Technology, School of Life Sciences and Medicine, Zibo, Shandong, China
| | - Dahu Chen
- Shandong University of Technology, School of Life Sciences and Medicine, Zibo, Shandong, China
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8
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Amini-Farsani Z, Hashemi Sheikhshabani S, Shaygan N, Asgharzade S. The impact of oleuropein on miRNAs regulating cell death signaling pathway in human cervical cancer cells. Biotechnol Appl Biochem 2024; 71:61-71. [PMID: 37849224 DOI: 10.1002/bab.2521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 10/01/2023] [Indexed: 10/19/2023]
Abstract
Cervical cancer is known as the second most pervasive malignancy in women across the globe. The role played by microRNAs (miRNAs) in the initiation, progression, and metastasis of this cancer has received specific attention. The use of natural compounds leading cancer cells toward apoptosis is a feasible strategy for cancer therapy. Oleuropein, an olive-extracted phenolic substance, displays anticancer properties. Here, it was attempted to assess the role played by oleuropein in cell viability in cervical cancer and changes in the expression of some miRNAs associated with cervical cancer as well as some of their possible target genes selected using bioinformatics analysis. For this purpose, HeLa cell line was exposed to several oleuropein concentrations for 48 and 72 h. After that, 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay and flow cytometry were employed to assess cell viability and apoptosis, respectively. In addition, to conduct bioinformatics analysis, Cytoscape computer program was used based on STRING database. Furthermore, to examine the role played by oleuropein in the expression of miRNAs of interest as well as their potential target genes, real-time PCR was employed. The findings indicated that oleuropein reduced cell viability through inducing apoptosis. As a result of treatment with oleuropein, miR-34a, miR-125b, and miR-29a showed increased expression levels, whereas miR-181b, miR-221, and miR-16 showed decreased expression levels. Furthermore, oleuropein reduced the expression of the anti-apoptotic genes Bcl-2 and Mcl1, whereas it elevated the expression of the pro-apoptotic Bid, Fas, and TNFRSF10B genes and the p53 tumor suppressor. Our results indicate that the apoptosis induction is a mechanism of action of oleuropein in HeLa cells. Because of its effect on the reflation of the expression of genes and miRNAs effective in the pathogenesis of cervical cancer, oleuropein shows potential as an effective research tool for developing new natural drugs for treating cervical cancer.
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Affiliation(s)
- Zeinab Amini-Farsani
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | | | - Nasibeh Shaygan
- Department of Plant Breeding and Biotechnology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Samira Asgharzade
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
- Department of Molecular, Medicine, School of Advanced Technologies, Shahrekord University of Medical Sciences, Shahrekord, Iran
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9
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Jiao W, Hao J, Liu JM, Gao WN, Zhao JJ, Li YJ. Mesenchymal stem cells-derived extracellular vesicle-incorporated H19 attenuates cardiac remodeling in rats with heart failure. Kaohsiung J Med Sci 2024; 40:46-62. [PMID: 37885317 DOI: 10.1002/kjm2.12774] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 09/12/2023] [Accepted: 09/22/2023] [Indexed: 10/28/2023] Open
Abstract
Cardiac remodeling is manifested by hypertrophy and apoptosis of cardiomyocytes, resulting in the progression of cardiovascular diseases. Long noncoding RNAs (lncRNAs) serve as modifiers of cardiac remodeling. In this study, we aimed to explore the molecular mechanism of H19 shuttled by mesenchymal stem cells (MSC)-derived extracellular vesicles (EV) in cardiac remodeling upon heart failure (HF). Using the GEO database, H19, microRNA (miR)-29b-3p, and CDC42 were screened out as differentially expressed biomolecules in HF. H19 and CDC42 were elevated, and miR-29b-3p was decreased after MSC-EV treatment in rats subjected to ligation of the coronary artery. MSC-EV alleviated myocardial injury in rats with HF. H19 downregulation exacerbated myocardial injury, while miR-29b-3p inhibitor alleviated myocardial injury. By contrast, CDC42 downregulation aggravated the myocardial injury again. PI3K/AKT pathway was activated by MSC-EV. These findings provide insights into how H19 shuttled by EV mitigates cardiac remodeling through a competitive endogenous RNA network regarding miR-29b-3p and CDC42.
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Affiliation(s)
- Wei Jiao
- Department of Cardiology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, People's Republic of China
| | - Jie Hao
- Department of Cardiology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, People's Republic of China
| | - Jin-Ming Liu
- Department of Cardiology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, People's Republic of China
| | - Wei-Nian Gao
- Department of Cardiac Macrovascular Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, People's Republic of China
| | - Jia-Jia Zhao
- Graduate Academy of Hebei Medical University, Shijiazhuang, Hebei, People's Republic of China
| | - Yong-Jun Li
- Department of Cardiology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, People's Republic of China
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10
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Fanale D, Corsini LR, Bono M, Randazzo U, Barraco N, Brando C, Cancelliere D, Contino S, Giurintano A, Magrin L, Pedone E, Perez A, Piraino P, Pivetti A, Giovanni ED, Russo TDB, Prestifilippo O, Gennusa V, Pantuso G, Russo A, Bazan V. Clinical relevance of exosome-derived microRNAs in Ovarian Cancer: Looking for new tumor biological fingerprints. Crit Rev Oncol Hematol 2024; 193:104220. [PMID: 38036154 DOI: 10.1016/j.critrevonc.2023.104220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 11/17/2023] [Accepted: 11/24/2023] [Indexed: 12/02/2023] Open
Abstract
Specific tumor-derived extracellular vesicles, called exosomes, are considered as potential key players in cross-talk between immune system and tumor microenvironment in several solid tumors. Different studies highlighted the clinical relevance of exosomes in ovarian cancer (OC) for their role in early diagnosis, prognosis, chemoresistance, targeted therapy. The exosomes are nanosize vesicles carrying lipids, proteins, and nucleic acids. In particular, exosomes shuttle a wide spectrum of microRNAs (miRNAs) able to induce phenotypic reprogramming of target cells, contributing to tumor progression. In this review, we will discuss the promising role of miRNAs shuttled by exosomes, called exosomal miRNAs (exo-miRNAs), as potential biomarkers for early detection, tumour progression and metastasis, prognosis, and response to therapy in OC women, in order to search for new potential biological fingerprints able to better characterize the evolution of this malignancy and provide a clinically relevant non-invasive approach useful for adopting, in future, personalized therapeutic strategies.
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Affiliation(s)
- Daniele Fanale
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy
| | - Lidia Rita Corsini
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy
| | - Marco Bono
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy
| | - Ugo Randazzo
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy
| | - Nadia Barraco
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy
| | - Chiara Brando
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy
| | - Daniela Cancelliere
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy
| | - Silvia Contino
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy
| | - Ambra Giurintano
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy
| | - Luigi Magrin
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy
| | - Erika Pedone
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy
| | - Alessandro Perez
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy
| | - Paola Piraino
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy
| | - Alessia Pivetti
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy
| | - Emilia Di Giovanni
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy
| | - Tancredi Didier Bazan Russo
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy
| | - Ornella Prestifilippo
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy
| | - Vincenzo Gennusa
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy
| | - Gianni Pantuso
- Division of General and Oncological Surgery, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy
| | - Antonio Russo
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy.
| | - Viviana Bazan
- Department of Biomedicine, Neuroscience and Advanced Diagnostics, University of Palermo, 90127 Palermo, Italy
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11
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Jeong Y, Kim SB, Yang CE, Yu MS, Choi WS, Jeon Y, Lim JY. Overcoming the therapeutic limitations of EZH2 inhibitors in Burkitt's lymphoma: a comprehensive study on the combined effects of MS1943 and Ibrutinib. Front Oncol 2023; 13:1252658. [PMID: 37752998 PMCID: PMC10518396 DOI: 10.3389/fonc.2023.1252658] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Accepted: 08/23/2023] [Indexed: 09/28/2023] Open
Abstract
Enhancer of zeste homolog 2 (EZH2) and Bruton's tyrosine kinase (BTK) are both key factors involved in the development and progression of hematological malignancies. Clinical studies have demonstrated the potential of various EZH2 inhibitors, which target the methyltransferase activity of EZH2, for the treatment of lymphomas. However, despite their ability to effectively reduce the H3K27me3 levels, these inhibitors have shown limited efficacy in blocking the proliferation of lymphoma cells. To overcome this challenge, we employed a hydrophobic tagging approach utilizing MS1943, a selective EZH2 degrader. In this study, we investigated the inhibitory effects of two drugs, the FDA-approved EZH2 inhibitor Tazemetostat, currently undergoing clinical trials, and the novel drug MS1943, on Burkitt's lymphoma. Furthermore, we assessed the potential synergistic effect of combining these drugs with the BTK inhibitor Ibrutinib. In this study, we evaluated the effects of combination therapy with MS1943 and Ibrutinib on the proliferation of three Burkitt's lymphoma cell lines, namely RPMI1788, Ramos, and Daudi cells. Our results demonstrated that the combination of MS1943 and Ibrutinib significantly suppressed cell proliferation to a greater extent compared to the combination of Tazemetostat and Ibrutinib. Additionally, we investigated the underlying mechanisms of action and found that the combination therapy of MS1943 and Ibrutinib led to the upregulation of miR29B-mediated p53-upregulated modulator of apoptosis PUMA, BAX, cleaved PARP, and cleaved caspase-3 in Burkitt's lymphoma cells. These findings highlight the potential of this innovative therapeutic strategy as an alternative to traditional EZH2 inhibitors, offering promising prospects for improving treatment outcomes in Burkitt's lymphoma.
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Affiliation(s)
- Yurim Jeong
- Department of Biomedical Laboratory Science, Inje University, Gimhae, Republic of Korea
| | - Se Been Kim
- Department of Biomedical Laboratory Science, Inje University, Gimhae, Republic of Korea
| | - Chae-Eun Yang
- Department of Biomedical Laboratory Science, Inje University, Gimhae, Republic of Korea
| | - Min Seo Yu
- Department of Biomedical Laboratory Science, Inje University, Gimhae, Republic of Korea
| | - Wan-Su Choi
- Department of Biomedical Laboratory Science, Inje University, Gimhae, Republic of Korea
- Department of Digital Anti-aging Health Care, Inje University, Gimhae, Republic of Korea
| | - Youngwoo Jeon
- Department of Hematology, Yeouido St. Mary Hospital, School of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jung-Yeon Lim
- Department of Biomedical Laboratory Science, Inje University, Gimhae, Republic of Korea
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12
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Awuson-David B, Williams AC, Wright B, Hill LJ, Di Pietro V. Common microRNA regulated pathways in Alzheimer's and Parkinson's disease. Front Neurosci 2023; 17:1228927. [PMID: 37719162 PMCID: PMC10502311 DOI: 10.3389/fnins.2023.1228927] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Accepted: 08/02/2023] [Indexed: 09/19/2023] Open
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs involved in gene regulation. Recently, miRNA dysregulation has been found in neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). The diagnosis of Alzheimer's and Parkinson's is currently challenging, mainly occurring when pathology is already present, and although treatments are available for both diseases, the role of treatment is primarily to prevent or delay the progress of the diseases instead of fully overcoming the diseases. Therefore, the challenge in the near future will be to determine effective drugs to tackle the dysregulated biological pathways in neurodegenerative diseases. In the present study, we describe the dysregulation of miRNAs in blood of Alzheimer's and Parkinson's patients with the aim to identify common mechanisms between the 2 pathologies and potentially to identify common therapeutic targets which can stop or delay the progression of two most frequent neuropathologies. Two independent systematic reviews, bioinformatic analysis, and experiment validation were performed to identify whether AD and PD share common pathways. A total of 15 common miRNAs were found in the literature and 13 common KEGG pathways. Among the common miRNAs, two were selected for validation in a small cohort of AD and PD patients. Let-7f-5p and miR-29b-3p showed to be good predictors in blood of PD patients.
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Affiliation(s)
- Betina Awuson-David
- School of Biomedical Sciences, Institute of Clinical Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Adrian C. Williams
- Department of Neurology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Benjamin Wright
- Department of Neurology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Lisa J. Hill
- School of Biomedical Sciences, Institute of Clinical Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Valentina Di Pietro
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom
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13
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Jo HR, Hwang J, Jeong JH. MicroRNA miR-214-5p induces senescence of microvascular endothelial cells by targeting the JAG1/Notch signaling pathway. Noncoding RNA Res 2023; 8:385-391. [PMID: 37260583 PMCID: PMC10227379 DOI: 10.1016/j.ncrna.2023.05.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 04/10/2023] [Accepted: 05/01/2023] [Indexed: 06/02/2023] Open
Abstract
During cellular senescence, irreversible cell cycle arrest is accompanied by morphological and genetic alterations. MicroRNAs (miRNAs) play a critical role in regulating senescence by modulating the abundance of crucial senescence regulatory proteins. Therefore, to identify novel senescence-associated miRNAs, we analyzed differentially expressed miRNAs in microvascular endothelial cells (MVEC). Among the 80 differentially expressed miRNAs in replicative senescent MVECs, 16 miRNAs of unknown gene ontology were used in the senescence-associated β-galactosidase assay. Thus, we identified miR-214-5p as having high senescence-inducing activity, inhibiting the proliferation and angiogenesis activity of MVECs. To reveal the senescence-regulating mechanism of miR-214-5p, we searched for target genes through sequence- and literature-based analysis. Molecular manipulation of miR-214-5p demonstrated that miR-214-5p regulated the expression and function of Jagged 1 (JAG1) in senescent MVECs. Silencing JAG1 or downstream genes of JAG1-Notch signaling, accelerated the senescence of MVECs. Additionally, ectopic overexpression of JAG1 reversed the senescence-inducing activity of miR-214-5p. In conclusion, we identified miR-214-5p as a senescence-associated miRNA. Targeting miR-214-5p may be a potential strategy to delay vascular aging and overcome the detrimental effects of senescence and age-related diseases.
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Affiliation(s)
- Hye-ram Jo
- Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Science, Seoul, 01812, South Korea
- Radiological and Medico-Oncological Sciences, University of Science and Technology, Daejeon, 34113, South Korea
| | - Jiwon Hwang
- Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Science, Seoul, 01812, South Korea
- Department of Life Sciences, Korea University, Seoul, 02841, South Korea
| | - Jae-Hoon Jeong
- Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Science, Seoul, 01812, South Korea
- Radiological and Medico-Oncological Sciences, University of Science and Technology, Daejeon, 34113, South Korea
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14
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Wan L, Thomas-Ahner JM, Pearl DK, Erdman JW, Moran NE, Clinton SK. Orchestration of miRNA Patterns by Testosterone and Dietary Tomato Carotenoids during Early Prostate Carcinogenesis in TRAMP Mice. J Nutr 2023; 153:1877-1888. [PMID: 37187350 PMCID: PMC10375503 DOI: 10.1016/j.tjnut.2023.05.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 04/27/2023] [Accepted: 05/11/2023] [Indexed: 05/17/2023] Open
Abstract
BACKGROUND The integrative effects of prostate cancer risk factors, such as diet and endocrine status, on cancer-associated miRNA expression are poorly defined. OBJECTIVES This study aimed to define the influence of androgens and diet (tomato and lycopene) on prostatic miRNA expression during early carcinogenesis in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. METHODS Wild type (WT) and TRAMP mice were fed control, tomato-containing, or lycopene-containing diets from 4 to 10 weeks of age. Mice underwent either sham (intact) or castration surgery at 8 wk, and half of the castrated mice received testosterone (2.5 mg/kg body weight/d) at 9 wk. Mice were killed at 10 wk, and dorsolateral prostate expression of 602 miRNAs was assessed. RESULTS We detected expression of 88 miRNAs (15% of 602), all of which were present in the TRAMP, in comparison with 49 miRNAs being detectable (8%) in WT. Expression of 61 miRNAs differed by TRAMP genotype, with the majority upregulated in TRAMP. Of the 61 miRNAs, 42 were responsive to androgen status. Diet affected 41% of the miRNAs, which differed by genotype (25/61) and 48% of the androgen-sensitive miRNAs (20/42), indicating overlapping genetic and dietary influences on prostate miRNAs. Tomato and lycopene feeding influenced miRNAs previously associated with the regulation of androgen (miR-145 and let-7), MAPK (miR-106a, 204, 145/143, and 200b/c), and p53 signaling (miR-125 and miR-98) pathways. CONCLUSIONS Expression of miRNAs in early prostate carcinogenesis is sensitive to genetic, endocrine, and diet drivers, suggesting novel mechanisms by which tomato and lycopene feeding modulate early prostate carcinogenesis.
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Affiliation(s)
- Lei Wan
- The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA; Interdisciplinary Nutrition Program
| | | | - Dennis K Pearl
- Department of Statistics, The Pennsylvania State University, University Park, PA, USA
| | - John W Erdman
- Department of Food Science and Human Nutrition, University of Illinois, Urbana, IL, USA
| | - Nancy E Moran
- The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA; USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
| | - Steven K Clinton
- The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA; Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
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15
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Natalicchio A, Montagnani M, Gallo M, Marrano N, Faggiano A, Zatelli MC, Mazzilli R, Argentiero A, Danesi R, D'Oronzo S, Fogli S, Giuffrida D, Gori S, Ragni A, Renzelli V, Russo A, Franchina T, Tuveri E, Sciacca L, Monami M, Cirino G, Di Cianni G, Colao A, Avogaro A, Cinieri S, Silvestris N, Giorgino F. MiRNA dysregulation underlying common pathways in type 2 diabetes and cancer development: an Italian Association of Medical Oncology (AIOM)/Italian Association of Medical Diabetologists (AMD)/Italian Society of Diabetology (SID)/Italian Society of Endocrinology (SIE)/Italian Society of Pharmacology (SIF) multidisciplinary critical view. ESMO Open 2023; 8:101573. [PMID: 37263082 PMCID: PMC10245125 DOI: 10.1016/j.esmoop.2023.101573] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 03/27/2023] [Accepted: 04/26/2023] [Indexed: 06/03/2023] Open
Abstract
Increasing evidence suggests that patients with diabetes, particularly type 2 diabetes (T2D), are characterized by an increased risk of developing different types of cancer, so cancer could be proposed as a new T2D-related complication. On the other hand, cancer may also increase the risk of developing new-onset diabetes, mainly caused by anticancer therapies. Hyperinsulinemia, hyperglycemia, and chronic inflammation typical of T2D could represent possible mechanisms involved in cancer development in diabetic patients. MicroRNAs (miRNAs) are a subset of non-coding RNAs, ⁓22 nucleotides in length, which control the post-transcriptional regulation of gene expression through both translational repression and messenger RNA degradation. Of note, miRNAs have multiple target genes and alteration of their expression has been reported in multiple diseases, including T2D and cancer. Accordingly, specific miRNA-regulated pathways are involved in the pathogenesis of both conditions. In this review, a panel of experts from the Italian Association of Medical Oncology (AIOM), Italian Association of Medical Diabetologists (AMD), Italian Society of Diabetology (SID), Italian Society of Endocrinology (SIE), and Italian Society of Pharmacology (SIF) provide a critical view of the evidence about the involvement of miRNAs in the pathophysiology of both T2D and cancer, trying to identify the shared miRNA signature and pathways able to explain the strong correlation between the two conditions, as well as to envision new common pharmacological approaches.
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Affiliation(s)
- A Natalicchio
- Department of Precision and Regenerative Medicine and Ionian Area, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Bari, Italy
| | - M Montagnani
- Department of Precision and Regenerative Medicine and Ionian Area, Section of Pharmacology, Medical School, University of Bari Aldo Moro, Bari, Italy
| | - M Gallo
- Endocrinology and Metabolic Diseases Unit, AO SS Antonio e Biagio e Cesare Arrigo of Alessandria, Alessandria, Italy
| | - N Marrano
- Department of Precision and Regenerative Medicine and Ionian Area, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Bari, Italy
| | - A Faggiano
- Endocrinology Unit, Department of Clinical and Molecular Medicine, Sant'Andrea Hospital, ENETS Center of Excellence, Sapienza University of Rome, Rome, Italy
| | - M C Zatelli
- Section of Endocrinology, Geriatrics, and Internal Medicine, Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - R Mazzilli
- Endocrinology Unit, Department of Clinical and Molecular Medicine, Sant'Andrea Hospital, ENETS Center of Excellence, Sapienza University of Rome, Rome, Italy
| | - A Argentiero
- Medical Oncology Unit, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy
| | - R Danesi
- Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - S D'Oronzo
- Interdisciplinary Department of Medicine, University of Bari Aldo Moro, Bari, Italy
| | - S Fogli
- Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - D Giuffrida
- Department of Oncology, Istituto Oncologico del Mediterraneo, Viagrande, Catania, Italy
| | - S Gori
- Oncologia Medica, IRCCS Ospedale Don Calabria-Sacro Cuore di Negrar, Verona, Italy
| | - A Ragni
- Endocrinology and Metabolic Diseases Unit, AO SS Antonio e Biagio e Cesare Arrigo of Alessandria, Alessandria, Italy
| | - V Renzelli
- Diabetologist and Endocrinologist, Italian Association of Clinical Diabetologists, Rome, Italy
| | - A Russo
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy
| | - T Franchina
- Medical Oncology Unit, Department of Human Pathology "G. Barresi", University of Messina, Messina, Italy
| | - E Tuveri
- Diabetology, Endocrinology and Metabolic Diseases Service, ASL-Sulcis, Carbonia, Sardinia, Italy
| | - L Sciacca
- Department of Clinical and Experimental Medicine, Endocrinology Section, University of Catania, Catania, Italy
| | - M Monami
- Diabetology, Careggi Hospital and University of Florence, Firenze, Italy
| | - G Cirino
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - G Di Cianni
- Diabetes Unit, Livorno Hospital, Livorno, Italy
| | - A Colao
- Endocrinology, Diabetology and Andrology Unit, Department of Clinical Medicine and Surgery, Federico II University of Naples, Naples, Italy; UNESCO Chair, Education for Health and Sustainable Development, Federico II University, Naples, Italy
| | - A Avogaro
- Department of Medicine, University of Padova, Padua, Italy
| | - S Cinieri
- Medical Oncology Division and Breast Unit, Senatore Antonio Perrino Hospital, ASL Brindisi, Brindisi, Italy
| | - N Silvestris
- Medical Oncology Unit, Department of Human Pathology "G. Barresi", University of Messina, Messina, Italy
| | - F Giorgino
- Department of Precision and Regenerative Medicine and Ionian Area, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Bari, Italy.
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16
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Xi T, Wang R, Pi D, Ouyang J, Yang J. The p53/miR-29a-3p axis mediates the antifibrotic effect of leonurine on angiotensin II-stimulated rat cardiac fibroblasts. Exp Cell Res 2023; 426:113556. [PMID: 36933858 DOI: 10.1016/j.yexcr.2023.113556] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 02/20/2023] [Accepted: 03/15/2023] [Indexed: 03/18/2023]
Abstract
Overactivation of cardiac fibroblasts (CFs) is one of the main causes of myocardial fibrosis (MF), and inhibition of CF activation is a crucial strategy for MF therapy. A previous study by our group demonstrated that leonurine (LE) effectively inhibits collagen synthesis and myofibroblast generation originated from CFs, and eventually mitigates the progression of MF (where miR-29a-3p is likely to be a vital mediator). However, the underlying mechanisms involved in this process remain unknown. Thus, the present study aimed to investigate the precise role of miR-29a-3p in LE-treated CFs, and to elucidate the pharmacological effects of LE on MF. Neonatal rat CFs were isolated and stimulated by angiotensin II (Ang II) to mimic the pathological process of MF in vitro. The results show that LE distinctly inhibits collagen synthesis, as well as the proliferation, differentiation and migration of CFs, all of which could be induced by Ang II. In addition, LE promotes apoptosis in CFs under Ang II stimulation. During this process, the down-regulated expressions of miR-29a-3p and p53 are partly restored by LE. Either knockdown of miR-29a-3p or inhibition of p53 by PFT-α (a p53 inhibitor) blocks the antifibrotic effect of LE. Notably, PFT-α suppresses miR-29a-3p levels in CFs under both normal and Ang II-treated conditions. Furthermore, ChIP analysis confirmed that p53 is bound to the promoter region of miR-29a-3p, and directly regulates its expression. Overall, our study demonstrates that LE upregulates p53 and miR-29a-3p expression, and subsequently inhibits CF overactivation, suggesting that the p53/miR-29a-3p axis may play a crucial role in mediating the antifibrotic effect of LE against MF.
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Affiliation(s)
- Tianlan Xi
- Department of Pharmacy, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China; Institute of Life Science, Chongqing Medical University, Chongqing, China
| | - Ruiyu Wang
- Institute of Life Science, Chongqing Medical University, Chongqing, China
| | - Damao Pi
- Department of Pharmacy, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jing Ouyang
- Clinical Research Center, Chongqing Public Health Medical Center, Chongqing, China.
| | - Jiadan Yang
- Department of Pharmacy, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
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17
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Tasopoulou KM, Argiriou C, Tsaroucha AK, Georgiadis GS. Circulating miRNAs as biomarkers for diagnosis, surveillance and post-operative follow-up of abdominal aortic aneurysms. Ann Vasc Surg 2023:S0890-5096(23)00144-9. [PMID: 36921794 DOI: 10.1016/j.avsg.2023.02.029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 02/21/2023] [Accepted: 02/23/2023] [Indexed: 03/15/2023]
Abstract
OBJECTIVE To provide a summary of the current state of research in English medical literature on circulating miRNAs, as biomarkers for AAA. Additionally, for the most commonly mentioned circulating miRNAs in the literature, to attempt a documentation of the biological mechanisms underlying their role in AAA development. METHODS A literature search was undertaken in the MEDLINE database. Only reports that involved peripheral blood samples (whole blood, plasma, serum) were included. The following terms were used in combination: microrna, mirna, abdominal aortic aneurysm, human, circulating, plasma, serum, endovascular and EVAR. RESULTS A total of 25 reports, published from 2012 to 2022 were included with a total of 1259 patients with AAA, predominantly men (N= 1040, 90%). Six of these reports recruited healthy donors who underwent ultrasound screening for AAA as control samples. The majority of studies were undertaken in plasma samples and the most preferred microRNA profiling method was Real - Time quantitative polymerase chain reaction (qRT-PCR). The following nine miRNAs (out of a total of 76) were studied in more than two references: miR-145, miR-24, miR-33, miR-125, let-7, miR-15, miR-191, miR-29 and miR-133. CONCLUSION The nine miRNAs described in this study, are implicated in known pathogenetic mechanisms of AAA such as atherosclerosis, vascular smooth muscle cell phenotype switch and apoptosis, vascular inflammation, extracellular matrix degradation and lipid metabolism. Identifying disease-specific miRNAs, in combination with other clinical parameters, as indicators of AAA, is crucial for early diagnosis as well as follow-up of AAAs. For future research on miRNAs as AAA biomarkers, strict case and control group definitions, sample acquisition protocols, and miRNA expression profiling techniques are warranted.
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Affiliation(s)
- Kalliopi-Maria Tasopoulou
- Department of Vascular Surgery, Medical School, Democritus University of Thrace, University General Hospital of Evros, Alexandroupolis, Greece.
| | - Christos Argiriou
- Department of Vascular Surgery, Medical School, Democritus University of Thrace, University General Hospital of Evros, Alexandroupolis, Greece
| | - Alexandra K Tsaroucha
- Laboratory of Experimental Surgery and Surgical Research, School of Medicine, Democritus University of Thrace, Alexandroupolis, Greece
| | - George S Georgiadis
- Department of Vascular Surgery, Medical School, Democritus University of Thrace, University General Hospital of Evros, Alexandroupolis, Greece
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18
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Waly OM, El-Mahdy NA, El-Shitany NAEA, Mohammedsaleh ZM, El-Kadem AH. Protective role of naftidrofuryl against methotrexate-induced testicular damage via the amelioration of the p53/miRNA-29a/CDC42 apoptotic pathway, inflammation, and oxidative stress. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2023; 98:104067. [PMID: 36649853 DOI: 10.1016/j.etap.2023.104067] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 12/17/2022] [Accepted: 01/12/2023] [Indexed: 06/17/2023]
Abstract
This study aimed to assess the possible protective effects of naftidrofuryl (Naf) against methotrexate (MTX)-induced testicular toxicity in rats. Male rats were randomly distributed into four groups: control, Naf, MTX, and MTX+Naf groups. MTX administration induced oxidative stress, inflammation, and apoptosis in the testicular tissue, while pretreatment with Naf attenuated these pathways. Naf pretreatment significantly decreased malondialdehyde and interleukin-6 contents, microRNA-29a (miRNA-29a) expression level, and nuclear factor kappa B and p53 immunostaining in the testicular tissues compared to the MTX group. Conversely, it significantly increased Johnsen's score, serum testosterone level, serum total antioxidant capacity, testicular superoxide dismutase activity, testicular catalase activity, and testicular cell division cycle 42 (CDC42) expression compared to the MTX group. In conclusion, Naf exerted a significant protective effect against MTX-induced testicular toxicity via antioxidant and anti-inflammatory mechanisms and modulating the p53/miRNA-29a/CDC42 apoptotic pathway.
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Affiliation(s)
- Ola Mahmoud Waly
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Tanta University, Tanta, Egypt.
| | - Nageh Ahmed El-Mahdy
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Tanta University, Tanta, Egypt
| | | | - Zuhair M Mohammedsaleh
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk, Saudi Arabia
| | - Aya Hassan El-Kadem
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Tanta University, Tanta, Egypt
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19
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DNA Double-Strand Break-Related Competitive Endogenous RNA Network of Noncoding RNA in Bovine Cumulus Cells. Genes (Basel) 2023; 14:genes14020290. [PMID: 36833217 PMCID: PMC9956238 DOI: 10.3390/genes14020290] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 01/14/2023] [Accepted: 01/18/2023] [Indexed: 01/26/2023] Open
Abstract
(1) Background: DNA double strand breaks (DSBs) are the most serious form of DNA damage that affects oocyte maturation and the physiological state of follicles and ovaries. Non-coding RNAs (ncRNAs) play a crucial role in DNA damage and repair. This study aims to analyze and establish the network of ncRNAs when DSB occurs and provide new ideas for next research on the mechanism of cumulus DSB. (2) Methods: Bovine cumulus cells (CCs) were treated with bleomycin (BLM) to construct a DSB model. We detected the changes of the cell cycle, cell viability, and apoptosis to determine the effect of DSBs on cell biology, and further evaluated the relationship between the transcriptome and competitive endogenous RNA (ceRNA) network and DSBs. (3) Results: BLM increased γH2AX positivity in CCs, disrupted the G1/S phase, and decreased cell viability. Totals of 848 mRNAs, 75 long noncoding RNAs (lncRNAs), 68 circular RNAs (circRNAs), and 71 microRNAs (miRNAs) in 78 groups of lncRNA-miRNA-mRNA regulatory networks, 275 groups of circRNA-miRNA-mRNA regulatory networks, and five groups of lncRNA/circRNA-miRNA-mRNA co-expression regulatory networks were related to DSBs. Most differentially expressed ncRNAs were annotated to cell cycle, p53, PI3K-AKT, and WNT signaling pathways. (4) Conclusions: The ceRNA network helps to understand the effects of DNA DSBs activation and remission on the biological function of CCs.
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20
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Lei L, Lu Q, Ma G, Li T, Deng J, Li W. P53 protein and the diseases in central nervous system. Front Genet 2023; 13:1051395. [PMID: 36712862 PMCID: PMC9880595 DOI: 10.3389/fgene.2022.1051395] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 12/08/2022] [Indexed: 01/11/2023] Open
Abstract
P53 protein is the product of P53 gene, which is a well acknowledged tumor suppressor gene. The function of P53 and the relevant mechanisms of anti-neoplasm have raised the interest of researchers since many years ago. It is demonstrated that P53 is a basic cell cycle regulator and a strong inhibitor for versatile cancers in humans. However, most research focuses on other organs and systems instead of the central nervous system (CNS). In fact, in recent years, more and more studies have been suggesting that P53 plays a significant role in multiple CNS tumors and other diseases and disorders such as cerebral stroke and neurodegenerative diseases. In this work, we mainly reviewed the P53's relationship with CNS tumors, cerebral stroke and neurodegenerative diseases, together with the relevant mechanisms, aiming to summarize the research achievements and providing new insight to the future study on diseases in CNS.
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Affiliation(s)
- Li Lei
- The Affiliated Hospital of Kunming University of Science and Technology, The Department of Neurosurgery, The First People's Hospital of Yunnan Province, Kunming, Yunnan, China
| | - Qixiong Lu
- The Affiliated Hospital of Kunming University of Science and Technology, The Department of Neurosurgery, The First People's Hospital of Yunnan Province, Kunming, Yunnan, China
| | - Guifang Ma
- Department of Ear, Nose and Throat (ENT) and Head and Neck (HN) Surgery, The First People’s Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, China
| | - Tao Li
- The Affiliated Hospital of Kunming University of Science and Technology, The Department of Neurosurgery, The First People's Hospital of Yunnan Province, Kunming, Yunnan, China
| | - Jiahong Deng
- Department of Ear, Nose and Throat (ENT) and Head and Neck (HN) Surgery, The First People’s Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, China,*Correspondence: Jiahong Deng, ; Weijia Li,
| | - Weijia Li
- The Affiliated Hospital of Kunming University of Science and Technology, The Department of Neurosurgery, The First People's Hospital of Yunnan Province, Kunming, Yunnan, China,*Correspondence: Jiahong Deng, ; Weijia Li,
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21
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Wang L, Xiong Y, Fu B, Guo D, Zaky MY, Lin X, Wu H. MicroRNAs as immune regulators and biomarkers in tuberculosis. Front Immunol 2022; 13:1027472. [PMID: 36389769 PMCID: PMC9647078 DOI: 10.3389/fimmu.2022.1027472] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Accepted: 10/12/2022] [Indexed: 07/26/2023] Open
Abstract
Tuberculosis (TB), which is caused by Mycobacterium tuberculosis (Mtb), is one of the most lethal infectious disease worldwide, and it greatly affects human health. Some diagnostic and therapeutic methods are available to effectively prevent and treat TB; however, only a few systematic studies have described the roles of microRNAs (miRNAs) in TB. Combining multiple clinical datasets and previous studies on Mtb and miRNAs, we state that pathogens can exploit interactions between miRNAs and other biomolecules to avoid host mechanisms of immune-mediated clearance and survive in host cells for a long time. During the interaction between Mtb and host cells, miRNA expression levels are altered, resulting in the changes in the miRNA-mediated regulation of host cell metabolism, inflammatory responses, apoptosis, and autophagy. In addition, differential miRNA expression can be used to distinguish healthy individuals, patients with TB, and patients with latent TB. This review summarizes the roles of miRNAs in immune regulation and their application as biomarkers in TB. These findings could provide new opportunities for the diagnosis and treatment of TB.
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Affiliation(s)
- Lulu Wang
- Department of Biology, School of Life Sciences, Chongqing University, Chongqing, China
| | - Yan Xiong
- Department of Biology, School of Life Sciences, Chongqing University, Chongqing, China
| | - Beibei Fu
- Department of Biology, School of Life Sciences, Chongqing University, Chongqing, China
| | - Dong Guo
- Department of Biology, School of Life Sciences, Chongqing University, Chongqing, China
| | - Mohamed Y. Zaky
- Department of Zoology, Molecular Physiology Division, Faculty of Science, Beni-Suef University, Beni-Suef, Egypt
| | - Xiaoyuan Lin
- Department of Biology, School of Life Sciences, Chongqing University, Chongqing, China
| | - Haibo Wu
- Department of Biology, School of Life Sciences, Chongqing University, Chongqing, China
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22
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Bai X, Wang J, Zhang X, Tang Y, He Y, Zhao J, Han L, Fang R, Liu Z, Dong H, Li Q, Ge J, Ma Y, Yu M, Sun R, Wang J, Fei J, Huang F. Deficiency of miR-29a/b1 leads to premature aging and dopaminergic neuroprotection in mice. Front Mol Neurosci 2022; 15:978191. [PMID: 36277485 PMCID: PMC9582353 DOI: 10.3389/fnmol.2022.978191] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2022] [Accepted: 09/01/2022] [Indexed: 11/13/2022] Open
Abstract
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by progressive degeneration of midbrain dopaminergic neurons. The miR-29s family, including miR-29a and miR-29b1 as well as miR-29b2 and miR-29c, are implicated in aging, metabolism, neuronal survival, and neurological disorders. In this study, the roles of miR-29a/b1 in aging and PD were investigated. miR-29a/b1 knockout mice (named as 29a KO hereafter) and their wild-type (WT) controls were used to analyze aging-related phenotypes. After challenged with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), dopaminergic injuries, glial activation, and mouse behaviors were evaluated. Primary glial cells were further cultured to explore the underlying mechanisms. Additionally, the levels of miR-29s in the cerebrospinal fluid (CSF) of PD patients (n = 18) and healthy subjects (n = 17) were quantified. 29a KO mice showed dramatic weight loss, kyphosis, and along with increased and deepened wrinkles in skins, when compared with WT mice. Moreover, both abdominal and brown adipose tissues reduced in 29a KO mice, compared to their WT counterpart. However, in MPTP-induced PD mouse model, the deficiency of miR-29a/b1 led to less severe damages of dopaminergic system and mitigated glial activation in the nigrostriatal pathway, and subsequently alleviated the motor impairments in 3-month-old mice. Eight-month-old mutant mice maintained such a resistance to MPTP intoxication. Mechanistically, the deficiency of miR-29a/b-1 promoted the expression of neurotrophic factors in 1-Methyl-4-phenylpyridinium (MPP+)-treated primary mixed glia and primary astrocytes. In lipopolysaccharide (LPS)-treated primary microglia, knockout of miR-29a/b-1 inhibited the expression of inflammatory factors, and promoted the expression of anti-inflammatory factors and neurotrophic factors. Knockout of miR-29a/b1 increased the activity of AMP-activated protein kinase (AMPK) and repressed NF-κB/p65 signaling in glial cells. Moreover, we found miR-29a level was increased in the CSF of patients with PD. Our results suggest that 29a KO mice display the peripheral premature senility. The combined effects of less activated glial cells might contribute to the mitigated inflammatory responses and elicit resistance to MPTP intoxication in miR-29a/b1 KO mice.
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Affiliation(s)
- Xiaochen Bai
- Department of Translational Neuroscience, MOE Frontiers Center for Brain Science, Institutes of Brain Science, State Key Laboratory of Medical Neurobiology, Jing’an District Centre Hospital of Shanghai, Fudan University, Shanghai, China
- Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China
- Department of Rehabilitation Medicine, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
| | - Jinghui Wang
- Department of Translational Neuroscience, MOE Frontiers Center for Brain Science, Institutes of Brain Science, State Key Laboratory of Medical Neurobiology, Jing’an District Centre Hospital of Shanghai, Fudan University, Shanghai, China
| | - Xiaoshuang Zhang
- Department of Translational Neuroscience, MOE Frontiers Center for Brain Science, Institutes of Brain Science, State Key Laboratory of Medical Neurobiology, Jing’an District Centre Hospital of Shanghai, Fudan University, Shanghai, China
| | - Yilin Tang
- Department of Translational Neuroscience, MOE Frontiers Center for Brain Science, Institutes of Brain Science, State Key Laboratory of Medical Neurobiology, Jing’an District Centre Hospital of Shanghai, Fudan University, Shanghai, China
- Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China
| | - Yongtao He
- Department of Translational Neuroscience, MOE Frontiers Center for Brain Science, Institutes of Brain Science, State Key Laboratory of Medical Neurobiology, Jing’an District Centre Hospital of Shanghai, Fudan University, Shanghai, China
| | - Jiayin Zhao
- Department of Translational Neuroscience, MOE Frontiers Center for Brain Science, Institutes of Brain Science, State Key Laboratory of Medical Neurobiology, Jing’an District Centre Hospital of Shanghai, Fudan University, Shanghai, China
| | - Linlin Han
- Department of Translational Neuroscience, MOE Frontiers Center for Brain Science, Institutes of Brain Science, State Key Laboratory of Medical Neurobiology, Jing’an District Centre Hospital of Shanghai, Fudan University, Shanghai, China
- Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China
| | - Rong Fang
- Department of Translational Neuroscience, MOE Frontiers Center for Brain Science, Institutes of Brain Science, State Key Laboratory of Medical Neurobiology, Jing’an District Centre Hospital of Shanghai, Fudan University, Shanghai, China
| | - Zhaolin Liu
- Department of Translational Neuroscience, MOE Frontiers Center for Brain Science, Institutes of Brain Science, State Key Laboratory of Medical Neurobiology, Jing’an District Centre Hospital of Shanghai, Fudan University, Shanghai, China
| | - Hongtian Dong
- Department of Translational Neuroscience, MOE Frontiers Center for Brain Science, Institutes of Brain Science, State Key Laboratory of Medical Neurobiology, Jing’an District Centre Hospital of Shanghai, Fudan University, Shanghai, China
| | - Qing Li
- Department of Translational Neuroscience, MOE Frontiers Center for Brain Science, Institutes of Brain Science, State Key Laboratory of Medical Neurobiology, Jing’an District Centre Hospital of Shanghai, Fudan University, Shanghai, China
- Shanghai Engineering Research Center for Model Organisms, SMOC, Shanghai, China
| | - Jingyu Ge
- Department of Translational Neuroscience, MOE Frontiers Center for Brain Science, Institutes of Brain Science, State Key Laboratory of Medical Neurobiology, Jing’an District Centre Hospital of Shanghai, Fudan University, Shanghai, China
| | - Yuanyuan Ma
- Department of Translational Neuroscience, MOE Frontiers Center for Brain Science, Institutes of Brain Science, State Key Laboratory of Medical Neurobiology, Jing’an District Centre Hospital of Shanghai, Fudan University, Shanghai, China
| | - Mei Yu
- Department of Translational Neuroscience, MOE Frontiers Center for Brain Science, Institutes of Brain Science, State Key Laboratory of Medical Neurobiology, Jing’an District Centre Hospital of Shanghai, Fudan University, Shanghai, China
| | - Ruilin Sun
- Shanghai Engineering Research Center for Model Organisms, SMOC, Shanghai, China
| | - Jian Wang
- Department of Translational Neuroscience, MOE Frontiers Center for Brain Science, Institutes of Brain Science, State Key Laboratory of Medical Neurobiology, Jing’an District Centre Hospital of Shanghai, Fudan University, Shanghai, China
- Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China
- Jian Wang,
| | - Jian Fei
- Shanghai Engineering Research Center for Model Organisms, SMOC, Shanghai, China
- School of Life Science and Technology, Tongji University, Shanghai, China
- *Correspondence: Jian Fei,
| | - Fang Huang
- Department of Translational Neuroscience, MOE Frontiers Center for Brain Science, Institutes of Brain Science, State Key Laboratory of Medical Neurobiology, Jing’an District Centre Hospital of Shanghai, Fudan University, Shanghai, China
- Fang Huang,
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Melnik BC, Schmitz G. Milk Exosomal microRNAs: Postnatal Promoters of β Cell Proliferation but Potential Inducers of β Cell De-Differentiation in Adult Life. Int J Mol Sci 2022; 23:ijms231911503. [PMID: 36232796 PMCID: PMC9569743 DOI: 10.3390/ijms231911503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 09/15/2022] [Accepted: 09/20/2022] [Indexed: 11/16/2022] Open
Abstract
Pancreatic β cell expansion and functional maturation during the birth-to-weaning period is driven by epigenetic programs primarily triggered by growth factors, hormones, and nutrients provided by human milk. As shown recently, exosomes derived from various origins interact with β cells. This review elucidates the potential role of milk-derived exosomes (MEX) and their microRNAs (miRs) on pancreatic β cell programming during the postnatal period of lactation as well as during continuous cow milk exposure of adult humans to bovine MEX. Mechanistic evidence suggests that MEX miRs stimulate mTORC1/c-MYC-dependent postnatal β cell proliferation and glycolysis, but attenuate β cell differentiation, mitochondrial function, and insulin synthesis and secretion. MEX miR content is negatively affected by maternal obesity, gestational diabetes, psychological stress, caesarean delivery, and is completely absent in infant formula. Weaning-related disappearance of MEX miRs may be the critical event switching β cells from proliferation to TGF-β/AMPK-mediated cell differentiation, whereas continued exposure of adult humans to bovine MEX miRs via intake of pasteurized cow milk may reverse β cell differentiation, promoting β cell de-differentiation. Whereas MEX miR signaling supports postnatal β cell proliferation (diabetes prevention), persistent bovine MEX exposure after the lactation period may de-differentiate β cells back to the postnatal phenotype (diabetes induction).
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Affiliation(s)
- Bodo C. Melnik
- Department of Dermatology, Environmental Medicine and Health Theory, University of Osnabrück, D-49076 Osnabrück, Germany
- Correspondence: ; Tel.: +49-52-4198-8060
| | - Gerd Schmitz
- Institute for Clinical Chemistry and Laboratory Medicine, University Hospital of Regensburg, University of Regensburg, D-93053 Regensburg, Germany
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Zygo-Albuside A: New Saponin from Zygophyllum album L. with Significant Antioxidant, Anti-Inflammatory and Antiapoptotic Effects against Methotrexate-Induced Testicular Damage. Int J Mol Sci 2022; 23:ijms231810799. [PMID: 36142712 PMCID: PMC9501557 DOI: 10.3390/ijms231810799] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 09/09/2022] [Accepted: 09/10/2022] [Indexed: 12/23/2022] Open
Abstract
Chemical investigation of the crude extract of the aerial part of Zygophyllum album L. (Z. album) led to the isolation of a new saponin, Zygo-albuside A (7), together with seven known compounds, one of them (caffeic acid, compound 4) is reported in the genus for the first time. NMR (1D and 2D) and mass spectrometric analysis, including high-resolution mass spectrometry (HRMS), were utilized to set up the chemical structures of these compounds. The present biological study aimed to investigate the protective antioxidant, anti-inflammatory, and antiapoptotic activities of the crude extract from the aerial part of Z. album and two of its isolated compounds, rutin and the new saponin zygo-albuside A, against methotrexate (MTX)-induced testicular injury, considering the role of miRNA-29a. In all groups except for the normal control group, which received a mixture of distilled water and DMSO (2:1) as vehicle orally every day for ten days, testicular damage was induced on the fifth day by intraperitoneal administration of MTX at a single dose of 20 mg/kg. Histopathological examination showed that pre-treatment with the crude extract of Z. album, zygo-albuside A, or rutin reversed the testicular damage induced by MTX. In addition, biochemical analysis in the protected groups showed a decrease in malondialdehyde (MDA), interleukin-6 (IL-6) and IL-1β, Bcl-2-associated-protein (Bax), and an increase in B-cell lymphoma 2 (Bcl-2) protein, catalase (CAT), superoxide dismutase (SOD) in the testis, along with an increase in serum testosterone levels compared with the unprotected (positive control) group. The mRNA expression levels of nuclear factor-kappa B (NF-κB), tumor necrosis factor-α (TNF-α), p53, and miRNA-29a were downregulated in the testicular tissues of the protected groups compared with the unprotected group. In conclusion, the study provides sufficient evidence that Z. album extract, and its isolated compounds, zygo-albuside A and rutin, could alleviate testicular damage caused by the chemotherapeutic agent MTX.
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Mendonca A, Thandapani P, Nagarajan P, Venkatesh S, Sundaresan S. Role of microRNAs in regulation of insulin secretion and insulin signaling involved in type 2 diabetes mellitus. J Biosci 2022. [DOI: 10.1007/s12038-022-00295-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2022]
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26
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The Role of miR-29 Family in TGF-β Driven Fibrosis in Glaucomatous Optic Neuropathy. Int J Mol Sci 2022; 23:ijms231810216. [PMID: 36142127 PMCID: PMC9499597 DOI: 10.3390/ijms231810216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2022] [Revised: 08/30/2022] [Accepted: 09/02/2022] [Indexed: 11/17/2022] Open
Abstract
Primary open angle glaucoma (POAG), a chronic optic neuropathy, remains the leading cause of irreversible blindness worldwide. It is driven in part by the pro-fibrotic cytokine transforming growth factor beta (TGF-β) and leads to extracellular matrix remodelling at the lamina cribrosa of the optic nerve head. Despite an array of medical and surgical treatments targeting the only known modifiable risk factor, raised intraocular pressure, many patients still progress and develop significant visual field loss and eventual blindness. The search for alternative treatment strategies targeting the underlying fibrotic transformation in the optic nerve head and trabecular meshwork in glaucoma is ongoing. MicroRNAs are small non-coding RNAs known to regulate post-transcriptional gene expression. Extensive research has been undertaken to uncover the complex role of miRNAs in gene expression and miRNA dysregulation in fibrotic disease. MiR-29 is a family of miRNAs which are strongly anti-fibrotic in their effects on the TGF-β signalling pathway and the regulation of extracellular matrix production and deposition. In this review, we discuss the anti-fibrotic effects of miR-29 and the role of miR-29 in ocular pathology and in the development of glaucomatous optic neuropathy. A better understanding of the role of miR-29 in POAG may aid in developing diagnostic and therapeutic strategies in glaucoma.
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27
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Capuozzo M, Santorsola M, Bocchetti M, Perri F, Cascella M, Granata V, Celotto V, Gualillo O, Cossu AM, Nasti G, Caraglia M, Ottaiano A. p53: From Fundamental Biology to Clinical Applications in Cancer. BIOLOGY 2022; 11:1325. [PMID: 36138802 PMCID: PMC9495382 DOI: 10.3390/biology11091325] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 09/04/2022] [Accepted: 09/06/2022] [Indexed: 11/18/2022]
Abstract
p53 tumour suppressor gene is our major barrier against neoplastic transformation. It is involved in many cellular functions, including cell cycle arrest, senescence, DNA repair, apoptosis, autophagy, cell metabolism, ferroptosis, immune system regulation, generation of reactive oxygen species, mitochondrial function, global regulation of gene expression, miRNAs, etc. Its crucial importance is denounced by the high percentage of amino acid sequence identity between very different species (Homo sapiens, Drosophila melanogaster, Rattus norvegicus, Danio rerio, Canis lupus familiaris, Gekko japonicus). Many of its activities allowed life on Earth (e.g., repair from radiation-induced DNA damage) and directly contribute to its tumour suppressor function. In this review, we provide paramount information on p53, from its discovery, which is an interesting paradigm of science evolution, to potential clinical applications in anti-cancer treatment. The description of the fundamental biology of p53 is enriched by specific information on the structure and function of the protein as well by tumour/host evolutionistic perspectives of its role.
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Affiliation(s)
| | - Mariachiara Santorsola
- Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, Via M. Semmola, 80131 Naples, Italy
| | - Marco Bocchetti
- Department of Precision Medicine, University of Campania “L. Vanvitelli”, Via L. De Crecchio 7, 80138 Naples, Italy
- Laboratory of Molecular and Precision Oncology, Biogem Scarl, Institute of Genetic Research, 83031 Ariano Irpino, Italy
| | - Francesco Perri
- Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, Via M. Semmola, 80131 Naples, Italy
| | - Marco Cascella
- Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, Via M. Semmola, 80131 Naples, Italy
| | - Vincenza Granata
- Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, Via M. Semmola, 80131 Naples, Italy
| | - Venere Celotto
- Coordinamento Farmaceutico, ASL-Naples-3, 80056 Ercolano, Italy
| | - Oreste Gualillo
- SERGAS (Servizo Galego de Saude) and IDIS (Instituto de Investigación Sanitaria de Santiago), NEIRID Lab (Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases), Research Laboratory 9, Santiago University Clinical Hospital, 15706 Santiago de Compostela, Spain
| | - Alessia Maria Cossu
- Department of Precision Medicine, University of Campania “L. Vanvitelli”, Via L. De Crecchio 7, 80138 Naples, Italy
- Laboratory of Molecular and Precision Oncology, Biogem Scarl, Institute of Genetic Research, 83031 Ariano Irpino, Italy
| | - Guglielmo Nasti
- Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, Via M. Semmola, 80131 Naples, Italy
| | - Michele Caraglia
- Department of Precision Medicine, University of Campania “L. Vanvitelli”, Via L. De Crecchio 7, 80138 Naples, Italy
| | - Alessandro Ottaiano
- Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, Via M. Semmola, 80131 Naples, Italy
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Nguyen TTP, Suman KH, Nguyen TB, Nguyen HT, Do DN. The Role of miR-29s in Human Cancers—An Update. Biomedicines 2022; 10:biomedicines10092121. [PMID: 36140219 PMCID: PMC9495592 DOI: 10.3390/biomedicines10092121] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2022] [Revised: 08/22/2022] [Accepted: 08/24/2022] [Indexed: 11/25/2022] Open
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that directly bind to the 3’ untranslated region (3’-UTR) of the target mRNAs to inhibit their expression. The miRNA-29s (miR-29s) are suggested to be either tumor suppressors or oncogenic miRNAs that are strongly dysregulated in various types of cancer. Their dysregulation alters the expression of their target genes, thereby exerting influence on different cellular pathways including cell proliferation, apoptosis, migration, and invasion, thereby contributing to carcinogenesis. In the present review, we aimed to provide an overview of the current knowledge on the miR-29s biological network and its functions in cancer, as well as its current and potential applications as a diagnostic and prognostic biomarker and/or a therapeutic target in major types of human cancer.
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Affiliation(s)
- Thuy T. P. Nguyen
- Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Kamrul Hassan Suman
- Department of Fisheries, Ministry of Fisheries and Livestock, Dhaka 1205, Bangladesh
| | - Thong Ba Nguyen
- Department of Anatomy, Biochemistry, and Physiology, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, HI 96813, USA
| | - Ha Thi Nguyen
- Institute of Research and Development, Duy Tan University, Danang 550000, Vietnam
- Center for Molecular Biology, College of Medicine and Pharmacy, Duy Tan University, Danang 550000, Vietnam
- Correspondence: (H.T.N.); (D.N.D.)
| | - Duy Ngoc Do
- Department of Animal Science and Aquaculture, Dalhousie University, Truro, NS B2N 5E3, Canada
- Correspondence: (H.T.N.); (D.N.D.)
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Perron G, Jandaghi P, Moslemi E, Nishimura T, Rajaee M, Alkallas R, Lu T, Riazalhosseini Y, Najafabadi HS. Pan-cancer analysis of mRNA stability for decoding tumour post-transcriptional programs. Commun Biol 2022; 5:851. [PMID: 35987939 PMCID: PMC9392771 DOI: 10.1038/s42003-022-03796-w] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Accepted: 08/04/2022] [Indexed: 11/25/2022] Open
Abstract
Measuring mRNA decay in tumours is a prohibitive challenge, limiting our ability to map the post-transcriptional programs of cancer. Here, using a statistical framework to decouple transcriptional and post-transcriptional effects in RNA-seq data, we uncover the mRNA stability changes that accompany tumour development and progression. Analysis of 7760 samples across 18 cancer types suggests that mRNA stability changes are ~30% as frequent as transcriptional events, highlighting their widespread role in shaping the tumour transcriptome. Dysregulation of programs associated with >80 RNA-binding proteins (RBPs) and microRNAs (miRNAs) drive these changes, including multi-cancer inactivation of RBFOX and miR-29 families. Phenotypic activation or inhibition of RBFOX1 highlights its role in calcium signaling dysregulation, while modulation of miR-29 shows its impact on extracellular matrix organization and stemness genes. Overall, our study underlines the integral role of mRNA stability in shaping the cancer transcriptome, and provides a resource for systematic interrogation of cancer-associated stability pathways. The role of mRNA stability in shaping the cancer transcriptome is revealed using a statistical analysis of transcriptomic data.
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30
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Eltamany EE, Mosalam EM, Mehanna ET, Awad BM, Mosaad SM, Abdel-Kader MS, Ibrahim AK, Badr JM, Goda MS. Potential Gonado-Protective Effect of Cichorium endivia and Its Major Phenolic Acids against Methotrexate-Induced Testicular Injury in Mice. Biomedicines 2022; 10:1986. [PMID: 36009533 PMCID: PMC9406180 DOI: 10.3390/biomedicines10081986] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 07/23/2022] [Accepted: 08/12/2022] [Indexed: 11/16/2022] Open
Abstract
Cichorium endivia L. (Asteraceae) is a wide edible plant that grows in the Mediterranean region. In this study, a phytochemical investigation of C. endivia L. ethanolic extract led to the isolation of stigmasterol (1), ursolic acid (2), β-amyrin (3), azelaic acid (4), vanillic acid (5), (6S, 7E)-6-hydroxy-4,7-megastigmadien-3,9-dione (S(+)-dehydrovomifoliol) (6), 4-hydroxy phenyl acetic acid (7), vomifoliol (8), ferulic acid (9), protocatechuic acid (10), kaempferol (11), p. coumaric acid (12), and luteolin (13). In addition, the total phenolic content as well as the in vitro antioxidant activity of C. endivia L. extract were estimated. Moreover, we inspected the potential gonado-protective effect of C. endivia crude extract, its phenolic fraction, and the isolated coumaric, vanillic, and ferulic acids against methotrexate (MTX)-induced testicular injury in mice. There were seven groups: normal control, MTX control, MTX + C. endivia crude extract, MTX + C. endivia phenolic fraction, MTX + isolated coumaric acid, MTX + isolated vanillic acid, and MTX + isolated ferulic acid. MTX was given by i.p. injection of a 20 mg/kg single dose. The crude extract and phenolic fraction were given with a dose of 100 mg/kg/day, whereas the compounds were given at a dose of 10 mg/kg/day. A histopathological examination was done. The testosterone level was detected in serum together with the testicular content of malondialdehyde (MDA), catalase (CAT), superoxide dismutase (SOD), interleukin 1β (IL-1β), IL-6, tumor necrosis factor alpha (TNF-α), nuclear factor kappa B (NF-κB), B-cell lymphoma 2 (Bcl-2), Bcl-2 associated x protein (Bax), p53, and miR-29a. C. endivia crude extract, the phenolic fraction, and the isolated compounds showed significant elevation in their levels of testosterone, CAT, SOD, Bcl-2 with a significant decrease in their levels of MDA, TNF-α, IL-1β, IL-6, NF-κB, Bax, P53, and miR-29a compared to those of the MTX control group. In conclusion, C. endivia mitigated MTX-induced germ cell toxicity via anti-inflammatory, antioxidant, and antiapoptotic effects.
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Affiliation(s)
- Enas E. Eltamany
- Department of Pharmacognosy, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt
| | - Esraa M. Mosalam
- Department of Biochemistry, Faculty of Pharmacy, Menoufia University, Shebin El-Koum 32511, Egypt
| | - Eman T. Mehanna
- Department of Biochemistry, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt
| | - Basma M. Awad
- Department of Pharmacognosy, Faculty of Pharmacy, Sinai University, El-Arish 45518, Egypt
| | - Sarah M. Mosaad
- Division of Pharmacology and Therapeutics, Department of Continuous Medical Education, General Authority of Healthcare, Ismailia 41522, Egypt
| | - Maged S. Abdel-Kader
- Department of Pharmacognosy, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
- Department of Pharmacognosy, Faculty of Pharmacy, Alexandria University, Alexandria 21215, Egypt
| | - Amany K. Ibrahim
- Department of Pharmacognosy, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt
| | - Jihan M. Badr
- Department of Pharmacognosy, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt
| | - Marwa S. Goda
- Department of Pharmacognosy, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt
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Dalgaard LT, Sørensen AE, Hardikar AA, Joglekar MV. The microRNA-29 family - role in metabolism and metabolic disease. Am J Physiol Cell Physiol 2022; 323:C367-C377. [PMID: 35704699 DOI: 10.1152/ajpcell.00051.2022] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The microRNA-29a family members miR-29a-3p, miR-29b-3p and miR-29c-3p are ubiquitously expressed and consistently increased in various tissues and cell types in conditions of metabolic disease; obesity, insulin resistance and type 2 diabetes. In pancreatic beta cells, miR-29a is required for normal exocytosis, but increased levels are associated with impaired beta cell function. Similarly, in liver miR-29 species are higher in models of insulin resistance and type 2 diabetes, and either knock-out or depletion using a microRNA inhibitor improves hepatic insulin resistance. In skeletal muscle, miR-29 upregulation is associated with insulin resistance and altered substrate oxidation, and similarly, in adipocytes over-expression of miR-29a leads to insulin resistance. Blocking miR-29a using nucleic acid antisense therapeutics show promising results in preclinical animal models of obesity and type 2 diabetes, although the widespread expression pattern of miR-29 family members complicates the exploration of single target tissues. However, in fibrotic diseases, such as in late complications of diabetes and metabolic disease (diabetic kidney disease, non-alcoholic steatohepatitis), miR-29 expression is suppressed by TGFβ allowing increased extracellular matrix collagen to form. In the clinical setting circulating levels of miR-29a and miR-29b are consistently increased in type 2 diabetes and in gestational diabetes, and are also possible prognostic markers for deterioration of glucose tolerance. In conclusion, miR-29 plays an essential role in various organs relevant to intermediary metabolism and its upregulation contribute to impaired glucose metabolism, while it suppresses fibrosis development. Thus, a correct balance of miR-29a levels seems important for cellular and organ homeostasis in metabolism.
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Affiliation(s)
- Louise T Dalgaard
- Department of Science and Environment, Roskilde University, Roskilde, Denmark
| | - Anja E Sørensen
- Department of Science and Environment, Roskilde University, Roskilde, Denmark
| | - Anandwardhan A Hardikar
- Diabetes and Islet Biology Group, School of Medicine, Western Sydney University, Sydney, NSW, Australia
| | - Mugdha V Joglekar
- Diabetes and Islet Biology Group, School of Medicine, Western Sydney University, Sydney, NSW, Australia
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The Complex Interaction between P53 and miRNAs Joins New Awareness in Physiological Stress Responses. Cells 2022; 11:cells11101631. [PMID: 35626668 PMCID: PMC9139524 DOI: 10.3390/cells11101631] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 05/07/2022] [Accepted: 05/10/2022] [Indexed: 12/14/2022] Open
Abstract
This review emphasizes the important role of cross-talk between P53 and microRNAs in physiological stress signaling. P53 responds to stress in a variety of ways ranging from activating survival-promotion pathways to triggering programmed cell death to eliminate damaged cells. In physiological stress generated by any external or internal condition that challenges cell homeostasis, P53 exerts its function as a transcription factor for target genes or by regulating the expression and maturation of a class of small non-coding RNA molecules (miRNAs). The miRNAs control the level of P53 through direct control of P53 or through indirect control of P53 by targeting its regulators (such as MDMs). In turn, P53 controls the expression level of miRNAs targeted by P53 through the regulation of their transcription or biogenesis. This elaborate regulatory scheme emphasizes the relevance of miRNAs in the P53 network and vice versa.
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Biggar Y, Ingelson-Filpula WA, Storey KB. Pro- and anti-apoptotic microRNAs are differentially regulated during estivation in Xenopus laevis. Gene 2022; 819:146236. [PMID: 35114277 DOI: 10.1016/j.gene.2022.146236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 01/12/2022] [Accepted: 01/18/2022] [Indexed: 11/17/2022]
Abstract
Xenopus laevis, the African clawed frog, undergoes seasonal estivation to survive periods of drought when its lake-bed habitats dry up. The frog can lose ∼30% of its total body water, leading to conditions of impaired blood flow and ischemia which risk cellular survival under these harsh conditions. MicroRNAs are short, noncoding, single-stranded RNAs 21-24 nt long that have been widely implicated in hypometabolic responses, and serve functions including apoptosis survival. The levels of three pro-apoptotic and four anti-apoptotic miRNAs were measured in liver and skeletal muscle of estivating X. laevis, and bioinformatic analysis was performed to verify potential mRNA targets of these miRNAs. Members of pro-apoptotic miRNAs miR-15a, miR-16, and miR-101 showed upregulation as a result of dehydration stress, while anti-apoptotic miRNAs miR-19b, miR-21, miR-92a, and miR-155 showed differential regulation between the two tissues. Together, these miRNAs act in a more diverse fashion than arbitrarily pro- or anti-apoptotic, and encompass functions ranging from the inhibition of cell proliferation through cell cycle arrest to the prevention of skeletal muscle atrophy.
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Affiliation(s)
- Yulia Biggar
- Institute of Biochemistry and Department of Biology, Carleton University, 1125 Colonel By Drive, Ottawa, Ontario K1S 5B6, Canada
| | - W Aline Ingelson-Filpula
- Institute of Biochemistry and Department of Biology, Carleton University, 1125 Colonel By Drive, Ottawa, Ontario K1S 5B6, Canada
| | - Kenneth B Storey
- Institute of Biochemistry and Department of Biology, Carleton University, 1125 Colonel By Drive, Ottawa, Ontario K1S 5B6, Canada.
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Smith ES, Whitty E, Yoo B, Moore A, Sempere LF, Medarova Z. Clinical Applications of Short Non-Coding RNA-Based Therapies in the Era of Precision Medicine. Cancers (Basel) 2022; 14:cancers14061588. [PMID: 35326738 PMCID: PMC8946086 DOI: 10.3390/cancers14061588] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 03/10/2022] [Accepted: 03/15/2022] [Indexed: 12/12/2022] Open
Abstract
Simple Summary RNA-based drugs are an attractive approach for personalized treatment of cancer and other diseases. This review focuses on two related classes of short non-coding RNA: microRNAs (miRNAs) and small interfering RNAs (siRNAs). miRNAs are endogenous short RNAs that bind multiple messenger RNAs (mRNAs) and prevent the production of their gene-products, whereas siRNAs are exogenous RNAs that target a single and specific mRNA for degradation. This review describes the development, challenges, and clinical successes of short RNA-based drugs. We provide several examples of how these RNA drugs are designed, chemically modified and delivered for treatment of different cancer types, cardiovascular disease, and rare genetic disorders. We highlight the similarities, differences, and considerations to maximize the treatment efficacy of miRNA-based vs. siRNA-based drugs. Abstract Traditional targeted therapeutic agents have relied on small synthetic molecules or large proteins, such as monoclonal antibodies. These agents leave a lot of therapeutic targets undruggable because of the lack or inaccessibility of active sites and/or pockets in their three-dimensional structure that can be chemically engaged. RNA presents an attractive, transformative opportunity to reach any genetic target with therapeutic intent. RNA therapeutic design is amenable to modularity and tunability and is based on a computational blueprint presented by the genetic code. Here, we will focus on short non-coding RNAs (sncRNAs) as a promising therapeutic modality because of their potency and versatility. We review recent progress towards clinical application of small interfering RNAs (siRNAs) for single-target therapy and microRNA (miRNA) activity modulators for multi-target therapy. siRNAs derive their potency from the fact that the underlying RNA interference (RNAi) mechanism is catalytic and reliant on post-transcriptional mRNA degradation. Therapeutic siRNAs can be designed against virtually any mRNA sequence in the transcriptome and specifically target a disease-causing mRNA variant. Two main classes of microRNA activity modulators exist to increase (miRNA mimics) or decrease (anti-miRNA inhibitors) the function of a specific microRNA. Since a single microRNA regulates the expression of multiple target genes, a miRNA activity modulator can have a more profound effect on global gene expression and protein output than siRNAs do. Both types of sncRNA-based drugs have been investigated in clinical trials and some siRNAs have already been granted FDA approval for the treatment of genetic, cardiometabolic, and infectious diseases. Here, we detail clinical results using siRNA and miRNA therapeutics and present an outlook for the potential of these sncRNAs in medicine.
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Affiliation(s)
- Ellen S. Smith
- Department of Biochemistry, Northeastern University, Boston, MA 02115, USA;
| | - Eric Whitty
- Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA; (E.W.); (B.Y.)
| | - Byunghee Yoo
- Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA; (E.W.); (B.Y.)
| | - Anna Moore
- Precision Health Program, Michigan State University, East Lansing, MI 48824, USA;
- Department of Radiology, College of Human Medicine, Michigan State University, East Lansing, MI 48824, USA
| | - Lorenzo F. Sempere
- Precision Health Program, Michigan State University, East Lansing, MI 48824, USA;
- Department of Radiology, College of Human Medicine, Michigan State University, East Lansing, MI 48824, USA
- Correspondence: (L.F.S.); (Z.M.)
| | - Zdravka Medarova
- Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA; (E.W.); (B.Y.)
- Transcode Therapeutics, Inc., Boston, MA 02109, USA
- Correspondence: (L.F.S.); (Z.M.)
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35
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Jo HR, Jeong JH. MicroRNA-Mediated Downregulation of HMGB2 Contributes to Cellular Senescence in Microvascular Endothelial Cells. Cells 2022; 11:cells11030584. [PMID: 35159393 PMCID: PMC8834370 DOI: 10.3390/cells11030584] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 01/29/2022] [Accepted: 02/07/2022] [Indexed: 11/24/2022] Open
Abstract
High mobility group box 2 (HMGB2) is a non-histone chromosomal protein involved in various biological processes, including cellular senescence. However, its role in cellular senescence has not been evaluated extensively. To determine the regulatory role and mechanism of HMGB2 in cellular senescence, we performed gene expression analysis, senescence staining, and tube formation assays using young and senescent microvascular endothelial cells (MVECs) after small RNA treatment or HMGB2 overexpression. HMGB2 expression decreased with age and was regulated at the transcriptional level. siRNA-mediated downregulation inhibited cell proliferation and accelerated cellular senescence. In contrast, ectopic overexpression delayed senescence and maintained relatively higher tube-forming activity. To determine the HMGB2 downregulation mechanism, we screened miRNAs that were significantly upregulated in senescent MVECs and selected HMGB2-targeting miRNAs. Six miRNAs, miR-23a-3p, 23b-3p, -181a-5p, -181b-5p, -221-3p, and -222-3p, were overexpressed in senescent MVECs. Ectopic introduction of miR-23a-3p, -23b-3p, -181a-5p, -181b-5p, and -221-3p, with the exception of miR-222-3p, led to the downregulation of HMGB2, upregulation of senescence-associated markers, and decreased tube formation activity. Inhibition of miR-23a-3p, -181a-5p, -181b-5p, and -221-3p delayed cellular senescence. Restoration of HMGB2 expression using miRNA inhibitors represents a potential strategy to overcome the detrimental effects of cellular senescence in endothelial cells.
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Affiliation(s)
- Hye-Ram Jo
- Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Science, Seoul 01812, Korea;
- Radiological and Medico-Oncological Sciences, University of Science and Technology, Daejeon 34113, Korea
| | - Jae-Hoon Jeong
- Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Science, Seoul 01812, Korea;
- Radiological and Medico-Oncological Sciences, University of Science and Technology, Daejeon 34113, Korea
- Correspondence: ; Tel.: +82-2970-1386
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Das T, Das TK, Khodarkovskaya A, Dash S. Non-coding RNAs and their bioengineering applications for neurological diseases. Bioengineered 2021; 12:11675-11698. [PMID: 34756133 PMCID: PMC8810045 DOI: 10.1080/21655979.2021.2003667] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Engineering of cellular biomolecules is an emerging landscape presenting creative therapeutic opportunities. Recently, several strategies such as biomimetic materials, drug-releasing scaffolds, stem cells, and dynamic culture systems have been developed to improve specific biological functions, however, have been confounded with fundamental and technical roadblocks. Rapidly emerging investigations on the bioengineering prospects of mammalian ribonucleic acid (RNA) is expected to result in significant biomedical advances. More specifically, the current trend focuses on devising non-coding (nc) RNAs as therapeutic candidates for complex neurological diseases. Given the pleiotropic and regulatory role, ncRNAs such as microRNAs and long non-coding RNAs are deemed as attractive therapeutic candidates. Currently, the list of non-coding RNAs in mammals is evolving, which presents the plethora of hidden possibilities including their scope in biomedicine. Herein, we critically review on the emerging repertoire of ncRNAs in neurological diseases such as Alzheimer’s disease, Parkinson’s disease, neuroinflammation and drug abuse disorders. Importantly, we present the advances in engineering of ncRNAs to improve their biocompatibility and therapeutic feasibility as well as provide key insights into the applications of bioengineered non-coding RNAs that are investigated for neurological diseases.
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Affiliation(s)
- Tuhin Das
- Quanta Therapeutics, San Francisco, CA, 94158, USA.,RayBiotech, Inc, 3607 Parkway Lane, Peachtree Corners, GA, 30092, USA
| | - Tushar Kanti Das
- Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA
| | - Anne Khodarkovskaya
- Department of Pathology, Weill Cornell Medicine, Medical College of Cornell University, New York, NY, 10065, USA
| | - Sabyasachi Dash
- Department of Pathology, Weill Cornell Medicine, Medical College of Cornell University, New York, NY, 10065, USA.,School of Biotechnology, Kalinga Institute of Industrial Technology, Bhubaneswar, Odisha, 751024 India
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37
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Li PP, Li RG, Huang YQ, Lu JP, Zhang WJ, Wang ZY. LncRNA OTUD6B-AS1 promotes paclitaxel resistance in triple negative breast cancer by regulation of miR-26a-5p/MTDH pathway-mediated autophagy and genomic instability. Aging (Albany NY) 2021; 13:24171-24191. [PMID: 34740994 PMCID: PMC8610138 DOI: 10.18632/aging.203672] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 10/28/2021] [Indexed: 12/13/2022]
Abstract
Genomic instability (GIN) is pivotal in regulating tumor drug resistance, which blocked the treatment of triple negative breast cancer (TNBC). Although recent studies implied that non-coding RNA (ncRNA)-mediated autophagy abolishment promoted tumorigenesis by up-regulation of GIN, autophagy was known as a risk factor in tumor drug resistance. However, previous study also pointed that up-regulation of autophagy promoted GIN. Therefore, the relationship between autophagy and GIN is not clear, and more work is needed. And, if an ncRNA is identified to be a co-regulator of autophagy and GIN, it will be a potential therapy target of chemotherapy resistance in TNBC. In our study, we recognized both autophagy-GIN-associated microRNA (mi-26a-5p) by big data analysis, which was prognosis-correlated in breast cancer. Next, we identified the up-stream regulators (long non-coding RNA, lncRNA) and down-stream targets of miR-26a-5p by bioinformatics analysis (online public databases). Finally, we established lncRNA OTUD6B-AS1/miR-26a-5p/MTDH signaling pathway, and verified their functions by cytological, molecular biological and zoological experiments. In general, our study found (1) miR-26a-5p was a protective factor of breast cancer, while OTUD6B-AS1 and MTDH were risk factors; (2) OTUD6B-AS1 was the up-stream regulator of miR-26a-5p verified by luciferase; (3) up-regulation of miR-26a-5p and down-regulation of MTDH promoted cellular cytotoxicity of paclitaxel (PTX) in vitro and in vivo. (4) down-regulation of miR-26a-5p, overexpression of MTDH and OTUD6B-AS1 promoted autophagy and DNA damage; (5) up-regulation of OTUD6B-AS1 and MTDH inhibited DNA damage response (DDR) by inhibiting the phosphorylated activation of RAD51, ATR and ATM.
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Affiliation(s)
- Peng-Ping Li
- Department of Breast-Thyroid Surgery, Department of General Surgery, The First Hospital of Xiaoshan District, Hangzhou, Zhejiang Province 311000, China
| | - Rong-Guo Li
- Department of Breast-Thyroid Surgery, Department of General Surgery, The First Hospital of Xiaoshan District, Hangzhou, Zhejiang Province 311000, China
| | - Yu-Qing Huang
- Department of Breast-Thyroid Surgery, Department of General Surgery, The First Hospital of Xiaoshan District, Hangzhou, Zhejiang Province 311000, China
| | - Jin-Pian Lu
- The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province 310000, China
| | - Wei-Jun Zhang
- Department of Breast-Thyroid Surgery, Department of General Surgery, The First Hospital of Xiaoshan District, Hangzhou, Zhejiang Province 311000, China
| | - Zhen-Yu Wang
- Department of Breast-Thyroid Surgery, Department of General Surgery, The First Hospital of Xiaoshan District, Hangzhou, Zhejiang Province 311000, China
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38
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Saliani M, Mirzaiebadizi A, Mosaddeghzadeh N, Ahmadian MR. RHO GTPase-Related Long Noncoding RNAs in Human Cancers. Cancers (Basel) 2021; 13:5386. [PMID: 34771549 PMCID: PMC8582479 DOI: 10.3390/cancers13215386] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 10/21/2021] [Accepted: 10/22/2021] [Indexed: 12/27/2022] Open
Abstract
RHO GTPases are critical signal transducers that regulate cell adhesion, polarity, and migration through multiple signaling pathways. While all these cellular processes are crucial for the maintenance of normal cell homeostasis, disturbances in RHO GTPase-associated signaling pathways contribute to different human diseases, including many malignancies. Several members of the RHO GTPase family are frequently upregulated in human tumors. Abnormal gene regulation confirms the pivotal role of lncRNAs as critical gene regulators, and thus, they could potentially act as oncogenes or tumor suppressors. lncRNAs most likely act as sponges for miRNAs, which are known to be dysregulated in various cancers. In this regard, the significant role of miRNAs targeting RHO GTPases supports the view that the aberrant expression of lncRNAs may reciprocally change the intensity of RHO GTPase-associated signaling pathways. In this review article, we summarize recent advances in lncRNA research, with a specific focus on their sponge effects on RHO GTPase-targeting miRNAs to crucially mediate gene expression in different cancer cell types and tissues. We will focus in particular on five members of the RHO GTPase family, including RHOA, RHOB, RHOC, RAC1, and CDC42, to illustrate the role of lncRNAs in cancer progression. A deeper understanding of the widespread dysregulation of lncRNAs is of fundamental importance for confirmation of their contribution to RHO GTPase-dependent carcinogenesis.
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Affiliation(s)
- Mahsa Saliani
- Institute of Biochemistry and Molecular Biology II, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine University, 40225 Düsseldorf, Germany
- Department of Chemistry, Faculty of Science, Ferdowsi University of Mashhad, Mashhad 9177948974, Iran
| | - Amin Mirzaiebadizi
- Institute of Biochemistry and Molecular Biology II, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine University, 40225 Düsseldorf, Germany
| | - Niloufar Mosaddeghzadeh
- Institute of Biochemistry and Molecular Biology II, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine University, 40225 Düsseldorf, Germany
| | - Mohammad Reza Ahmadian
- Institute of Biochemistry and Molecular Biology II, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine University, 40225 Düsseldorf, Germany
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Pan D, Du Y, Li R, Shen A, Liu X, Li C, Hu B. miR-29b-3p Increases Radiosensitivity in Stemness Cancer Cells via Modulating Oncogenes Axis. Front Cell Dev Biol 2021; 9:741074. [PMID: 34604239 PMCID: PMC8481616 DOI: 10.3389/fcell.2021.741074] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Accepted: 08/10/2021] [Indexed: 12/12/2022] Open
Abstract
Radioresistance conferred by cancer stem cells (CSCs) is the principal cause of the failure of cancer radiotherapy. Eradication of CSCs is a prime therapeutic target and a requirement for effective radiotherapy. Three dimensional (3D) cell-cultured model could mimic the morphology of cells in vivo and induce CSC properties. Emerging evidence suggests that microRNAs (miRNAs) play crucial roles in the regulation of radiosensitivity in cancers. In this study, we aim to investigate the effects of miRNAs on the radiosensitivity of 3D cultured stem-like cells. Using miRNA microarray analysis in 2D and 3D cell culture models, we found that the expression of miR-29b-3p was downregulated in 3D cultured A549 and MCF7 cells compared with monolayer (2D) cells. Clinic data analysis from The Cancer Genome Atlas database exhibited that miR-29b-3p high expression showed significant advantages in lung adenocarcinoma and breast invasive carcinoma patients’ prognosis. The subsequent experiments proved that miR-29b-3p overexpression decreased the radioresistance of cells in 3D culture and tumors in vivo through interfering kinetics process of DNA damage repair and inhibiting oncogenes RBL1, PIK3R1, AKT2, and Bcl-2. In addition, miR-29b-3p knockdown enhanced cancer cells invasion and migration capability. MiR-29b-3p overexpression decreased the stemness of 3D cultured cells. In conclusion, our results demonstrate that miR-29b-3p could be a sensitizer of radiation killing in CSC-like cells via inhibiting oncogenes expression. MiR-29b-3p could be a novel therapeutic candidate target for radiotherapy.
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Affiliation(s)
- Dong Pan
- Department of Radiation Medicine, School of Public Health and Management, Wenzhou Medical University, Wenzhou, China.,Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Key Laboratory of Space Radiobiology of Gansu Province, Institute of Modern Physics, Chinese Academy of Sciences (CAS), Lanzhou, China.,Department of Dermatology, Duke University Medical Center, Durham, NC, United States
| | - Yarong Du
- Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Key Laboratory of Space Radiobiology of Gansu Province, Institute of Modern Physics, Chinese Academy of Sciences (CAS), Lanzhou, China
| | - Rong Li
- Department of Radiation Medicine, School of Public Health and Management, Wenzhou Medical University, Wenzhou, China
| | - Aihua Shen
- Department of Radiation Medicine, School of Public Health and Management, Wenzhou Medical University, Wenzhou, China
| | - Xiaodong Liu
- Department of Radiation Medicine, School of Public Health and Management, Wenzhou Medical University, Wenzhou, China
| | - Chuanyuan Li
- Department of Dermatology, Duke University Medical Center, Durham, NC, United States
| | - Burong Hu
- Department of Radiation Medicine, School of Public Health and Management, Wenzhou Medical University, Wenzhou, China.,Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Key Laboratory of Space Radiobiology of Gansu Province, Institute of Modern Physics, Chinese Academy of Sciences (CAS), Lanzhou, China
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40
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Xiao L, Ma XX, Luo J, Chung HK, Kwon MS, Yu TX, Rao JN, Kozar R, Gorospe M, Wang JY. Circular RNA CircHIPK3 Promotes Homeostasis of the Intestinal Epithelium by Reducing MicroRNA 29b Function. Gastroenterology 2021; 161:1303-1317.e3. [PMID: 34116030 PMCID: PMC8463477 DOI: 10.1053/j.gastro.2021.05.060] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 05/04/2021] [Accepted: 05/25/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Circular RNAs (circRNAs) are a class of endogenous noncoding RNAs that form covalently closed circles. Although circRNAs influence many biological processes, little is known about their role in intestinal epithelium homeostasis. We surveyed circRNAs required to maintain intestinal epithelial integrity and identified circular homeodomain-interacting protein kinase 3 (circHIPK3) as a major regulator of intestinal epithelial repair after acute injury. METHODS Intestinal mucosal tissues were collected from mice exposed to cecal ligation and puncture for 48 hours and patients with inflammatory bowel diseases and sepsis. We isolated primary enterocytes from the small intestine of mice and derived intestinal organoids. The levels of circHIPK3 were silenced in intestinal epithelial cells (IECs) by transfection with small interfering RNAs targeting the circularization junction of circHIPK3 or elevated using a plasmid vector that overexpressed circHIPK3. Intestinal epithelial repair was examined in an in vitro injury model by removing part of the monolayer. The association of circHIPK3 with microRNA 29b (miR-29b) was determined by biotinylated RNA pull-down assays. RESULTS Genome-wide profile analyses identified ∼300 circRNAs, including circHIPK3, differentially expressed in the intestinal mucosa of mice after cecal ligation and puncture relative to sham mice. Intestinal mucosa from patients with inflammatory bowel diseases and sepsis had reduced levels of circHIPK3. Increasing the levels of circHIPK3 enhanced intestinal epithelium repair after wounding, whereas circHIPK3 silencing repressed epithelial recovery. CircHIPK3 silencing also inhibited growth of IECs and intestinal organoids, and circHIPK3 overexpression promoted intestinal epithelium renewal in mice. Mechanistic studies revealed that circHIPK3 directly bound to miR-29b and inhibited miR-29 activity, thus increasing expression of Rac1, Cdc42, and cyclin B1 in IECs after wounding. CONCLUSIONS In studies of mice, IECs, and human tissues, our results indicate that circHIPK3 improves repair of the intestinal epithelium at least in part by reducing miR-29b availability.
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Affiliation(s)
- Lan Xiao
- Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland; Baltimore Veterans Affairs Medical Center, Baltimore, Maryland
| | - Xiang-Xue Ma
- Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland
| | - Jason Luo
- Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland
| | - Hee K Chung
- Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland
| | - Min S Kwon
- Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland
| | - Ting-Xi Yu
- Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland
| | - Jaladanki N Rao
- Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland; Baltimore Veterans Affairs Medical Center, Baltimore, Maryland
| | - Rosemary Kozar
- Shock Trauma Center, University of Maryland School of Medicine, Baltimore, Maryland
| | - Myriam Gorospe
- Laboratory of Genetics and Genomics, National Institute on Aging-Intramural Research Program, National Institutes of Health, Baltimore, Maryland
| | - Jian-Ying Wang
- Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland; Baltimore Veterans Affairs Medical Center, Baltimore, Maryland; Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland.
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41
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Unchiti K, Leurcharusmee P, Samerchua A, Pipanmekaporn T, Chattipakorn N, Chattipakorn SC. The potential role of dexmedetomidine on neuroprotection and its possible mechanisms: Evidence from in vitro and in vivo studies. Eur J Neurosci 2021; 54:7006-7047. [PMID: 34561931 DOI: 10.1111/ejn.15474] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Revised: 09/15/2021] [Accepted: 09/16/2021] [Indexed: 12/24/2022]
Abstract
Neurological disorders following brain injuries and neurodegeneration are on the rise worldwide and cause disability and suffering in patients. It is crucial to explore novel neuroprotectants. Dexmedetomidine, a selective α2-adrenoceptor agonist, is commonly used for anxiolysis, sedation and analgesia in clinical anaesthesia and critical care. Recent studies have shown that dexmedetomidine exerts protective effects on multiple organs. This review summarized and discussed the current neuroprotective effects of dexmedetomidine, as well as the underlying mechanisms. In preclinical studies, dexmedetomidine reduced neuronal injury and improved functional outcomes in several models, including hypoxia-induced neuronal injury, ischaemic-reperfusion injury, intracerebral haemorrhage, post-traumatic brain injury, anaesthetic-induced neuronal injury, substance-induced neuronal injury, neuroinflammation, epilepsy and neurodegeneration. Several mechanisms are associated with the neuroprotective function of dexmedetomidine, including neurotransmitter regulation, inflammatory response, oxidative stress, apoptotic pathway, autophagy, mitochondrial function and other cell signalling pathways. In summary, dexmedetomidine has the potential to be a novel neuroprotective agent for a wide range of neurological disorders.
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Affiliation(s)
- Kantarakorn Unchiti
- Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.,Department of Anesthesiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Prangmalee Leurcharusmee
- Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.,Department of Anesthesiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Artid Samerchua
- Department of Anesthesiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Tanyong Pipanmekaporn
- Department of Anesthesiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Nipon Chattipakorn
- Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.,Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, Thailand
| | - Siriporn C Chattipakorn
- Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.,Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, Thailand.,Department of Oral Biology and Diagnostic Sciences, Faculty of Dentistry, Chiang Mai University, Chiang Mai, Thailand
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Choi JY, Seok HJ, Kim RK, Choi MY, Lee SJ, Bae IH. miR-519d-3p suppresses tumorigenicity and metastasis by inhibiting Bcl-w and HIF-1α in NSCLC. Mol Ther Oncolytics 2021; 22:368-379. [PMID: 34553025 PMCID: PMC8430049 DOI: 10.1016/j.omto.2021.06.015] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Accepted: 06/30/2021] [Indexed: 12/11/2022] Open
Abstract
Bcl-w, a member of the Bcl-2 family, is highly expressed in various solid tumor, including lung cancer, suggesting that it is involved in cancer cell survival and carcinogenesis. Solid cancer-induced hypoxia has been reported to increase angiogenesis, growth factor, gene instability, invasion, and metastasis. Despite many studies on the treatment of non-small cell lung cancer (NSCLC) with a high incidence rate, the survival rate of patients has not improved because the cancer cells acquired resistance to treatment. This study investigated the correlation between Bcl-w expression and hypoxia in tumor malignancy of NSCLC. Meanwhile, microRNAs (miRNAs) are involved in a variety of key signaling mechanisms associated with hypoxia. Therefore, we discovered miR-519d-3p, which inhibits the expression of Bcl-w and hypoxia-inducing factor (HIF)-1α, and found that it reduces hypoxia-induced tumorigenesis. Spearman's correlation analysis showed that the expression levels of miR-519d-3p and Bcl-w/HIF-1α were negatively correlated, respectively. This showed that miR-519d-3p can be used as a diagnostic biomarker and target therapy for NSCLC.
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Affiliation(s)
- Jae Yeon Choi
- Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul 01812, Republic of Korea
| | - Hyun Jeong Seok
- Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul 01812, Republic of Korea
| | - Rae-Kwon Kim
- Department of Life Science, Hanyang University, Seoul, Republic of Korea
| | - Mi Young Choi
- Department of Life Science, Hanyang University, Seoul, Republic of Korea
| | - Su-Jae Lee
- Department of Life Science, Hanyang University, Seoul, Republic of Korea
| | - In Hwa Bae
- Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul 01812, Republic of Korea
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Bai X, Zhang X, Fang R, Wang J, Ma Y, Liu Z, Dong H, Li Q, Ge J, Yu M, Fei J, Sun R, Huang F. Deficiency of miR-29b2/c leads to accelerated aging and neuroprotection in MPTP-induced Parkinson's disease mice. Aging (Albany NY) 2021; 13:22390-22411. [PMID: 34543233 PMCID: PMC8507277 DOI: 10.18632/aging.203545] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 09/07/2021] [Indexed: 12/13/2022]
Abstract
Studies reveal a linkage of miR-29s in aging and Parkinson's disease (PD). Here we show that the serum levels of miR-29s in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice exhibited dynamic changes. The role of miR-29b2/c in aging and PD was studied utilizing miR-29b2/c gene knockout mice (miR-29b2/c KO). miR-29b2/c KO mice were characterized by a markedly lighter weight, kyphosis, muscle weakness and abnormal gait, when compared with wild-type (WT) mice. The WT also developed apparent dermis thickening and adipose tissue reduction. However, deficiency of miR-29b2/c alleviated MPTP-induced damages of the dopaminergic system and glial activation in the nigrostriatal pathway and consequently improved the motor function of MPTP-treated KO mice. Knockout of miR-29b2/c inhibited the expression of inflammatory factors in 1-methyl-4-phenylpyridinium (MPP+)-treated primary cultures of mixed glia, primary astrocytes, or LPS-treated primary microglia. Moreover, miR-29b2/c deficiency enhanced the activity of AMPK but repressed the NF-κB p65 signaling in glial cells. Our results show that miR-29b2/c KO mice display the progeria-like phenotype. Less activated glial cells and repressed neuroinflammation might bring forth dopaminergic neuroprotection in miR-29b2/c KO mice. Conclusively, miR-29b2/c is involved in the regulation of aging and plays a detrimental role in Parkinson's disease.
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Affiliation(s)
- Xiaochen Bai
- Department of Translational Neuroscience, Jing'an District Centre Hospital of Shanghai, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai 200032, China.,Department of Rehabilitation Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Xiaoshuang Zhang
- Department of Translational Neuroscience, Jing'an District Centre Hospital of Shanghai, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai 200032, China
| | - Rong Fang
- Department of Translational Neuroscience, Jing'an District Centre Hospital of Shanghai, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai 200032, China
| | - Jinghui Wang
- Department of Translational Neuroscience, Jing'an District Centre Hospital of Shanghai, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai 200032, China
| | - Yuanyuan Ma
- Department of Translational Neuroscience, Jing'an District Centre Hospital of Shanghai, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai 200032, China
| | - Zhaolin Liu
- Department of Translational Neuroscience, Jing'an District Centre Hospital of Shanghai, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai 200032, China
| | - Hongtian Dong
- Department of Translational Neuroscience, Jing'an District Centre Hospital of Shanghai, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai 200032, China
| | - Qing Li
- Department of Translational Neuroscience, Jing'an District Centre Hospital of Shanghai, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai 200032, China
| | - Jingyu Ge
- Department of Translational Neuroscience, Jing'an District Centre Hospital of Shanghai, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai 200032, China
| | - Mei Yu
- Department of Translational Neuroscience, Jing'an District Centre Hospital of Shanghai, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai 200032, China
| | - Jian Fei
- School of Life Science and Technology, Tongji University, Shanghai 200092, China.,Shanghai Engineering Research Center for Model Organisms, Shanghai Model Organisms Center, INC, Shanghai 201203, China
| | - Ruilin Sun
- Shanghai Engineering Research Center for Model Organisms, Shanghai Model Organisms Center, INC, Shanghai 201203, China
| | - Fang Huang
- Department of Translational Neuroscience, Jing'an District Centre Hospital of Shanghai, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai 200032, China
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Seok HJ, Choi YE, Choi JY, Yi JM, Kim EJ, Choi MY, Lee SJ, Bae IH. Novel miR-5088-5p promotes malignancy of breast cancer by inhibiting DBC2. MOLECULAR THERAPY-NUCLEIC ACIDS 2021; 25:127-142. [PMID: 34457998 PMCID: PMC8365326 DOI: 10.1016/j.omtn.2021.05.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Accepted: 05/05/2021] [Indexed: 12/30/2022]
Abstract
Breast cancer is the most common female cancer in the world. Despite the active research on metastatic breast cancer, the treatment of breast cancer patients is still difficult because the mechanism is not well known. Therefore, research on new targets and mechanisms for diagnosis and treatment of breast cancer patients is required. On the other hand, microRNA (miRNA) has the advantage of simultaneously regulating the expression of many target genes, so it has been proposed as an effective biomarker for the treatment of various diseases including cancer. This study analyzed the role and mechanism of DBC2 (deleted in breast cancer 2), which is known to inhibit its expression in breast cancer, and proposed microRNA (miR)-5088-5p, which regulates its expression. It was revealed that the biogenesis of miR-5088-5p was upregulated by hypomethylation of its promoter, promoted by Fyn, and was involved in malignancy in breast cancer. With the use of the cellular level, clinical samples, and published data, we verified that the expression patterns of DBC2 and miR-5088-5p were negatively related, suggesting the potential as novel biomarkers for the diagnosis of breast cancer patients.
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Affiliation(s)
- Hyun Jeong Seok
- Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul, Republic of Korea
| | - Young Eun Choi
- Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul, Republic of Korea
| | - Jae Yeon Choi
- Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul, Republic of Korea
| | - Joo Mi Yi
- Department of Microbiology and Immunology, College of Medicine, Inje University, Busan, Republic of Korea
| | - Eun Joo Kim
- Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul, Republic of Korea.,Radiological & Medico-Oncological Sciences, University of Science and Technology, Daejeon, Republic of Korea
| | - Mi Young Choi
- Department of Life Science, Hanyang University, Seoul, Republic of Korea
| | - Su-Jae Lee
- Department of Life Science, Hanyang University, Seoul, Republic of Korea
| | - In Hwa Bae
- Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul, Republic of Korea
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Fan Y, Tang Z, Sun J, Zhao X, Li Z, Zheng Y, Zeng X, Feng J. MicroRNA-29a promotes the proliferation of human nasal epithelial cells and inhibits their apoptosis and promotes the development of allergic rhinitis by down-regulating FOS expression. PLoS One 2021; 16:e0255480. [PMID: 34383804 PMCID: PMC8360612 DOI: 10.1371/journal.pone.0255480] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Accepted: 07/18/2021] [Indexed: 11/19/2022] Open
Abstract
OBJECTIVE To explore the regulation of microRNA-29a (miR-29a) on FOS in human nasal epithelial cells and its molecular mechanism, as well as the effects of miR-29a on the cell proliferation and apoptosis. METHODS By cell transfection, gene silencing, quantitative real-time polymerase chain reaction (qRT-PCR), flow cytometry and TUNEL assay (for cell apoptosis), CCK-8 assay (for cell proliferation), dual-luciferase reporter gene assay and Western Blot, it was validated that miR-29a promoted the proliferation of human nasal epithelial cells and inhibited their apoptosis by down-regulating FOS expression in RPMI2650 and HNEpC cell lines. RESULTS ①Compared with healthy controls, miR-29a expression was up-regulated and FOS mRNA expression was down-regulated in the nasal tissues from the patients with allergic rhinitis (AR). ②MiR-29a over-expression promoted the proliferation of RPMI2650 cells and HNEpC cells but inhibited their apoptosis. ③MiR-29a targeted at FOS. ④MiR-29a over-expression and FOS silencing both significantly promoted cell proliferation and inhibited cell apoptosis. After transfection with both miR-29a and FOS, there was a decrease in the proliferation but an increase in the apoptosis of cells.⑤MiR-29a promoted the proliferation of human nasal epithelial cells and inhibited their apoptosis by down-regulating FOS expression. CONCLUSION MiR-29a-/FOS axis can be regarded as a potential marker and a new therapy for AR.
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Affiliation(s)
- Yuqin Fan
- Department of Otolaryngology-Head and Neck Surgery, Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Ear Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhiyuan Tang
- Department of Otorhinolaryngology, Shenzhen Longgang E.N.T Hospital & Shenzhen Key Laboratory of E.N.T., Institute of E.N.T., Shenzhen, Guangdong, China
| | - Jie Sun
- Department of Otorhinolaryngology, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Xiaorui Zhao
- Department of Otorhinolaryngology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Zhen Li
- Department of Otorhinolaryngology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Yiqing Zheng
- Department of Otolaryngology, Sun Yat-Sen Memorial Hospital, Guangzhou, Guangdong, P.R. China
| | - Xianhai Zeng
- Department of Otorhinolaryngology, Shenzhen Longgang E.N.T Hospital & Shenzhen Key Laboratory of E.N.T., Institute of E.N.T., Shenzhen, Guangdong, China
| | - Juan Feng
- Department of Otorhinolaryngology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
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The Role of miRNA in the Pathophysiology of Neuroendocrine Tumors. Int J Mol Sci 2021; 22:ijms22168569. [PMID: 34445276 PMCID: PMC8395312 DOI: 10.3390/ijms22168569] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 07/16/2021] [Accepted: 08/06/2021] [Indexed: 12/14/2022] Open
Abstract
Neuroendocrine tumors (NETs) represent a tumor group that is both rare and heterogeneous. Prognosis is largely determined by the tumor grading and the site of the primary tumor and metastases. Despite intensive research efforts, only modest advances in diagnostic and therapeutic approaches have been achieved in recent years. For patients with non-respectable tumor stages, prognosis is poor. In this context, the development of novel diagnostic tools for early detection of NETs and prediction of tumor response to therapy as well as estimation of the overall prognosis would greatly improve the clinical management of NETs. However, identification of novel diagnostic molecules is hampered by an inadequate understanding of the pathophysiology of neuroendocrine malignancies. It has recently been demonstrated that microRNA (miRNA), a family of small RNA molecules with an established role in the pathophysiology of quite different cancer entities, may also play a role as a biomarker. Here, we summarize the available knowledge on the role of miRNAs in the development of NET and highlight their potential use as serum-based biomarkers in the context of this disease. We discuss important challenges currently preventing their use in clinical routine and give an outlook on future directions of miRNA research in NET.
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Tao B, Wang D, Yang S, Liu Y, Wu H, Li Z, Chang L, Yang Z, Liu W. Cucurbitacin B Inhibits Cell Proliferation by Regulating X-Inactive Specific Transcript Expression in Tongue Cancer. Front Oncol 2021; 11:651648. [PMID: 34295808 PMCID: PMC8290325 DOI: 10.3389/fonc.2021.651648] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Accepted: 06/18/2021] [Indexed: 01/28/2023] Open
Abstract
Cucurbitacin B (CuB), a natural product, has anti-tumor effects on various cancers. In order to investigate the expression of long non-coding RNAs (lncRNA), we carried out RNA sequencing (RNA-seq) and quantitative PCR (qPCR). The data indicated that CAL27 and SCC9 tongue squamous cell carcinoma (TSCC) cells had reduced expression of X-inactive specific transcript (XIST) after CuB treatment. Moreover, our results showed increased expression of XIST in human tongue cancer. In this study, CuB treatment inhibited proliferation, migration and invasion of SCC9 cells, and induced cellular apoptosis. Interestingly, knockdown of XIST led to inhibition of cell proliferation and induced apoptosis in vitro. In addition, reduced expression of XIST suppressed cell migration and invasion. MicroRNA 29b (miR-29b) was identified as a direct target of XIST. Previous reports indicated that miR-29b regulates p53 protein. Our results suggest that increased expression of miR-29b induces cell apoptosis through p53 protein. The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (CRISPR/Cas9) system validated the role of XIST knockout in tumor development in vivo. Together, these results suggest that CuB exerts significant anti-cancer activity by regulating expression of XIST via miR-29b.
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Affiliation(s)
- Boqiang Tao
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China.,Laboratory Animal Center, College of Animal Science, Jilin University, Changchun, China.,Jilin Provincial Key Laboratory of Oral Biomedical Engineering, Changchun, China
| | - Dongxu Wang
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China.,Laboratory Animal Center, College of Animal Science, Jilin University, Changchun, China
| | - Shuo Yang
- Laboratory Animal Center, College of Animal Science, Jilin University, Changchun, China
| | - Yingkun Liu
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
| | - Han Wu
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
| | - Zhanjun Li
- Laboratory Animal Center, College of Animal Science, Jilin University, Changchun, China
| | - Lu Chang
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
| | - Zhijing Yang
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
| | - Weiwei Liu
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
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Gajek A, Gralewska P, Marczak A, Rogalska A. Current Implications of microRNAs in Genome Stability and Stress Responses of Ovarian Cancer. Cancers (Basel) 2021; 13:cancers13112690. [PMID: 34072593 PMCID: PMC8199164 DOI: 10.3390/cancers13112690] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 05/25/2021] [Accepted: 05/26/2021] [Indexed: 12/16/2022] Open
Abstract
Genomic alterations and aberrant DNA damage signaling are hallmarks of ovarian cancer (OC), the leading cause of mortality among gynecological cancers worldwide. Owing to the lack of specific symptoms and late-stage diagnosis, survival chances of patients are significantly reduced. Poly (ADP-ribose) polymerase (PARP) inhibitors and replication stress response inhibitors present attractive therapeutic strategies for OC. Recent research has focused on ovarian cancer-associated microRNAs (miRNAs) that play significant regulatory roles in various cellular processes. While miRNAs have been shown to participate in regulation of tumorigenesis and drug responses through modulating the DNA damage response (DDR), little is known about their potential influence on sensitivity to chemotherapy. The main objective of this review is to summarize recent findings on the utility of miRNAs as cancer biomarkers, in particular, ovarian cancer, and their regulation of DDR or modified replication stress response proteins. We further discuss the suppressive and promotional effects of various miRNAs on ovarian cancer and their participation in cell cycle disturbance, response to DNA damage, and therapeutic functions in multiple cancer types, with particular focus on ovarian cancer. Improved understanding of the mechanisms by which miRNAs regulate drug resistance should facilitate the development of effective combination therapies for ovarian cancer.
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49
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Chen Q, Wang W, Chen S, Chen X, Lin Y. miR-29a sensitizes the response of glioma cells to temozolomide by modulating the P53/MDM2 feedback loop. Cell Mol Biol Lett 2021; 26:21. [PMID: 34044759 PMCID: PMC8161631 DOI: 10.1186/s11658-021-00266-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 05/18/2021] [Indexed: 02/07/2023] Open
Abstract
Recently, pivotal functions of miRNAs in regulating common tumorigenic processes and manipulating signaling pathways in brain tumors have been recognized; notably, miR‐29a is closely associated with p53 signaling, contributing to the development of glioma. However, the molecular mechanism of the interaction between miR-29a and p53 signaling is still to be revealed. Herein, a total of 30 glioma tissues and 10 non-cancerous tissues were used to investigate the expression of miR‐29a. CCK-8 assay and Transwell assay were applied to identify the effects of miR-29a altered expression on the malignant biological behaviors of glioma cells in vitro, including proliferation, apoptosis, migration and invasion. A dual-luciferase reporter assay was used to further validate the regulatory effect of p53 or miR-29a on miR-29a or MDM2, respectively, at the transcriptional level. The results showed that miR-29a expression negatively correlated with tumor grade of human gliomas; at the same time it inhibited cell proliferation, migration, and invasion and promoted apoptosis of glioma cells in vitro. Mechanistically, miR-29a expression was induced by p53, leading to aberrant expression of MDM2 targeted by miR-29a, and finally imbalanced the activity of the p53-miR-29a-MDM2 feedback loop. Moreover, miR-29a regulating p53/MDM2 signaling sensitized the response of glioma cells to temozolomide treatment. Altogether, the study demonstrated a potential molecular mechanism in the tumorigenesis of glioma, while offering a possible target for treating human glioma in the future.
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Affiliation(s)
- Qiudan Chen
- The Department of Central Laboratory, Clinical Laboratory, Jing'an District Center Hospital of Shanghai, Fudan University, Shanghai, 200040, China
| | - Weifeng Wang
- Department of Central Laboratory, Clinical Medicine Scientific and Technical Innovation Park, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200435, China
| | - Shuying Chen
- Department of Laboratory Medicine, Huashan Hospital, Fudan University, Shanghai, 20040, China
| | - Xiaotong Chen
- Department of Laboratory Medicine, Huashan Hospital, Fudan University, Shanghai, 20040, China
| | - Yong Lin
- Department of Laboratory Medicine, Huashan Hospital, Fudan University, Shanghai, 20040, China.
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Prieto-Colomina A, Fernández V, Chinnappa K, Borrell V. MiRNAs in early brain development and pediatric cancer: At the intersection between healthy and diseased embryonic development. Bioessays 2021; 43:e2100073. [PMID: 33998002 DOI: 10.1002/bies.202100073] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 04/12/2021] [Accepted: 04/15/2021] [Indexed: 12/15/2022]
Abstract
The size and organization of the brain are determined by the activity of progenitor cells early in development. Key mechanisms regulating progenitor cell biology involve miRNAs. These small noncoding RNA molecules bind mRNAs with high specificity, controlling their abundance and expression. The role of miRNAs in brain development has been studied extensively, but their involvement at early stages remained unknown until recently. Here, recent findings showing the important role of miRNAs in the earliest phases of brain development are reviewed, and it is discussed how loss of specific miRNAs leads to pathological conditions, particularly adult and pediatric brain tumors. Let-7 miRNA downregulation and the initiation of embryonal tumors with multilayered rosettes (ETMR), a novel link recently discovered by the laboratory, are focused upon. Finally, it is discussed how miRNAs may be used for the diagnosis and therapeutic treatment of pediatric brain tumors, with the hope of improving the prognosis of these devastating diseases.
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Affiliation(s)
- Anna Prieto-Colomina
- Instituto de Neurociencias, Consejo Superior de Investigaciones Científicas & Universidad Miguel Hernández, Sant Joan d'Alacant, Spain
| | - Virginia Fernández
- Neurobiology of miRNA, Fondazione Istituto Italiano di Tecnologia (IIT), Genoa, Italy
| | - Kaviya Chinnappa
- Instituto de Neurociencias, Consejo Superior de Investigaciones Científicas & Universidad Miguel Hernández, Sant Joan d'Alacant, Spain
| | - Víctor Borrell
- Instituto de Neurociencias, Consejo Superior de Investigaciones Científicas & Universidad Miguel Hernández, Sant Joan d'Alacant, Spain
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