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He F, Guan W. The role of miR-21 as a biomarker and therapeutic target in cardiovascular disease. Clin Chim Acta 2025; 574:120304. [PMID: 40220984 DOI: 10.1016/j.cca.2025.120304] [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: 03/08/2025] [Revised: 04/09/2025] [Accepted: 04/09/2025] [Indexed: 04/14/2025]
Abstract
Cardiovascular diseases (CVDs) are the leading causes of death worldwide, accounting for a significant burden on global health systems. The complexity of CVDs arises from their multifactorial etiology, including genetic, environmental, and lifestyle factors. Early diagnosis and effective treatment remain critical for reducing mortality and improving patient outcomes, yet conventional methods often fall short in providing precise, timely information for disease management. MicroRNAs are small non-coding RNAs that regulate gene expression and play pivotal roles in various biological processes, including cardiovascular health. Among them, miR-21 has garnered significant attention due to its involvement in cardiac remodeling, fibrosis, inflammation, and hypertrophy. Elevated levels of miR-21 are frequently observed in conditions such as myocardial infarction, heart failure, and coronary artery disease, positioning it as a potential biomarker for early detection and disease progression. Furthermore, therapeutic strategies targeting miR-21, such as antagomirs and innovative delivery systems, have shown promise in preclinical studies, though challenges like off-target effects and delivery inefficiencies persist. This review aims to provide a comprehensive understanding of miR-21's role in CVDs, addressing its potential as a diagnostic biomarker and therapeutic target. We discuss recent advancements, limitations, and future prospects in miR-21 research, emphasizing the importance of integrating this knowledge into clinical practice to improve CVD management.
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Affiliation(s)
- Fanlong He
- Department of Cardiovascular, Hangzhou Linping District Integrated Traditional Chinese and Western Medicine Hospital, Hangzhou 311100, China
| | - Wenqing Guan
- Department of Public Health, Hangzhou Linping District Integrated Traditional Chinese and Western Medicine Hospital, Hangzhou 311100, China.
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Liu L, Liu X, Gao C, Liu M, Peng M, Wang L. Hsa-miR-21 promoted the progression of lung adenocarcinoma by regulating LRIG1 expression. BMC Pulm Med 2025; 25:189. [PMID: 40269842 PMCID: PMC12016109 DOI: 10.1186/s12890-025-03620-1] [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: 11/16/2024] [Accepted: 03/24/2025] [Indexed: 04/25/2025] Open
Abstract
Lung cancer is the foremost cause of cancer-related fatalities globally, and lung adenocarcinoma (LUAD) is one of the common types of lung cancer with significant molecular heterogeneity. Leucine rich repeats and immunoglobulin like domains 1 (LRIG1) has been demonstrated to be down-regulated in lung cancer and related to prognosis of patients. The purpose of this work is to explore the targeting miRNAs of LRIG1, and the related regulatory mechanisms in LUAD. The data of LUAD patients were collected from The Cancer Genome Atlas and Gene Expression Omnibus databases. The differential expression analysis and gene set enrichment analysis (GSEA) were performed using "limma" and "clusterProfiler" function package, respectively. The levels of hsa-miR-21 mRNA and LRIG1 mRNA and LRIG1 protein expressions were analyzed using RT-qPCR and western blot analysis. The infiltration of immune cells was determined using CIBERSORT software. In LUAD patients, hsa-miR-21 expression was observably related to LRIG1 expression. Hsa-miR-21 might negatively modulate the LRIG1 expression in LUAD. LUAD patients with hsa-miR-21 up-regulation exhibited inferior prognosis. In addition, those with LUAD who had high hsa-miR-21 expression but low LRIG1 expression had a worse prognosis, whereas those with low hsa-miR-21 expression but high LRIG1 expression had a better prognosis. Functional enrichment analysis indicated that metabolic related signaling pathways (EGFR tyrosine kinase inhibitor resistance) were significantly activated in LUAD patients with LRIG1 up-regulation. Finally, we found that relative content of naive B cells, plasma cells and resting CD4 + T cells were significantly increased and regulatory T cells and Macrophages M0 were decreased in LRIG1 high expression group and hsa-miR-21 low expression group. We firstly reported that hsa-miR-21 might regulate the LRIG1 expression in LUAD, thereby effecting the onset and progression of LUAD. Clinical trial number: Not applicable.
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Affiliation(s)
- Li Liu
- Department of Respiratory, Weifang People's Hospital, No. 151 Guangwen Street, Kuiwen District, Weifang, 261041, Shandong Province, P. R. China
| | - Xinhua Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Hangzhou Normal University, Yuhang District, Hangzhou, 311121, Zhejiang Province, P. R. China
| | - Chengpeng Gao
- Department of Respiratory, Weifang People's Hospital, No. 151 Guangwen Street, Kuiwen District, Weifang, 261041, Shandong Province, P. R. China
| | - Meijuan Liu
- Department of Respiratory, Weifang People's Hospital, No. 151 Guangwen Street, Kuiwen District, Weifang, 261041, Shandong Province, P. R. China.
| | - Mengmeng Peng
- Department of Respiratory, Weifang People's Hospital, No. 151 Guangwen Street, Kuiwen District, Weifang, 261041, Shandong Province, P. R. China
| | - Leqiang Wang
- Department of Respiratory, Weifang People's Hospital, No. 151 Guangwen Street, Kuiwen District, Weifang, 261041, Shandong Province, P. R. China
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Naeem S, Zhang J, Zhang Y, Wang Y. Nucleic acid therapeutics: Past, present, and future. MOLECULAR THERAPY. NUCLEIC ACIDS 2025; 36:102440. [PMID: 39897578 PMCID: PMC11786870 DOI: 10.1016/j.omtn.2024.102440] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/04/2025]
Abstract
Nucleic acid therapeutics have become increasingly recognized in recent years for their capability to target both coding and non-coding sequences. Several types of nucleic acid modalities, including siRNA, mRNA, aptamer, along with antisense oligo, have been approved by regulatory bodies for therapeutic use. The field of nucleic acid therapeutics has been brought to the forefront by the rapid development of vaccines against COVID-19, followed by a number of approvals for clinical use including much anticipated CRISPR-Cas9. However, obstacles such as the difficulty of achieving efficient and targeted delivery to diseased sites remain. This review provides an overview of nucleic acid therapeutics and highlights substantial advancements, including critical engineering, conjugation, and delivery strategies, that are paving the way for their growing role in modern medicine.
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Affiliation(s)
- Sajid Naeem
- College of Life Sciences and Oceanography, Shenzhen University, Shenzhen 518060, China
- College of Physics and Optoelectronic Engineering, Shenzhen University, Shenzhen 518060, China
| | - Ju Zhang
- College of Life Sciences and Oceanography, Shenzhen University, Shenzhen 518060, China
- College of Physics and Optoelectronic Engineering, Shenzhen University, Shenzhen 518060, China
| | - Yang Zhang
- School of Biomedical Engineering, Harbin Institute of Technology (Shenzhen), Shenzhen 518055, Guangdong, China
| | - Yu Wang
- College of Life Sciences and Oceanography, Shenzhen University, Shenzhen 518060, China
- Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
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Tong Z, Xu X, Shen C, Yang D, Li Y, Li Q, Yang W, Xu F, Wu Z, Zhou L, Zhan C, Mao H. All-in-one multiple extracellular vesicle miRNA detection on a miniaturized digital microfluidic workstation. Biosens Bioelectron 2025; 270:116976. [PMID: 39591923 DOI: 10.1016/j.bios.2024.116976] [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: 09/16/2024] [Revised: 11/06/2024] [Accepted: 11/19/2024] [Indexed: 11/28/2024]
Abstract
Extracellular vesicles (EVs) and EV-derived microRNAs (EV-miRNAs) are emerging as promising circulating biomarkers for early detection of malignant tumors such as non-small cell lung cancer (NSCLC). However, utilization of the gold standard method of RNA detection, the reverse transcription - quantitative polymerase chain reaction (RT-qPCR), on EV-miRNAs is hindered by laborious sample purification requirements and time-consuming multi-step procedures. Herein, we propose and demonstrate a miniaturized digital microfluidic (DMF) workstation for all-in-one EV-miRNA detection based on RT-qPCR. In comparison with the previously reported DMF platform for EV isolation, the system further integrates parallel on-chip real-time PCR capability with a comparable detection sensitivity with in-vitro RT-qPCR (limit of detection = 2 copies/μL), realizing automated, miniaturized, and facile EV-miRNA detection. Meanwhile, major methodological improvements were made, including one-step stem-looped RT-qPCR for miRNAs with both high sensitivity and specificity, and a simplified DMF substrate rework strategy for cost-effectiveness. As a demonstration, the detection of NSCLC-related EV-miRNAs within 20 μL of plasma samples was implemented, indicating the potential applicability of the DMF workstation and its automated protocol on point-of-care diagnosis of a wide range of diseases.
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Affiliation(s)
- Zhaoduo Tong
- State Key Laboratory of Transducer Technology, Shanghai Institute of Microsystem and Information Technology, Chinese Academy of Sciences, Shanghai, 200050, China; Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Xin Xu
- State Key Laboratory of Transducer Technology, Shanghai Institute of Microsystem and Information Technology, Chinese Academy of Sciences, Shanghai, 200050, China
| | - Chuanjie Shen
- State Key Laboratory of Transducer Technology, Shanghai Institute of Microsystem and Information Technology, Chinese Academy of Sciences, Shanghai, 200050, China; Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Dawei Yang
- Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Yan Li
- Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai, 200032, China
| | - Qiushi Li
- State Key Laboratory of Transducer Technology, Shanghai Institute of Microsystem and Information Technology, Chinese Academy of Sciences, Shanghai, 200050, China
| | - Weidong Yang
- State Key Laboratory of Transducer Technology, Shanghai Institute of Microsystem and Information Technology, Chinese Academy of Sciences, Shanghai, 200050, China; Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Fangliang Xu
- State Key Laboratory of Transducer Technology, Shanghai Institute of Microsystem and Information Technology, Chinese Academy of Sciences, Shanghai, 200050, China; Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Zhenhua Wu
- State Key Laboratory of Transducer Technology, Shanghai Institute of Microsystem and Information Technology, Chinese Academy of Sciences, Shanghai, 200050, China; Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Lin Zhou
- State Key Laboratory of Transducer Technology, Shanghai Institute of Microsystem and Information Technology, Chinese Academy of Sciences, Shanghai, 200050, China; Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing, 100049, China.
| | - Cheng Zhan
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
| | - Hongju Mao
- State Key Laboratory of Transducer Technology, Shanghai Institute of Microsystem and Information Technology, Chinese Academy of Sciences, Shanghai, 200050, China; Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing, 100049, China.
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Wei X, Xiong X, Chen Z, Chen B, Zhang C, Zhang W. MicroRNA155 in non-small cell lung cancer: a potential therapeutic target. Front Oncol 2025; 15:1517995. [PMID: 39963112 PMCID: PMC11830606 DOI: 10.3389/fonc.2025.1517995] [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: 10/27/2024] [Accepted: 01/09/2025] [Indexed: 02/20/2025] Open
Abstract
Lung cancer (LC) is the second most commonly diagnosed cancer among both men and women, and it stands as the leading cause of cancer-related mortality, characterized by high rates of morbidity and mortality. Among its subtypes, non-small cell lung cancer (NSCLC) is the most prevalent and one of the most challenging malignant tumors to treat. To date, various therapeutic approaches, including surgery, radiotherapy, and chemotherapy, have been employed in the management of lung cancer; however, due to its aggressive nature, the survival rates remain low. Consequently, exploring novel treatment strategies is of paramount importance. MicroRNAs (miRNAs), a large family of non-coding RNAs, play crucial roles in regulating several key biological processes, including cell proliferation, differentiation, inflammation, and apoptosis. Among these, microRNA155(miR-155) is one of the most conserved and versatile miRNAs, predominantly overexpressed in various diseases, including malignant tumors. This review elucidates the biological functions and roles of miR-155 in NSCLC and discusses its potential significance as a therapeutic target for future research directions and clinical applications.
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Affiliation(s)
- Xiangju Wei
- The First Clinical College, Xuzhou Medical University, Xuzhou, China
- Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Xianmin Xiong
- The First Clinical College, Xuzhou Medical University, Xuzhou, China
- Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Ze Chen
- The First Clinical College, Xuzhou Medical University, Xuzhou, China
| | - Bi Chen
- Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Cantang Zhang
- Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Wenhui Zhang
- Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
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Dawar P, Adhikari I, Mandal SN, Jayee B. RNA Metabolism and the Role of Small RNAs in Regulating Multiple Aspects of RNA Metabolism. Noncoding RNA 2024; 11:1. [PMID: 39846679 PMCID: PMC11755482 DOI: 10.3390/ncrna11010001] [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: 09/23/2024] [Revised: 12/07/2024] [Accepted: 12/17/2024] [Indexed: 01/24/2025] Open
Abstract
RNA metabolism is focused on RNA molecules and encompasses all the crucial processes an RNA molecule may or will undergo throughout its life cycle. It is an essential cellular process that allows all cells to function effectively. The transcriptomic landscape of a cell is shaped by the processes such as RNA biosynthesis, maturation (RNA processing, folding, and modification), intra- and inter-cellular transport, transcriptional and post-transcriptional regulation, modification, catabolic decay, and retrograde signaling, all of which are interconnected and are essential for cellular RNA homeostasis. In eukaryotes, sRNAs, typically 20-31 nucleotides in length, are a class of ncRNAs found to function as nodes in various gene regulatory networks. sRNAs are known to play significant roles in regulating RNA population at the transcriptional, post-transcriptional, and translational levels. Along with sRNAs, such as miRNAs, siRNAs, and piRNAs, new categories of ncRNAs, i.e., lncRNAs and circRNAs, also contribute to RNA metabolism regulation in eukaryotes. In plants, various genetic screens have demonstrated that sRNA biogenesis mutants, as well as RNA metabolism pathway mutants, exhibit similar growth and development defects, misregulated primary and secondary metabolism, as well as impaired stress response. In addition, sRNAs are both the "products" and the "regulators" in broad RNA metabolism networks; gene regulatory networks involving sRNAs form autoregulatory loops that affect the expression of both sRNA and the respective target. This review examines the interconnected aspects of RNA metabolism with sRNA regulatory pathways in plants. It also explores the potential conservation of these pathways across different kingdoms, particularly in plants and animals. Additionally, the review highlights how cellular RNA homeostasis directly impacts adaptive responses to environmental changes as well as different developmental aspects in plants.
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Affiliation(s)
- Pranav Dawar
- Department of Biological Sciences, Texas Tech University, Lubbock, TX 79409, USA;
| | - Indra Adhikari
- Department of Biological Sciences, Texas Tech University, Lubbock, TX 79409, USA;
| | | | - Bhumika Jayee
- Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, USA;
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Kazlauskaitė P, Vaicekauskaitė I, Venius J, Sabaliauskaitė R, Steponavičienė R. Plasma microRNAs as Biomarkers for Predicting Radiotherapy Treatment-Induced Cardiotoxicity in Lung Cancer. Life (Basel) 2024; 14:1619. [PMID: 39768327 PMCID: PMC11679788 DOI: 10.3390/life14121619] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Revised: 11/29/2024] [Accepted: 12/02/2024] [Indexed: 01/11/2025] Open
Abstract
Background: Lung cancer is the second most common malignancy and stands as a leading cause of cancer-related deaths worldwide. Currently, one of the main treatment options for lung cancer is radiotherapy, but this treatment is associated with complications, such as an increased risk of cardiac-related morbidity and mortality. However, currently available methods for predicting radiation-induced heart disease (RIHD) remain suboptimal. Methods: In this pilot study, using the RT-qPCR method, we analyzed the expression levels of six miRNAs (miRNA-1-3p, miRNA-21-5p, miRNA-24-3p, miRNA-29a-3p, miRNA-34a-5p, and miRNA-222-3p). Results: Fourteen pairs of locally advanced non-small-cell lung cancer patients' plasma samples, taken before and after radiotherapy, were examined. It was observed that miRNA-1-3p, miRNA-21-5p, miRNA-24-3p, miRNA-29a-3p, and miRNA-222-3p were downregulated, while miRNA-34a-5p was upregulated in lung cancer patients' plasma after treatment. Additionally, after definitive radiotherapy, patients with an increased NT-proBNP value displayed a statistically significant difference in miRNA-222-3p levels compared to the normal range of this indicator. The panel of the combined four miRNAs for assessing the risk of cardiac comorbidities demonstrated an AUC of 0.79, sensitivity of 71.43%, and specificity of 100%, with further improved values upon integration with clinical biomarker NT-proBNP. Conclusions: This pilot study shows that the identification of changes in miRNA expression levels in lung cancer patients' plasma before and after radiotherapy could be used for the early diagnosis of RIHD.
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Affiliation(s)
- Paulina Kazlauskaitė
- National Cancer Institute, 08406 Vilnius, Lithuania
- Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, 08661 Vilnius, Lithuania
| | - Ieva Vaicekauskaitė
- National Cancer Institute, 08406 Vilnius, Lithuania
- Institute of Biosciences, Life Sciences Center, Vilnius University, 10257 Vilnius, Lithuania
| | - Jonas Venius
- National Cancer Institute, 08406 Vilnius, Lithuania
| | - Rasa Sabaliauskaitė
- National Cancer Institute, 08406 Vilnius, Lithuania
- Institute of Biosciences, Life Sciences Center, Vilnius University, 10257 Vilnius, Lithuania
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Li X, Ding J, Zhang X, Zhang X, Jiang X, Chen R, Cheng Y, Sun Y, Wan J, Zhang Y, Cao J, Han S. MicroRNAs in opisthorchiids and their definitive hosts: Current Status and Perspectives. Mol Biochem Parasitol 2024; 260:111636. [PMID: 38880486 DOI: 10.1016/j.molbiopara.2024.111636] [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: 11/04/2023] [Revised: 06/05/2024] [Accepted: 06/10/2024] [Indexed: 06/18/2024]
Abstract
Opisthorchis felineus, Opisthorchis viverrini, and Clonorchis sinensis (family Opisthorchiidae) are parasitic flatworms that pose serious threats to humans in certain countries and cause opisthorchiasis/clonorchiasis. Opisthorchiid flukes parasitize the biliary tract of the host, causing cholangitis, cholecystitis, cholelithiasis and cholangiocarcinoma. In this review, we primarily focus on recent microRNAs (miRNAs) studies of opisthorchiid flukes and their definitive hosts. Many miRNAs are conserved and expressed in a developmentally stage specific manner in the three opisthorchiid flukes, which play important roles in the growth and development of Opisthorchiidae spp., as well as host-pathogen interactions. Some miRNAs might be potential biomarkers related to carcinogenesis of cholangiocarcinoma. Therefore, this review provides the basis for further investigating the roles of miRNAs in opisthorchiid flukes and their definitive hosts, as well as promoting the development of novel approaches to prevent and treat opisthorchiasis/clonorchiasis.
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Affiliation(s)
- Xiang Li
- Central Laboratory, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jian Ding
- West Coast New Area Center for Disease Prevention and Control, Qingdao, China
| | - Xiaoli Zhang
- Department of Parasitology, Harbin Medical University, Harbin, China
| | - Xueli Zhang
- Department of Parasitology, Harbin Medical University, Harbin, China
| | - Xu Jiang
- Department of Parasitology, Harbin Medical University, Harbin, China
| | - Rui Chen
- Department of orthopaedics, Affiliated Wuxi No. 2 Hospital, Wuxi, China
| | - Yang Cheng
- Laboratory of Pathogen Infection and Immunity, Department of Public Health and Preventive Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Yifan Sun
- Department of Clinical Laboratory, Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Jie Wan
- Laboratory of Pathogen Infection and Immunity, Department of Public Health and Preventive Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Yu Zhang
- Laboratory of Pathogen Infection and Immunity, Department of Public Health and Preventive Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Jianping Cao
- National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention, (Chinese Center for Tropical Diseases Research), Shanghai 200025, China.
| | - Su Han
- Laboratory of Pathogen Infection and Immunity, Department of Public Health and Preventive Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu 214122, China; Department of Parasitology, Harbin Medical University, Harbin, China.
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Nan F, Liu B, Yao C. Discovering the role of microRNAs and exosomal microRNAs in chest and pulmonary diseases: a spotlight on chronic obstructive pulmonary disease. Mol Genet Genomics 2024; 299:107. [PMID: 39527303 DOI: 10.1007/s00438-024-02199-2] [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: 09/20/2024] [Accepted: 10/26/2024] [Indexed: 11/16/2024]
Abstract
Chronic obstructive pulmonary disease (COPD) is a progressive respiratory condition and ranks as the fourth leading cause of mortality worldwide. Despite extensive research efforts, a reliable diagnostic or prognostic tool for COPD remains elusive. The identification of novel biomarkers may facilitate improved therapeutic strategies for patients suffering from this debilitating disease. MicroRNAs (miRNAs), which are small non-coding RNA molecules, have emerged as promising candidates for the prediction and diagnosis of COPD. Studies have demonstrated that dysregulation of miRNAs influences critical cellular and molecular pathways, including Notch, Wnt, hypoxia-inducible factor-1α, transforming growth factor, Kras, and Smad, which may contribute to the pathogenesis of COPD. Extracellular vesicles, particularly exosomes, merit further investigation due to their capacity to transport various biomolecules such as mRNAs, miRNAs, and proteins between cells. This intercellular communication can significantly impact the progression and severity of COPD by modulating signaling pathways in recipient cells. A deeper exploration of circulating miRNAs and the content of extracellular vesicles may lead to the discovery of novel diagnostic and prognostic biomarkers, ultimately enhancing the management of COPD. The current review focus on the pathogenic role of miRNAs and their exosomal counterparts in chest and respiratory diseases, centering COPD.
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Affiliation(s)
- FangYuan Nan
- Thoracic Surgery Department of the First People's Hospital of Jiangxia District, Wuhan, 430200, Hubei Province, China
| | - Bo Liu
- Thoracic Surgery Department of the First People's Hospital of Jiangxia District, Wuhan, 430200, Hubei Province, China
| | - Cheng Yao
- Infectious Diseases Department of the First People's Hospital of Jiangxia District, Wuhan, 430200, Hubei Province, China.
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Ritter A, Han J, Bianconi S, Henrich D, Marzi I, Leppik L, Weber B. The Ambivalent Role of miRNA-21 in Trauma and Acute Organ Injury. Int J Mol Sci 2024; 25:11282. [PMID: 39457065 PMCID: PMC11508407 DOI: 10.3390/ijms252011282] [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: 09/11/2024] [Revised: 10/14/2024] [Accepted: 10/18/2024] [Indexed: 10/28/2024] Open
Abstract
Since their initial recognition, miRNAs have been the subject of rising scientific interest. Especially in recent years, miRNAs have been recognized to play an important role in the mediation of various diseases, and further, their potential as biomarkers was recognized. Rising attention has also been given to miRNA-21, which has proven to play an ambivalent role as a biomarker. Responding to the demand for biomarkers in the trauma field, the present review summarizes the contrary roles of miRNA-21 in acute organ damage after trauma with a specific focus on the role of miRNA-21 in traumatic brain injury, spinal cord injury, cardiac damage, lung injury, and bone injury. This review is based on a PubMed literature search including the terms "miRNA-21" and "trauma", "miRNA-21" and "severe injury", and "miRNA-21" and "acute lung respiratory distress syndrome". The present summary makes it clear that miRNA-21 has both beneficial and detrimental effects in various acute organ injuries, which precludes its utility as a biomarker but makes it intriguing for mechanistic investigations in the trauma field.
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Affiliation(s)
- Aileen Ritter
- Department of Trauma, Hand and Reconstructive Surgery, University Hospital Frankfurt, Goethe University, 60486 Frankfurt am Main, Germany; (J.H.); (S.B.); (D.H.); (I.M.); (L.L.); (B.W.)
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Cohn DE, Souza VGP, Forder A, Telkar N, Stewart GL, Lam WL. Post-Transcriptional Modifications to miRNAs Undergo Widespread Alterations, Creating a Unique Lung Adenocarcinoma IsomiRome. Cancers (Basel) 2024; 16:3322. [PMID: 39409941 PMCID: PMC11476290 DOI: 10.3390/cancers16193322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Revised: 09/24/2024] [Accepted: 09/26/2024] [Indexed: 10/20/2024] Open
Abstract
BACKGROUND MicroRNAs (miRNAs) modulate the expression of oncogenes and tumor suppressor genes, functioning as significant epigenetic regulators in cancer. IsomiRs are miRNA molecules that have undergone small modifications during miRNA processing. These modifications can alter an isomiR's binding stability with mRNA targets, and certain isomiRs have been implicated in the development of specific cancers. Still, the isomiRomes of many tissues, including the lung, have not been characterized; Methods: In this study, we analyzed small RNA sequencing data for three cohorts of lung adenocarcinoma (LUAD) and adult non-malignant lung (ANL) samples. RESULTS We quantified isomiR expression and found 16 A-to-I edited isomiRs expressed in multiple cohorts, as well as 213 5' isomiRs, 128 3' adenylated isomiRs, and 100 3' uridylated isomiRs. Rates of A-to-I editing at editing hotspots correlated with mRNA expression of the editing enzymes ADAR and ADARB1, which were both observed to be deregulated in LUAD. LUAD samples displayed lower overall rates of A-to-I editing and 3' adenylation than ANL samples. Support vector machines and random forest models were trained on one cohort to distinguish ANL and stage I/II LUAD samples using reads per million (RPM) and frequency data for different types of isomiRs. Models trained on A-to-I editing rates at editing hotspots displayed high accuracy when tested on the other two cohorts and compared favorably to classifiers trained on miRNA expression alone; Conclusions: We have identified isomiRs in the human lung and found that their expression differs between non-malignant and tumor tissues, suggesting they hold potential as cancer biomarkers.
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Affiliation(s)
- David E. Cohn
- Department of Integrative Oncology, BC Cancer Research Institute, Vancouver, BC V5Z 1L3, Canada (W.L.L.)
| | - Vanessa G. P. Souza
- Department of Integrative Oncology, BC Cancer Research Institute, Vancouver, BC V5Z 1L3, Canada (W.L.L.)
| | - Aisling Forder
- Department of Integrative Oncology, BC Cancer Research Institute, Vancouver, BC V5Z 1L3, Canada (W.L.L.)
| | - Nikita Telkar
- Department of Integrative Oncology, BC Cancer Research Institute, Vancouver, BC V5Z 1L3, Canada (W.L.L.)
- British Columbia Children’s Hospital Research Institute, Vancouver, BC V5Z 4H4, Canada
| | - Greg L. Stewart
- Department of Integrative Oncology, BC Cancer Research Institute, Vancouver, BC V5Z 1L3, Canada (W.L.L.)
| | - Wan L. Lam
- Department of Integrative Oncology, BC Cancer Research Institute, Vancouver, BC V5Z 1L3, Canada (W.L.L.)
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12
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Lv X, Liang J, Wang Z. MiR-21-5p reduces apoptosis and inflammation in rats with spinal cord injury through PI3K/AKT pathway. Panminerva Med 2024; 66:256-265. [PMID: 32720795 DOI: 10.23736/s0031-0808.20.03974-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
BACKGROUND The aim of this study is to explore the effect of micro ribonucleic acid (miR)-21-5p on spinal cord injury (SCI) in rats and its mechanism of action. METHODS The rat model of SCI was established, and the key miRNAs were screened using the microarray assay and miRNA-mRNA interaction network. After intrathecal injection of agomir-21 and antagomir-21, the effect of miR-21 expression on motor function recovery of rats was evaluated using the Basso-Beattie-Bresnahan (BBB) score. The expression level of miR-21 in spinal cord tissues was determined via quantitative reverse transcription-polymerase chain reaction (qRT-PCR), and the effect of miR-21 expression on apoptosis in spinal cord tissues was determined via terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay and Western blotting. Moreover, the effects of agomir-21 and antagomir-21 on SCI-induced expressions of inflammatory factors interleukin-8 (IL-8), IL-1β, IL-6 and tumor necrosis factor-α (TNF-α) in spinal cord tissues were detected through qRT-PCR. Finally, Western blotting was performed to detect the effects of agomir-21 and antagomir-21 on the phosphatidylinositol 3-hydroxy kinase (PI3K)/protein kinase B (AKT) signaling pathway and its downstream molecules in each group. RESULTS The screening results of the microarray assay revealed that the mRNA and miRNA expression profiles in spinal cord tissues had significant differences in model group from those in sham group. The BBB score was significantly higher in agomir-21 group than that in model group. Compared with that in model group, the apoptosis of spinal cord tissues was obviously weakened in agomir-21 group, while it was obviously enhanced in antagomir-21 group. Agomir-21 group had evidently lower Bax/Bcl-2, and Caspase-3 and Caspase-9 protein expressions, while antagomir-21 group had evidently higher Bax/Bcl-2 and Caspase-3 protein expression than model group. Besides, the expressions of inflammatory factors IL-8, IL-1β, IL-6 and TNF-α were remarkably lower in agomir-21 group than those in model group, while they were remarkably higher in antagomir-21 group than those in model group. Finally, it was found that the protein expressions of phosphorylated PI3K (p-PI3K)/PI3K and p-AKT/AKT rose markedly, while the protein expressions of phosphatase and tensin homolog deleted on chromosome ten (PTEN) and endothelial nitric oxide synthase (eNOS) declined markedly in agomir-21 group compared with those in model group. However, the opposite results were observed in antagomir-21 group compared with those in model group. CONCLUSIONS MiR-21-5p may reduce the apoptosis and inflammation in spinal cord tissues of rats through the PI3K/AKT pathway.
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Affiliation(s)
- Xinwang Lv
- Department of Orthopedics, Caoxian People's Hospital, Heze, China
| | - Jian Liang
- Department of Orthopedics, Affiliated Hospital of Heze Medical College, Heze, China
| | - Zhipu Wang
- Department of Orthopedics, Caoxian Panshi Hospital, Heze, China -
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13
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Abou Madawi NA, Darwish ZE, Omar EM. Targeted gene therapy for cancer: the impact of microRNA multipotentiality. Med Oncol 2024; 41:214. [PMID: 39088082 PMCID: PMC11294399 DOI: 10.1007/s12032-024-02450-1] [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: 06/10/2024] [Accepted: 07/12/2024] [Indexed: 08/02/2024]
Abstract
Cancer is a life-threatening disease and its management is difficult due to its complex nature. Cancer is characterized by genomic instability and tumor-associated inflammation of the supporting stoma. With the advances in omics science, a treatment strategy for cancer has emerged, which is based on targeting cancer-driving molecules, known as targeted therapy. Gene therapy, a form of targeted therapy, is the introduction of nucleic acids into living cells to replace a defective gene, promote or repress gene expression to treat a disease. MicroRNAs (miRNAs) are non-coding RNAs (ncRNAs) that regulate gene expression and thus are involved in physiological processes like cell proliferation, differentiation, and cell death. miRNAs control the actions of many genes. They are deregulated in cancer and their abnormal expression influences genetic and epigenetic alterations inducing carcinogenesis. In this review, we will explain the role of miRNAs in normal and abnormal gene expression and their usefulness in monitoring cancer patients. Besides, we will discuss miRNA-based therapy as a method of gene therapy and its impact on the success of cancer management.
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Affiliation(s)
- Nourhan A Abou Madawi
- Oral Pathology Department, Faculty of Dentistry, Alexandria University, Champollion Street, Azarita, 21521, Alexandria, Egypt.
| | - Zeinab E Darwish
- Oral Pathology Department, Faculty of Dentistry, Alexandria University, Champollion Street, Azarita, 21521, Alexandria, Egypt
| | - Enas M Omar
- Oral Pathology Department, Faculty of Dentistry, Alexandria University, Champollion Street, Azarita, 21521, Alexandria, Egypt
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14
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Khair HHA, Karagöz ID. MiR-21-5p knockdown inhibits epithelial to mesenchymal transition in A549 lung adenocarcinoma cells by upregulating RhoB. Mol Biol Rep 2024; 51:837. [PMID: 39042337 DOI: 10.1007/s11033-024-09794-x] [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: 03/11/2024] [Accepted: 07/09/2024] [Indexed: 07/24/2024]
Abstract
BACKGROUND MiR-21-5p is a highly expressed microRNA that plays an important role in various cancer-promoting processes, including anchorage-independent growth, invasion, migration metastasis, and drug resistance in lung cancer. Studies indicate that miR-21-5p may contribute to these processes by promoting epithelial-mesenchymal transition (EMT). Ras homolog gene family member B (RhoB), a gene downregulated by miR-21-5p, has also been linked to EMT in lung cancer. However, the role of the miR-21-5p/RhoB axis in EMT regulation in lung adenocarcinoma remains unclear. In this study, we aimed to investigate the regulatory role of the miR-21-5p/RhoB axis in EMT and related in vitro functional characteristics such as migration, invasion, cisplatin resistance, and the formation of tumor spheroids. METHODS AND RESULTS A549 cells were transfected with the miR-21-5p inhibitor, RhoB siRNA, and their corresponding negative controls. Wound healing, transwell invasion, Methyl thiazole tetrazolium (MTT), and sphere formation assays were also performed to evaluate the migration, invasion, cisplatin resistance, and anchorage-independent growth of A549 cells. RT-qPCR was used to determine the mRNA expression levels of EMT markers. MiR-21-5p knockdown inhibited migration, invasion, cisplatin resistance, and sphere formation while upregulating E-cadherin and downregulating Slug. Furthermore, RhoB silencing restored EMT and related in vitro functional characteristics in A549 cells. CONCLUSIONS Knockdown of miR-21-5p inhibits EMT and related in vitro functional characteristics by upregulating RhoB, suggesting that miR-21-5p may promote EMT through downregulation of RhoB.
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Affiliation(s)
- Hiba Hussein A Khair
- Biology Department, Gaziantep University, University Boulevard, Şehitkamil, Gaziantep, 27310, Turkey.
| | - Işık Didem Karagöz
- Biology Department, Gaziantep University, University Boulevard, Şehitkamil, Gaziantep, 27310, Turkey
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15
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Bica C, Jurj A, Harangus A, Ciocan C, Moldovan A, Zanoaga O, Burz C, Ferracin M, Raduly L, Berindan-Neagoe I. miRNA patterns in male LUSC patients - the 3-way mirror: Tissue, plasma and exosomes. Transl Oncol 2024; 44:101951. [PMID: 38564933 PMCID: PMC11002298 DOI: 10.1016/j.tranon.2024.101951] [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: 06/22/2023] [Revised: 03/28/2024] [Accepted: 03/28/2024] [Indexed: 04/04/2024] Open
Abstract
Lung cancer remains one of the leading causes of cancer-related deaths worldwide. It is classified into two main histological groups: non-small cell lung cancer (NSCLC) and small cell lung cancer. Improving the outcome of cancer patients could be possible by enhancing the early diagnosis. In the current study, we evaluated the levels of three microRNAs - miR-21-5p, miR-155-5p, and miR-181a-5p in tumor (TT) vs adjacent normal tissue (NT), as well as their expression levels in plasma and extracellular vesicles (EVs) from plasma in lung squamous cell carcinoma (LUSC) male patients vs healthy individuals as means to identify a panel of miRNAs that could serve as novel biomarkers for the diagnosis of LUSC in male patients. Matched paired tissue samples from male LUSC (n=40) patients were used for miRNA expression analysis. MiR-21-5p and miR-155-5p in tumor tissue were overexpressed, while underexpression of miR-181a-5p was observed in LUSC TT vs NT. These results were further validated in the TCGA LUSC dataset, considering 279 male samples. These alterations of miR-21-5p, miR-181a-5p, and miR-155-5p in tumor tissue are also present in plasma and plasma extracellular vesicles in LUSC male patients. In addition, ROC curves were performed to assess the sensitivity and specificity of different combinations of these miRNAs, confirming a high diagnostic accuracy for LUSC of up to 88 % in male subjects. The expression levels in tissue samples and the abundance in plasma and plasma EVs of the three miRNAs combined - miR-21-5p, miR-155-5p and miR-181a-5p - could be considered for further studies on biomarkers for the early detection of LUSC in male subjects.
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Affiliation(s)
- Cecilia Bica
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, 400337, Romania; Research Center for Advanced Medicine-MedFUTURE, Department of Translational Medicine, "Iuliu Haţieganu" University of Medicine and Pharmacy, 400347 Cluj-Napoca, Romania
| | - Ancuta Jurj
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, 400337, Romania
| | | | - Cristina Ciocan
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, 400337, Romania
| | - Alin Moldovan
- Leon Daniello Pulmonology Hospital, Cluj-Napoca, Romania
| | - Oana Zanoaga
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, 400337, Romania
| | - Claudia Burz
- Department of Immunology and Allergology, Faculty of Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania; Department of Medical Oncology, The Oncology Institute "Prof. Dr. Ion Chiricuţă", 400015 Cluj-Napoca, Romania
| | - Manuela Ferracin
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
| | - Lajos Raduly
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, 400337, Romania.
| | - Ioana Berindan-Neagoe
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, 400337, Romania
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16
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Lv X, Yang L, Xie Y, Momeni MR. Non-coding RNAs and exosomal non-coding RNAs in lung cancer: insights into their functions. Front Cell Dev Biol 2024; 12:1397788. [PMID: 38859962 PMCID: PMC11163066 DOI: 10.3389/fcell.2024.1397788] [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: 03/08/2024] [Accepted: 05/02/2024] [Indexed: 06/12/2024] Open
Abstract
Lung cancer is the second most common form of cancer worldwide Research points to the pivotal role of non-coding RNAs (ncRNAs) in controlling and managing the pathology by controlling essential pathways. ncRNAs have all been identified as being either up- or downregulated among individuals suffering from lung cancer thus hinting that they may play a role in either promoting or suppressing the spread of the disease. Several ncRNAs could be effective non-invasive biomarkers to diagnose or even serve as effective treatment options for those with lung cancer, and several molecules have emerged as potential targets of interest. Given that ncRNAs are contained in exosomes and are implicated in the development and progression of the malady. Herein, we have summarized the role of ncRNAs in lung cancer. Moreover, we highlight the role of exosomal ncRNAs in lung cancer.
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Affiliation(s)
- Xiaolong Lv
- Department of Cardiothoracic Surgery, The People’s Hospital of Changshou, Chongqing, China
| | - Lei Yang
- Department of Cardiothoracic Surgery, The People’s Hospital of Tongliang District, Chongqing, China
| | - Yunbo Xie
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Tong Z, Yang D, Shen C, Li C, Xu X, Li Q, Wu Z, Ma H, Chen F, Mao H. Rapid automated extracellular vesicle isolation and miRNA preparation on a cost-effective digital microfluidic platform. Anal Chim Acta 2024; 1296:342337. [PMID: 38401929 DOI: 10.1016/j.aca.2024.342337] [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] [Revised: 01/28/2024] [Accepted: 02/04/2024] [Indexed: 02/26/2024]
Abstract
As a prerequisite for extracellular vesicle (EV) -based studies and diagnosis, effective isolation, enrichment and retrieval of EV biomarkers are crucial to subsequent analyses, such as miRNA-based liquid biopsy for non-small-cell lung cancer (NSCLC). However, most conventional approaches for EV isolation suffer from lengthy procedure, high cost, and intense labor. Herein, we introduce the digital microfluidic (DMF) technology to EV pretreatment protocols and demonstrate a rapid and fully automated sample preparation platform for clinical tumor liquid biopsy. Combining a reusable DMF chip technique with a low-cost EV isolation and miRNA preparation protocol, the platform completes automated sample processing in 20-30 min, supporting immediate RT-qPCR analyses on EV-derived miRNAs (EV-miRNAs). The utility and reliability of the platform was validated via clinical sample processing for EV-miRNA detection. With 23 tumor and 20 non-tumor clinical plasma samples, we concluded that EV-miR-486-5p and miR-21-5p are effective biomarkers for NSCLC with a small sample volumn (20-40 μL). The result was consistent to that of a commercial exosome miRNA extraction kit. These results demonstrate the effectiveness of DMF in EV pretreatment for miRNA detection, providing a facile solution to EV isolation for liquid biopsy.
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Affiliation(s)
- Zhaoduo Tong
- State Key Laboratory of Transducer Technology, Shanghai Institute of Microsystem and Information Technology, Chinese Academy of Sciences, Shanghai, 200050, China; Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Dawei Yang
- Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Chuanjie Shen
- State Key Laboratory of Transducer Technology, Shanghai Institute of Microsystem and Information Technology, Chinese Academy of Sciences, Shanghai, 200050, China; Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Chao Li
- Department of Neurosurgery, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200092, China
| | - Xin Xu
- State Key Laboratory of Transducer Technology, Shanghai Institute of Microsystem and Information Technology, Chinese Academy of Sciences, Shanghai, 200050, China
| | - Qiushi Li
- State Key Laboratory of Transducer Technology, Shanghai Institute of Microsystem and Information Technology, Chinese Academy of Sciences, Shanghai, 200050, China
| | - Zhenhua Wu
- State Key Laboratory of Transducer Technology, Shanghai Institute of Microsystem and Information Technology, Chinese Academy of Sciences, Shanghai, 200050, China; Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Hui Ma
- State Key Laboratory of Transducer Technology, Shanghai Institute of Microsystem and Information Technology, Chinese Academy of Sciences, Shanghai, 200050, China
| | - Fuxiang Chen
- Department of Clinical Immunology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Hongju Mao
- State Key Laboratory of Transducer Technology, Shanghai Institute of Microsystem and Information Technology, Chinese Academy of Sciences, Shanghai, 200050, China; Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing, 100049, China.
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18
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Zhao X, Cao Y, Lu R, Zhou Z, Huang C, Li L, Huang J, Chen R, Wang Y, Huang J, Cheng J, Zheng J, Fu Y, Yu J. Phosphorylation of AGO2 by TBK1 Promotes the Formation of Oncogenic miRISC in NSCLC. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2305541. [PMID: 38351659 PMCID: PMC11022703 DOI: 10.1002/advs.202305541] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 01/22/2024] [Indexed: 04/18/2024]
Abstract
Non-small-cell lung cancer (NSCLC) is a highly lethal tumor that often develops resistance to targeted therapy. It is shown that Tank-binding kinase 1 (TBK1) phosphorylates AGO2 at S417 (pS417-AGO2), which promotes NSCLC progression by increasing the formation of microRNA-induced silencing complex (miRISC). High levels of pS417-AGO2 in clinical NSCLC specimens are positively associated with poor prognosis. Interestingly, the treatment with EGFR inhibitor Gefitinib can significantly induce pS417-AGO2, thereby increasing the formation and activity of oncogenic miRISC, which may contribute to NSCLC resistance to Gefitinib. Based on these, two therapeutic strategies is developed. One is jointly to antagonize multiple oncogenic miRNAs highly expressed in NSCLC and use TBK1 inhibitor Amlexanox reducing the formation of oncogenic miRISC. Another approach is to combine Gefitinib with Amlexanox to inhibit the progression of Gefitinib-resistant NSCLC. This findings reveal a novel mechanism of oncogenic miRISC regulation by TBK1-mediated pS417-AGO2 and suggest potential therapeutic approaches for NSCLC.
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Affiliation(s)
- Xian Zhao
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and InflammationShanghai Jiao Tong University School of MedicineShanghai200025China
- Department of Thoracic Surgery, Ren Ji HospitalShanghai Jiao Tong University School of MedicineShanghai200120China
| | - Yingting Cao
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and InflammationShanghai Jiao Tong University School of MedicineShanghai200025China
| | - Runhui Lu
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and InflammationShanghai Jiao Tong University School of MedicineShanghai200025China
| | - Zihan Zhou
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and InflammationShanghai Jiao Tong University School of MedicineShanghai200025China
| | - Caihu Huang
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and InflammationShanghai Jiao Tong University School of MedicineShanghai200025China
| | - Lian Li
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and InflammationShanghai Jiao Tong University School of MedicineShanghai200025China
| | - Jiayi Huang
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and InflammationShanghai Jiao Tong University School of MedicineShanghai200025China
| | - Ran Chen
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and InflammationShanghai Jiao Tong University School of MedicineShanghai200025China
| | - Yanli Wang
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and InflammationShanghai Jiao Tong University School of MedicineShanghai200025China
| | - Jian Huang
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and InflammationShanghai Jiao Tong University School of MedicineShanghai200025China
| | - Jinke Cheng
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and InflammationShanghai Jiao Tong University School of MedicineShanghai200025China
| | - Junke Zheng
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of EducationShanghai Jiao Tong University School of MedicineShanghai200025China
| | - Yujie Fu
- Department of Thoracic Surgery, Ren Ji HospitalShanghai Jiao Tong University School of MedicineShanghai200120China
| | - Jianxiu Yu
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and InflammationShanghai Jiao Tong University School of MedicineShanghai200025China
- Department of Thoracic Surgery, Ren Ji HospitalShanghai Jiao Tong University School of MedicineShanghai200120China
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Choi JY, Seok HJ, Lee DH, Lee E, Kim TJ, Bae S, Shin I, Bae IH. Tumor-derived miR-6794-5p enhances cancer growth by promoting M2 macrophage polarization. Cell Commun Signal 2024; 22:190. [PMID: 38521953 PMCID: PMC10960442 DOI: 10.1186/s12964-024-01570-5] [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: 01/15/2024] [Accepted: 03/16/2024] [Indexed: 03/25/2024] Open
Abstract
BACKGROUND Solid tumors promote tumor malignancy through interaction with the tumor microenvironment, resulting in difficulties in tumor treatment. Therefore, it is necessary to understand the communication between cells in the tumor and the surrounding microenvironment. Our previous study revealed the cancer malignancy mechanism of Bcl-w overexpressed in solid tumors, but no study was conducted on its relationship with immune cells in the tumor microenvironment. In this study, we sought to discover key factors in exosomes secreted from tumors overexpressing Bcl-w and analyze the interaction with the surrounding tumor microenvironment to identify the causes of tumor malignancy. METHODS To analyze factors affecting the tumor microenvironment, a miRNA array was performed using exosomes derived from cancer cells overexpressing Bcl-w. The discovered miRNA, miR-6794-5p, was overexpressed and the tumorigenicity mechanism was confirmed using qRT-PCR, Western blot, invasion, wound healing, and sphere formation ability analysis. In addition, luciferase activity and Ago2-RNA immunoprecipitation assays were used to study the mechanism between miR-6794-5p and its target gene SOCS1. To confirm the interaction between macrophages and tumor-derived miR-6794-5p, co-culture was performed using conditioned media. Additionally, immunohistochemical (IHC) staining and flow cytometry were performed to analyze macrophages in the tumor tissues of experimental animals. RESULTS MiR-6794-5p, which is highly expressed in exosomes secreted from Bcl-w-overexpressing cells, was selected, and it was shown that the overexpression of miR-6794-5p increased migratory ability, invasiveness, and stemness maintenance by suppressing the expression of the tumor suppressor SOCS1. Additionally, tumor-derived miR-6794-5p was delivered to THP-1-derived macrophages and induced M2 polarization by activating the JAK1/STAT3 pathway. Moreover, IL-10 secreted from M2 macrophages increased tumorigenicity by creating an immunosuppressive environment. The in vitro results were reconfirmed by confirming an increase in M2 macrophages and a decrease in M1 macrophages and CD8+ T cells when overexpressing miR-6794-5p in an animal model. CONCLUSIONS In this study, we identified changes in the tumor microenvironment caused by miR-6794-5p. Our study indicates that tumor-derived miR-6794-5p promotes tumor aggressiveness by inducing an immunosuppressive environment through interaction with macrophage.
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Affiliation(s)
- Jae Yeon Choi
- Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 01812, Republic of Korea
- Department of Life Science, Hanyang University, Seoul, Republic of Korea
| | - Hyun Jeong Seok
- Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 01812, Republic of Korea
| | - Dong Hyeon Lee
- Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 01812, Republic of Korea
| | - Eunju Lee
- Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 01812, Republic of Korea
| | - Tae-Jin Kim
- Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 01812, Republic of Korea
| | - Sangwoo Bae
- Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 01812, Republic of Korea
| | - Incheol Shin
- Department of Life Science, Hanyang University, Seoul, Republic of Korea
| | - In Hwa Bae
- Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 01812, Republic of Korea.
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Zhu J, Luo J, Hua Z, Feng X, Cao X. SERS microfluidic chip integrated with double amplified signal off-on strategy for detection of microRNA in NSCLC. BIOMEDICAL OPTICS EXPRESS 2024; 15:594-607. [PMID: 38404336 PMCID: PMC10890848 DOI: 10.1364/boe.514425] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Revised: 12/19/2023] [Accepted: 12/21/2023] [Indexed: 02/27/2024]
Abstract
In this work, based on Fe3O4@AuNPs and double amplified signal Off-On strategy, a simple and sensitive SERS microfluidic chip was constructed to detect microRNA associated with non-small cell lung cancer (NSCLC). Fe3O4@AuNPs have two advantages of SERS enhanced and magnetic adsorption, the introduction of microfluidic chip can realize double amplification of SERS signal. First, the binding of complementary ssDNA and hpDNA moved the Raman signaling molecule away from Fe3O4@AuNPs, at which point the signal was turned off. Second, in the presence of the target microRNA, they were captured by complementary ssDNA and bound to them. HpDNA restored the hairpin conformation, the Raman signaling molecule moved closer to Fe3O4@AuNPs. At this time, the signal was turned on and strong Raman signal was generated. And last, through the magnetic component of SERS microfluidic chip, Fe3O4@AuNPs could be enriched to realize the secondary enhancement of SERS signal. In this way, the proposed SERS microfluidic chip can detect microRNA with high sensitivity and specificity. The corresponding detection of limit (LOD) for miR-21 versus miR-125b was 6.38 aM and 7.94 aM, respectively. This SERS microfluidic chip was promising in the field of early detection of NSCLC.
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Affiliation(s)
- Jiashan Zhu
- Department of Thoracic Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China
| | - Jinhua Luo
- Department of Thoracic Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China
| | - Zhaolai Hua
- People's Hospital of Yangzhong City, Zhenjiang 212000, Jiangsu, China
| | - Xiang Feng
- People's Hospital of Yangzhong City, Zhenjiang 212000, Jiangsu, China
| | - Xiaowei Cao
- People's Hospital of Yangzhong City, Zhenjiang 212000, Jiangsu, China
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Moeinafshar A, Nouri M, Shokrollahi N, Masrour M, Behnam A, Tehrani Fateh S, Sadeghi H, Miryounesi M, Ghasemi MR. Non-coding RNAs as potential therapeutic targets for receptor tyrosine kinase signaling in solid tumors: current status and future directions. Cancer Cell Int 2024; 24:26. [PMID: 38200584 PMCID: PMC10782702 DOI: 10.1186/s12935-023-03203-2] [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: 07/28/2023] [Accepted: 12/27/2023] [Indexed: 01/12/2024] Open
Abstract
This review article presents an in-depth analysis of the current state of research on receptor tyrosine kinase regulatory non-coding RNAs (RTK-RNAs) in solid tumors. RTK-RNAs belong to a class of non-coding RNAs (nc-RNAs) responsible for regulating the expression and activity of receptor tyrosine kinases (RTKs), which play a critical role in cancer development and progression. The article explores the molecular mechanisms through which RTK-RNAs modulate RTK signaling pathways and highlights recent advancements in the field. This include the identification of potential new RTK-RNAs and development of therapeutic strategies targeting RTK-RNAs. While the review discusses promising results from a variety of studies, encompassing in vitro, in vivo, and clinical investigations, it is important to acknowledge the challenges and limitations associated with targeting RTK-RNAs for therapeutic applications. Further studies involving various cancer cell lines, animal models, and ultimately, patients are necessary to validate the efficacy of targeting RTK-RNAs. The specificity of ncRNAs in targeting cellular pathways grants them tremendous potential, but careful consideration is required to minimize off-target effects, the article additionally discusses the potential clinical applications of RTK-RNAs as biomarkers for cancer diagnosis, prognosis, and treatment. In essence, by providing a comprehensive overview of the current understanding of RTK-RNAs in solid tumors, this review emphasizes their potential as therapeutic targets for cancer while acknowledging the associated challenges and limitations.
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Affiliation(s)
- Aysan Moeinafshar
- Center for Comprehensive Genetic Services, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Nouri
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nima Shokrollahi
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mahdi Masrour
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Center for Orthopedic Trans-Disciplinary Applied Research, Tehran University of Medical Sciences, Tehran, Iran
| | - Amirmohammad Behnam
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sahand Tehrani Fateh
- Center for Comprehensive Genetic Services, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Hossein Sadeghi
- Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Miryounesi
- Center for Comprehensive Genetic Services, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad-Reza Ghasemi
- Center for Comprehensive Genetic Services, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
- Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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22
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Khalaji A, Mehrtabar S, Jabraeilipour A, Doustar N, Rahmani Youshanlouei H, Tahavvori A, Fattahi P, Alavi SMA, Taha SR, Fazlollahpour-Naghibi A, Shariat Zadeh M. Inhibitory effect of microRNA-21 on pathways and mechanisms involved in cardiac fibrosis development. Ther Adv Cardiovasc Dis 2024; 18:17539447241253134. [PMID: 38819836 PMCID: PMC11143841 DOI: 10.1177/17539447241253134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Accepted: 04/18/2024] [Indexed: 06/01/2024] Open
Abstract
Cardiac fibrosis is a pivotal cardiovascular disease (CVD) process and represents a notable health concern worldwide. While the complex mechanisms underlying CVD have been widely investigated, recent research has highlighted microRNA-21's (miR-21) role in cardiac fibrosis pathogenesis. In this narrative review, we explore the molecular interactions, focusing on the role of miR-21 in contributing to cardiac fibrosis. Various signaling pathways, such as the RAAS, TGF-β, IL-6, IL-1, ERK, PI3K-Akt, and PTEN pathways, besides dysregulation in fibroblast activity, matrix metalloproteinases (MMPs), and tissue inhibitors of MMPs cause cardiac fibrosis. Besides, miR-21 in growth factor secretion, apoptosis, and endothelial-to-mesenchymal transition play crucial roles. miR-21 capacity regulatory function presents promising insights for cardiac fibrosis. Moreover, this review discusses numerous approaches to control miR-21 expression, including antisense oligonucleotides, anti-miR-21 compounds, and Notch signaling modulation, all novel methods of cardiac fibrosis inhibition. In summary, this narrative review aims to assess the molecular mechanisms of cardiac fibrosis and its essential miR-21 function.
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Affiliation(s)
- Amirreza Khalaji
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 5166/15731, Iran
- Connective Tissue Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Saba Mehrtabar
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Connective Tissue Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Nadia Doustar
- Faculty of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran
| | | | - Amir Tahavvori
- Department of Internal Medicine, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Payam Fattahi
- Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Seyed Reza Taha
- Oncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Andarz Fazlollahpour-Naghibi
- Infectious Diseases and Tropical Medicine Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
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23
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Trivedi A, Bose D, Saha P, Roy S, More M, Skupsky J, Klimas NG, Chatterjee S. Prolonged Antibiotic Use in a Preclinical Model of Gulf War Chronic Multisymptom-Illness Causes Renal Fibrosis-like Pathology via Increased micro-RNA 21-Induced PTEN Inhibition That Is Correlated with Low Host Lachnospiraceae Abundance. Cells 2023; 13:56. [PMID: 38201260 PMCID: PMC10777912 DOI: 10.3390/cells13010056] [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: 11/27/2023] [Revised: 12/21/2023] [Accepted: 12/25/2023] [Indexed: 01/12/2024] Open
Abstract
Gulf War (GW) veterans show gastrointestinal disturbances and gut dysbiosis. Prolonged antibiotic treatments commonly employed in veterans, especially the use of fluoroquinolones and aminoglycosides, have also been associated with dysbiosis. This study investigates the effect of prolonged antibiotic exposure on risks of adverse renal pathology and its association with gut bacterial species abundance in underlying GWI and aims to uncover the molecular mechanisms leading to possible renal dysfunction with aging. Using a GWI mouse model, administration of a prolonged antibiotic regimen involving neomycin and enrofloxacin treatment for 5 months showed an exacerbated renal inflammation with increased NF-κB activation and pro-inflammatory cytokines levels. Involvement of the high mobility group 1 (HMGB1)-mediated receptor for advanced glycation end products (RAGE) activation triggered an inflammatory phenotype and increased transforming growth factor-β (TGF-β) production. Mechanistically, TGF-β- induced microRNA-21 upregulation in the renal tissue leads to decreased phosphatase and tensin homolog (PTEN) expression. The above event led to the activation of protein kinase-B (AKT) signaling, resulting in increased fibronectin production and fibrosis-like pathology. Importantly, the increased miR-21 was associated with low levels of Lachnospiraceae in the host gut which is also a key to heightened HMGB1-mediated inflammation. Overall, though correlative, the study highlights the complex interplay between GWI, host gut dysbiosis, prolonged antibiotics usage, and renal pathology via miR-21/PTEN/AKT signaling.
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Affiliation(s)
- Ayushi Trivedi
- Environmental Health and Disease Laboratory, Department of Environmental and Occupational Health, Program in Public Health, Susan and Henry Samueli College of Health Sciences, University of California, Irvine, CA 92697, USA; (A.T.); (D.B.); (P.S.); (S.R.); (M.M.)
| | - Dipro Bose
- Environmental Health and Disease Laboratory, Department of Environmental and Occupational Health, Program in Public Health, Susan and Henry Samueli College of Health Sciences, University of California, Irvine, CA 92697, USA; (A.T.); (D.B.); (P.S.); (S.R.); (M.M.)
| | - Punnag Saha
- Environmental Health and Disease Laboratory, Department of Environmental and Occupational Health, Program in Public Health, Susan and Henry Samueli College of Health Sciences, University of California, Irvine, CA 92697, USA; (A.T.); (D.B.); (P.S.); (S.R.); (M.M.)
| | - Subhajit Roy
- Environmental Health and Disease Laboratory, Department of Environmental and Occupational Health, Program in Public Health, Susan and Henry Samueli College of Health Sciences, University of California, Irvine, CA 92697, USA; (A.T.); (D.B.); (P.S.); (S.R.); (M.M.)
| | - Madhura More
- Environmental Health and Disease Laboratory, Department of Environmental and Occupational Health, Program in Public Health, Susan and Henry Samueli College of Health Sciences, University of California, Irvine, CA 92697, USA; (A.T.); (D.B.); (P.S.); (S.R.); (M.M.)
| | | | - Nancy G. Klimas
- Institute for Neuro-Immune Medicine, College of Osteopathic Medicine, Nova Southeastern University, Fort Lauderdale, FL 33328, USA;
| | - Saurabh Chatterjee
- Environmental Health and Disease Laboratory, Department of Environmental and Occupational Health, Program in Public Health, Susan and Henry Samueli College of Health Sciences, University of California, Irvine, CA 92697, USA; (A.T.); (D.B.); (P.S.); (S.R.); (M.M.)
- Long Beach VA Medical Center, Long Beach, CA 90822, USA;
- Division of Infectious Diseases, Department of Medicine, School of Medicine, University of California, Irvine, CA 92697, USA
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24
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Ramazi S, Dadzadi M, Sahafnejad Z, Allahverdi A. Epigenetic regulation in lung cancer. MedComm (Beijing) 2023; 4:e401. [PMID: 37901797 PMCID: PMC10600507 DOI: 10.1002/mco2.401] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 09/04/2023] [Accepted: 09/08/2023] [Indexed: 10/31/2023] Open
Abstract
Lung cancer is indeed a major cause of cancer-related deaths worldwide. The development of tumors involves a complex interplay of genetic, epigenetic, and environmental factors. Epigenetic mechanisms, including DNA methylation (DNAm), histone modifications, and microRNA expression, play a crucial role in this process. Changes in DNAm patterns can lead to the silencing of important genes involved in cellular functions, contributing to the development and progression of lung cancer. MicroRNAs and exosomes have also emerged as reliable biomarkers for lung cancer. They can provide valuable information about early diagnosis and treatment assessment. In particular, abnormal hypermethylation of gene promoters and its effects on tumorigenesis, as well as its roles in the Wnt signaling pathway, have been extensively studied. Epigenetic drugs have shown promise in the treatment of lung cancer. These drugs target the aberrant epigenetic modifications that are involved in the development and progression of the disease. Several factors have been identified as drug targets in non-small cell lung cancer. Recently, combination therapy has been discussed as a successful strategy for overcoming drug resistance. Overall, understanding the role of epigenetic mechanisms and their targeting through drugs is an important area of research in lung cancer treatment.
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Affiliation(s)
- Shahin Ramazi
- Department of BiophysicsFaculty of Biological SciencesTarbiat Modares UniversityTehranIran
| | - Maedeh Dadzadi
- Department of BiotechnologyFaculty of Advanced Science and TechnologyTehran Medical SciencesIslamic Azad UniversityTehranIran
| | - Zahra Sahafnejad
- Department of BiophysicsFaculty of Biological SciencesTarbiat Modares UniversityTehranIran
| | - Abdollah Allahverdi
- Department of BiophysicsFaculty of Biological SciencesTarbiat Modares UniversityTehranIran
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25
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Ertay A, Ewing RM, Wang Y. Synthetic lethal approaches to target cancers with loss of PTEN function. Genes Dis 2023; 10:2511-2527. [PMID: 37533462 PMCID: PMC7614861 DOI: 10.1016/j.gendis.2022.12.015] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Revised: 12/26/2022] [Accepted: 12/27/2022] [Indexed: 02/05/2023] Open
Abstract
Phosphatase and tensin homolog (PTEN) is a tumour suppressor gene and has a role in inhibiting the oncogenic AKT signalling pathway by dephosphorylating phosphatidylinositol 3,4,5-triphosphate (PIP3) into phosphatidylinositol 4,5-bisphosphate (PIP2). The function of PTEN is regulated by different mechanisms and inactive PTEN results in aggressive tumour phenotype and tumorigenesis. Identifying targeted therapies for inactive tumour suppressor genes such as PTEN has been challenging as it is difficult to restore the tumour suppressor functions. Therefore, focusing on the downstream signalling pathways to discover a targeted therapy for inactive tumour suppressor genes has highlighted the importance of synthetic lethality studies. This review focuses on the potential synthetic lethality genes discovered in PTEN-inactive cancer types. These discovered genes could be potential targeted therapies for PTEN-inactive cancer types and may improve the treatment response rates for aggressive types of cancer.
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Affiliation(s)
- Ayse Ertay
- Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton SO17 1BJ, UK
| | - Rob M. Ewing
- Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton SO17 1BJ, UK
- Institute for Life Sciences, University of Southampton, Southampton SO17 1BJ, UK
| | - Yihua Wang
- Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton SO17 1BJ, UK
- Institute for Life Sciences, University of Southampton, Southampton SO17 1BJ, UK
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26
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Zhu W, Yu Y, Ye Y, Tu X, Zhang Y, Wu T, Ni L, Huang X, Wang Y, Cui R. MiR-196b-5p activates NF-κB signaling in non-small cell lung cancer by directly targeting NFKBIA. Transl Oncol 2023; 37:101755. [PMID: 37595393 PMCID: PMC10458993 DOI: 10.1016/j.tranon.2023.101755] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Revised: 07/06/2023] [Accepted: 08/02/2023] [Indexed: 08/20/2023] Open
Abstract
BACKGROUND Our recent study found that QKI-5 regulated miRNA, miR-196b-5p, promotes non-small cell lung cancer (NSCLC) progression by directly targeting GATA6, TSPAN12 and FAS. However, the biological functions of miR-196b-5p in NSCLC progression and metastasis still remain elusive. METHODS Cell proliferation, migration, colony formation, cell cycle assays were used to investigate cellular phenotypic changes. Quantitative real-time PCR (qRT-PCR) and western blot analyses were used to measure expressions of relative gene and protein. Interaction between QKI-5 and miR-196b-5p was determined by RNA immunoprecipitation (RIP) assay. Luciferase reporter assay was used to determine direct binding between miR-196b-5p and NFKBIA 3'-UTR. ELISA assay was used to measure secreted IL6 proteins. Mice xenograft model was used to assess the functions of NFKBIA on in vivo tumor growth. RESULTS We demonstrated that the miR-196b-5p facilitates lung cancer cell proliferation, migration, colony formation, and cell cycle by directly targeting NFKBIA, a negative regulator of NFκB signaling. Knocking down NFKBIA increases IL6 mediated phosphorylation of signal transducer and activator of transcription 3 (STAT3) to promote lung cancer cell growth by activating NFκB signaling. The expression of NFKBIA was significantly downregulated in NSCLC tissue samples, and was negatively correlated with the expression miR-196b-5p. In addition, we found that downregulated QKI-5 expression was associated with the elevated miR-224 expression in NSCLC. CONCLUSIONS Our findings indicated that the miR-224/QKI-5/miR-196b-5p/NFKBIA signaling pathway might play important functions in the progression of NSCLC, and suggested that targeting this pathway might be an effective therapeutic strategy in treating NSCLC.
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Affiliation(s)
- Wangyu Zhu
- Cellular and Molecular Biology Laboratory, Affiliated Zhoushan Hospital of Wenzhou Medical University, Zhoushan, Zhejiang 316020, China; Cancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Yun Yu
- Cellular and Molecular Biology Laboratory, Affiliated Zhoushan Hospital of Wenzhou Medical University, Zhoushan, Zhejiang 316020, China; Cancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Yuxin Ye
- Cancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Xinyue Tu
- Cancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Yan Zhang
- Cancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Tao Wu
- Cancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Lianli Ni
- Cancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Xiangjie Huang
- Cancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Yumin Wang
- Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.
| | - Ri Cui
- Cellular and Molecular Biology Laboratory, Affiliated Zhoushan Hospital of Wenzhou Medical University, Zhoushan, Zhejiang 316020, China; Cancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
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27
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Travis G, McGowan EM, Simpson AM, Marsh DJ, Nassif NT. PTEN, PTENP1, microRNAs, and ceRNA Networks: Precision Targeting in Cancer Therapeutics. Cancers (Basel) 2023; 15:4954. [PMID: 37894321 PMCID: PMC10605164 DOI: 10.3390/cancers15204954] [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: 09/11/2023] [Revised: 10/06/2023] [Accepted: 10/09/2023] [Indexed: 10/29/2023] Open
Abstract
The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a well characterised tumour suppressor, playing a critical role in the maintenance of fundamental cellular processes including cell proliferation, migration, metabolism, and survival. Subtle decreases in cellular levels of PTEN result in the development and progression of cancer, hence there is tight regulation of the expression, activity, and cellular half-life of PTEN at the transcriptional, post-transcriptional, and post-translational levels. PTENP1, the processed pseudogene of PTEN, is an important transcriptional and post-transcriptional regulator of PTEN. PTENP1 expression produces sense and antisense transcripts modulating PTEN expression, in conjunction with miRNAs. Due to the high sequence similarity between PTEN and the PTENP1 sense transcript, the transcripts possess common miRNA binding sites with the potential for PTENP1 to compete for the binding, or 'sponging', of miRNAs that would otherwise target the PTEN transcript. PTENP1 therefore acts as a competitive endogenous RNA (ceRNA), competing with PTEN for the binding of specific miRNAs to alter the abundance of PTEN. Transcription from the antisense strand produces two functionally independent isoforms (PTENP1-AS-α and PTENP1-AS-β), which can regulate PTEN transcription. In this review, we provide an overview of the post-transcriptional regulation of PTEN through interaction with its pseudogene, the cellular miRNA milieu and operation of the ceRNA network. Furthermore, its importance in maintaining cellular integrity and how disruption of this PTEN-miRNA-PTENP1 axis may lead to cancer but also provide novel therapeutic opportunities, is discussed. Precision targeting of PTENP1-miRNA mediated regulation of PTEN may present as a viable alternative therapy.
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Affiliation(s)
- Glena Travis
- Cancer Biology, Faculty of Science, School of Life Sciences, University of Technology Sydney, Ultimo, NSW 2007, Australia; (G.T.); (E.M.M.)
| | - Eileen M. McGowan
- Cancer Biology, Faculty of Science, School of Life Sciences, University of Technology Sydney, Ultimo, NSW 2007, Australia; (G.T.); (E.M.M.)
- Central Laboratory, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, China
| | - Ann M. Simpson
- Gene Therapy and Translational Molecular Analysis Laboratory, Faculty of Science, School of Life Sciences, University of Technology Sydney, Ultimo, NSW 2007, Australia;
| | - Deborah J. Marsh
- Translational Oncology Group, Faculty of Science, School of Life Sciences, University of Technology Sydney, Ultimo, NSW 2007, Australia;
| | - Najah T. Nassif
- Cancer Biology, Faculty of Science, School of Life Sciences, University of Technology Sydney, Ultimo, NSW 2007, Australia; (G.T.); (E.M.M.)
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28
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Gupta J, Tayyib NA, Jalil AT, Hlail SH, Zabibah RS, Vokhidov UN, Alsaikhan F, Ramaiah P, Chinnasamy L, Kadhim MM. Angiogenesis and prostate cancer: MicroRNAs comes into view. Pathol Res Pract 2023; 248:154591. [PMID: 37343381 DOI: 10.1016/j.prp.2023.154591] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 06/01/2023] [Accepted: 06/03/2023] [Indexed: 06/23/2023]
Abstract
Angiogenesis, the formation of new blood vessels, is an important stage in the growth of cancer. Extracellular matrix, endothelial cells, and soluble substances must be carefully coordinated during the multistep procedure of angiogenesis. Inducers and inhibitors have been found to control pretty much every phase. In addition to benign prostatic hyperplasia, prostatic intraepithelial neoplasia, and angiogenesis have a critical role in the initiation and progression of prostate cancer. MicroRNA (miRNA) is endogenous, short, non-coding RNA molecules of almost 22 nucleotides play a role in regulating cellular processes and regulating several genes' expression. Through controlling endothelial migration, differentiation, death, and cell proliferation, miRNAs have a significant function in angiogenesis. A number of pathological and physiological processes, particularly prostate cancer's emergence, depend on the regulation of angiogenesis. Investigating the functions played with miRNAs in angiogenesis is crucial because it might result in the creation of novel prostate cancer therapies that entail regulating angiogenesis. The function of several miRNAs and its targeting genes engaged in cancer of the prostate angiogenesis will be reviewed in this review in light of the most recent developments. The potential clinical utility of miRNAs potentially a novel therapeutic targets will also be explored, as well as their capacity to control prostate cancer angiogenesis and the underlying mechanisms.
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Affiliation(s)
- Jitendra Gupta
- Institute of Pharmaceutical Research, GLA University, Mathura 281406, U.P., India.
| | - Nahla A Tayyib
- Faculty of Nursing, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Abduladheem Turki Jalil
- Medical Laboratories Techniques Department, Al-Mustaqbal University College, Hilla 51001, Babylon, Iraq.
| | | | - Rahman S Zabibah
- Medical Laboratory Technology Department, College of Medical Technology, The Islamic University, Najaf, Iraq
| | - Ulug'bek N Vokhidov
- Department of ENT Diseases, Head of the Department of Quality Education, Tashkent State Dental Institute, Tashkent, Uzbekistan; Research scholar, Department of Scientific affairs, Samarkand State Medical Institute, Amir Temur Street 18, Samarkand, Uzbekistan
| | - Fahad Alsaikhan
- College of Pharmacy, Prince Sattam Bin Abdulaziz University, Alkharj, Saudi Arabia.
| | | | | | - Mustafa M Kadhim
- Department of Dentistry, Kut University College, Kut, Wasit 52001, Iraq; Medical Laboratory Techniques Department, Al-Farahidi University, Baghdad 10022 Iraq
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29
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Liu J, Pan Y, Liu Y, Wei W, Hu X, Xin W, Chen N. The regulation of PTEN: Novel insights into functions as cancer biomarkers and therapeutic targets. J Cell Physiol 2023; 238:1693-1715. [PMID: 37334436 DOI: 10.1002/jcp.31053] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 05/10/2023] [Accepted: 05/17/2023] [Indexed: 06/20/2023]
Abstract
This review summarizes the implications of the primary tumor suppressor protein phosphatase and tensin homolog (PTEN) in aggressive cancer development. PTEN interacts with other cellular proteins or factors suggesting the existence of an intricate molecular network that regulates their oncogenic function. Accumulating evidence has shown that PTEN exists and plays a role in the cytoplasmic organelles and in the nucleus. PTEN blocks phosphoinositide 3-kinases (PI3K)-protein kinase B-mammalian target of rapamycin signaling pathway by dephosphorylating phosphatidylinositol (PI)-3,4,5-triphosphate to PI-4,5-bisphosphate thus counteracting PI3K function. Studies have shown that PTEN expression is tightly regulated at transcriptional, posttranscriptional, and posttranslational levels (including protein-protein interactions and posttranslational modifications). Despite recent advances in PTEN research, the regulation and function of the PTEN gene remain largely unknown. How mutation or loss of specific exons in the PTEN gene occurs and involves in cancer development is not clear. This review illustrates the regulatory mechanisms of PTEN expression and discusses how PTEN participates in tumor development and/or suppression. Future prospects for the clinical applications are also highlighted.
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Affiliation(s)
- Jie Liu
- Department of Dermatology, Skin Research, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China
| | - Yongli Pan
- Department of Neurology, University Medical Center Göttingen, Göttingen, Germany
| | - Yuheng Liu
- Department of Neurology, University Medical Center Göttingen, Göttingen, Germany
| | - Wei Wei
- Department of Neurology, University Medical Center Göttingen, Göttingen, Germany
| | - Xiaoping Hu
- Department of Dermatology, Skin Research, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China
| | - Wenqiang Xin
- Department of Neurology, University Medical Center Göttingen, Göttingen, Germany
| | - Nan Chen
- Department of Gastroenterology, Liaocheng People's Hospital, Liaocheng, China
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30
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Siu MC, Voisey J, Zang T, Cuttle L. MicroRNAs involved in human skin burns, wound healing and scarring. Wound Repair Regen 2023; 31:439-453. [PMID: 37268303 DOI: 10.1111/wrr.13100] [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: 10/17/2022] [Revised: 05/09/2023] [Accepted: 05/18/2023] [Indexed: 06/04/2023]
Abstract
MicroRNAs are small, non-coding RNAs that regulate gene expression, and consequently protein synthesis. Downregulation and upregulation of miRNAs and their corresponding genes can alter cell apoptosis, proliferation, migration and fibroproliferative responses following a thermal injury. This review summarises the evidence for altered human miRNA expression post-burn, and during wound healing and scarring. In addition, the most relevant miRNA targets and their roles in potential pathways are described. Previous studies using molecular techniques have identified 197 miRNAs associated with human wound healing, burn wound healing and scarring. Five miRNAs alter the expression of fibroproliferative markers, proliferation and migration of fibroblasts and keratinocytes post-burn: hsa-miR-21 and hsa-miR-31 are increased after wounding, and hsa-miR-23b, hsa-miR-200b and hsa-let-7c are decreased. Four of these five miRNAs are associated with the TGF-β pathway. In the future, large scale, in vivo, longitudinal human studies utilising a range of cell types, ethnicity and clinical healing outcomes are fundamental to identify burn wound healing and scarring specific markers. A comprehensive understanding of the underlying pathways will facilitate the development of clinical diagnostic or prognostic tools for better scar management and the identification of novel treatment targets for improved healing outcomes in burn patients.
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Affiliation(s)
- Man Ching Siu
- Faculty of Health, School of Biomedical Sciences, Centre for Children's Health Research, Queensland University of Technology (QUT), Brisbane, Queensland, Australia
- Centre for Genomics and Personalised Health Research, QUT, Brisbane, Queensland, Australia
| | - Joanne Voisey
- Centre for Genomics and Personalised Health Research, QUT, Brisbane, Queensland, Australia
| | - Tuo Zang
- Faculty of Health, School of Biomedical Sciences, Centre for Children's Health Research, Queensland University of Technology (QUT), Brisbane, Queensland, Australia
| | - Leila Cuttle
- Faculty of Health, School of Biomedical Sciences, Centre for Children's Health Research, Queensland University of Technology (QUT), Brisbane, Queensland, Australia
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Saikia BJ, Bhardwaj J, Paul S, Sharma S, Neog A, Paul SR, Binukumar BK. Understanding the Roles and Regulation of Mitochondrial microRNAs (MitomiRs) in Neurodegenerative Diseases: Current Status and Advances. Mech Ageing Dev 2023:111838. [PMID: 37329989 DOI: 10.1016/j.mad.2023.111838] [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: 12/27/2022] [Revised: 06/13/2023] [Accepted: 06/13/2023] [Indexed: 06/19/2023]
Abstract
MicroRNAs (miRNA) are a class of small non-coding RNA, roughly 21 - 22 nucleotides in length, which are master gene regulators. These miRNAs bind to the mRNA's 3' - untranslated region and regulate post-transcriptional gene regulation, thereby influencing various physiological and cellular processes. Another class of miRNAs known as mitochondrial miRNA (MitomiRs) has been found to either originate from the mitochondrial genome or be translocated directly into the mitochondria. Although the role of nuclear DNA encoded miRNA in the progression of various neurological diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, etc. is well known, accumulating evidence suggests the possible role of deregulated mitomiRs in the progression of various neurodegenerative diseases with unknown mechanism. We have attempted to outline the current state of mitomiRs role in controlling mitochondrial gene expression and function through this review, paying particular attention to their contribution to neurological processes, their etiology, and their potential therapeutic use.
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Affiliation(s)
- Bhaskar Jyoti Saikia
- CSIR Institute of Genomics and Integrative Biology, Mall Road, New Delhi - 110007; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201002, India
| | - Juhi Bhardwaj
- CSIR Institute of Genomics and Integrative Biology, Mall Road, New Delhi - 110007; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201002, India
| | - Sangita Paul
- CSIR Institute of Genomics and Integrative Biology, Mall Road, New Delhi - 110007; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201002, India
| | - Srishti Sharma
- CSIR Institute of Genomics and Integrative Biology, Mall Road, New Delhi - 110007; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201002, India
| | - Anindita Neog
- CSIR Institute of Genomics and Integrative Biology, Mall Road, New Delhi - 110007
| | - Swaraj Ranjan Paul
- CSIR Institute of Genomics and Integrative Biology, Mall Road, New Delhi - 110007
| | - B K Binukumar
- CSIR Institute of Genomics and Integrative Biology, Mall Road, New Delhi - 110007; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201002, India.
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Tepebaşı MY, Öztürk Ö. miR-21, miR-221, and miR-222 upregulation in lung cancer promotes metastasis by reducing oxidative stress and apoptosis. REVISTA DA ASSOCIACAO MEDICA BRASILEIRA (1992) 2023; 69:e20221688. [PMID: 37283359 DOI: 10.1590/1806-9282.20221688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Accepted: 03/06/2023] [Indexed: 06/08/2023]
Abstract
OBJECTIVE The purpose of our research was to observe the effects of miR-21, miR-221, and miR-222, as well as their target genes on oxidative stress, lung cancer formation, and metastasis. METHODS Positron emission tomography/computed tomography, fiberoptic bronchoscopy, and/or endobronchial ultrasonography were performed on a total of 69 lung cancer patients to detect the presence or absence of metastasis, and the patients were classified based on the types of cancer. Total RNA and miRNA were isolated from the obtained biopsy samples. The quantitative analysis of hsa-miR-21-5p, hsa-miR-222-3p, and hsa-miR-221-3p and their target genes was performed by the RT-qPCR method. In determining oxidative stress, total antioxidant status and total oxidant status in tissue and total thiol and native thiol in blood were determined spectrophotometrically. OSI and disulfide were calculated. RESULTS We discovered that the metastasis group had higher levels of hsa-miR-21-5p, hsa-miR-221-3p, and hsa-miR-222-3p (p<0.05). While TIMP3, PTEN, and apoptotic genes decreased in metastasis, anti-apoptotic genes increased (p<0.05). In addition, while oxidative stress decreased in the metastasis group, no change was found in the serum (p>0.05). CONCLUSION Our findings show that upregulation of hsa-miR-21-5p, hsa-miR-221-3p, and hsa-miR-222-3p effectively contributes to both proliferation and invasion by influencing oxidative stress and mitochondrial apoptosis.
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Affiliation(s)
| | - Önder Öztürk
- University of Süleyman Demirel, Department of Chest Diseases - Isparta, Turkey
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33
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Srivastava R, Singh R, Jauhari S, Lodhi N, Srivastava R. Histone Demethylase Modulation: Epigenetic Strategy to Combat Cancer Progression. EPIGENOMES 2023; 7:epigenomes7020010. [PMID: 37218871 DOI: 10.3390/epigenomes7020010] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 05/09/2023] [Accepted: 05/10/2023] [Indexed: 05/24/2023] Open
Abstract
Epigenetic modifications are heritable, reversible changes in histones or the DNA that control gene functions, being exogenous to the genomic sequence itself. Human diseases, particularly cancer, are frequently connected to epigenetic dysregulations. One of them is histone methylation, which is a dynamically reversible and synchronously regulated process that orchestrates the three-dimensional epigenome, nuclear processes of transcription, DNA repair, cell cycle, and epigenetic functions, by adding or removing methylation groups to histones. Over the past few years, reversible histone methylation has become recognized as a crucial regulatory mechanism for the epigenome. With the development of numerous medications that target epigenetic regulators, epigenome-targeted therapy has been used in the treatment of malignancies and has shown meaningful therapeutic potential in preclinical and clinical trials. The present review focuses on the recent advances in our knowledge on the role of histone demethylases in tumor development and modulation, in emphasizing molecular mechanisms that control cancer cell progression. Finally, we emphasize current developments in the advent of new molecular inhibitors that target histone demethylases to regulate cancer progression.
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Affiliation(s)
- Rashmi Srivastava
- Department of Zoology, Babasaheb Bhimrao Ambedkar University, Lucknow 226025, Uttar Pradesh, India
| | - Rubi Singh
- Department of Hematology, Bioreference Laboratories, Elmwood Park, NJ 07407, USA
| | - Shaurya Jauhari
- Division of Education, Training, and Assessment, Global Education Center, Infosys Limited, Mysuru 570027, Karnataka, India
| | - Niraj Lodhi
- Clinical Research (Research and Development Division) Mirna Analytics LLC, Harlem Bio-Space, New York, NY 10027, USA
| | - Rakesh Srivastava
- Molecular Biology and Microbiology, GenTox Research and Development, Lucknow 226001, Uttar Pradesh, India
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34
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Patel D, Thankachan S, Abu Fawaz PP, Venkatesh T, Prasada Kabekkodu S, Suresh PS. Deciphering the role of MitomiRs in cancer: A comprehensive review. Mitochondrion 2023; 70:118-130. [PMID: 37120081 DOI: 10.1016/j.mito.2023.04.004] [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: 01/08/2023] [Revised: 04/01/2023] [Accepted: 04/23/2023] [Indexed: 05/01/2023]
Abstract
MicroRNAs (miRNAs) are short non-coding RNAs that regulate many metabolic and signal transduction pathways. The role of miRNAs, usually found in the cytoplasm, in regulating gene expression and cancer progression has been extensively studied in the last few decades. However, very recently, miRNAs were found to localize in the mitochondria. MiRNAs that specifically localize in the mitochondria and the cytoplasmic miRNAs associated with mitochondria that directly or indirectly modulate specific mitochondrial functions are termed as "mitomiRs". Although it is not clear about the origin of mitomiRs that are situated within mitochondria (nuclear or mitochondrial origin), it is evident that they have specific functions in modulating gene expression and regulating important mitochondrial metabolic pathways. Through this review, we aim to delineate the mechanisms by which mitomiRs alter mitochondrial metabolic pathways and influence the initiation and progression of cancer. We further discuss the functions of particular mitomiRs, which have been widely studied in the context of mitochondrial metabolism and oncogenic signaling pathways. Based on the current knowledge, we can conclude that mitomiRs contribute significantly to mitochondrial function and metabolic regulation, and that dysregulation of mitomiRs can aid the proliferation of cancer cells. Therefore, the less explored area of mitomiRs' biology can be an important topic of research investigation in the future for targeting cancer cells.
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Affiliation(s)
- Dimple Patel
- School of Biotechnology, National Institute of Technology, Calicut-673601, Kerala, India
| | - Sanu Thankachan
- School of Biotechnology, National Institute of Technology, Calicut-673601, Kerala, India
| | - P P Abu Fawaz
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipa1-576104, Karnataka, India
| | - Thejaswini Venkatesh
- Department of Biochemistry and Molecular Biology, Central University of Kerala, Kasaragod, Kerala 671316, India
| | - Shama Prasada Kabekkodu
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipa1-576104, Karnataka, India
| | - Padmanaban S Suresh
- School of Biotechnology, National Institute of Technology, Calicut-673601, Kerala, India.
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35
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Kiełbowski K, Ptaszyński K, Wójcik J, Wojtyś ME. The role of selected non-coding RNAs in the biology of non-small cell lung cancer. Adv Med Sci 2023; 68:121-137. [PMID: 36933328 DOI: 10.1016/j.advms.2023.02.004] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2022] [Revised: 11/26/2022] [Accepted: 02/27/2023] [Indexed: 03/18/2023]
Abstract
Lung cancer is the second most frequently diagnosed cancer worldwide and a leading cause of cancer-related deaths. Non-small cell lung carcinoma (NSCLC) represents 85% of all cases. Accumulating evidence highlights the outstanding role of non-coding RNA (ncRNA) in regulating the tumorigenesis process by modulating crucial signaling pathways. Micro RNA (miRNA), long non-coding RNA (lncRNA) and circular RNA (circRNA) are either up- or downregulated in lung cancer patients and can promote or suppress the progression of the disease. These molecules interact with messenger RNA (mRNA) and with each other to regulate gene expression and stimulate proto-oncogenes or silence tumor suppressors. NcRNAs provide a new strategy to diagnose or treat lung cancer patients and multiple molecules have already been identified as potential biomarkers or therapeutic targets. The aim of this review is to summarize the current evidence on the roles of miRNA, lncRNA and circRNA in NSCLC biology and present their clinical potential.
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Affiliation(s)
- Kajetan Kiełbowski
- Department of Thoracic Surgery and Transplantation, Pomeranian Medical University, Szczecin, Poland
| | - Konrad Ptaszyński
- Department of Pathology, Faculty of Medicine, Collegium Medicum, University of Warmia and Mazury in Olsztyn, Poland
| | - Janusz Wójcik
- Department of Thoracic Surgery and Transplantation, Pomeranian Medical University, Szczecin, Poland
| | - Małgorzata Edyta Wojtyś
- Department of Thoracic Surgery and Transplantation, Pomeranian Medical University, Szczecin, Poland.
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36
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Tan C, Du H, Wang Y, Zhao J, Cheng X, Lan H. LncRNA GABPB1-IT1 inhibits the tumorigenesis of renal cancer via the miR-21/PTEN axis. J Biochem Mol Toxicol 2023; 37:e23288. [PMID: 36756790 DOI: 10.1002/jbt.23288] [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: 04/24/2022] [Revised: 10/25/2022] [Accepted: 12/09/2022] [Indexed: 02/10/2023]
Abstract
Long noncoding RNA (lncRNA) (GABPB1-IT1) has been reported to be downregulated in lung cancer, while its expression and function in other cancers are unknown. In this study, the expression levels of GABPB1-IT1 in tissue samples from 62 ccRCC patients were measured by performing RT-qPCR. Potential base pairing formed between GABPB1-IT1 and miR-21 was explored using the online program IntaRNA 2.0 and further confirmed by Dual-luciferase activity assay and RNA pulldown assay. The role of GABPB1-IT1 and miR-21 in regulating the expression of PTEN was evaluated by RT-qPCR and Western blot. The role of GABPB1-IT1, miR-21, and PTEN in regulating the proliferation of Caki-2 cells was explored by CCK-8 assay. It was observed that GABPB1-IT1 was downregulated in ccRCC and predicted poor survival. GABPB1-IT1 directly interacted with miR-21, while it did not regulate the expression of each other. Moreover, upregulation of PTEN, which is a target of miR-21, was observed in ccRCC cells with overexpression of GABPB1-IT1. Overexpression of GABPB1-IT1 and PTEN decreased the proliferation rates of ccRCC cells. In addition, overexpression of GABPB1-IT1 reduced the enhancing effects of miR-21 on cell proliferation. Therefore, GABPB1-IT1 may upregulate PTEN by sponging miR-21 in ccRCC to inhibit cancer cell proliferation. Our study characterized a novel GABPB1-IT1/miR-21/PTEN axis in ccRCC.
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Affiliation(s)
- Chao Tan
- Second Department of Urology, Affiliated Hospital of Hebei Engineering University, Handan City, Hebei Province, China
| | - Huasheng Du
- Department of Nephrology, Qingdao Municipal Hospital, Qingdao City, Shandong Province, China
| | - Yang Wang
- Department of reproductive medicine, Xingtai People's Hospital, Xingtai City, Hebei Province, China
| | - Jianjun Zhao
- Second Department of Urology, Affiliated Hospital of Hebei Engineering University, Handan City, Hebei Province, China
| | - Xiaolong Cheng
- Second Department of Urology, Affiliated Hospital of Hebei Engineering University, Handan City, Hebei Province, China
| | - Haihe Lan
- Department of Urology, Hanzhong Central Hospital, Hanzhong City, Shaanxi Province, China
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Zhang X, Zhang Q, Li T, Liu L, Miao Y. LINC00312 Inhibits Lung Cancer Progression through the miR-3175/SEMA6A Axis. Crit Rev Eukaryot Gene Expr 2023; 33:41-53. [PMID: 36734856 DOI: 10.1615/critreveukaryotgeneexpr.2022044042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
This study aims to clarify molecular mechanisms and tumor-associated functions of LINC00312 in lung cancer. GEO database was used to acquire lung cancer-related expression microarrays. Then, relevant databases were applied to predict the downstream miRNA for LINC00312 and the target mRNA for the potential miRNA, with their associations deeply confirmed through dual-luciferase and RIP assays. The expression levels of epithelial-mesenchymal transition -related proteins (N-cadherin, Vimentin, MMP-2, and MMP-9) were examined by Western blot. The proliferation, migration, and invasion were evaluated through in vitro experiments including CCK-8 and Transwell assays and further validated by nude mouse xenograft tumor experiment. LINC00312, serving as a tumor suppressor, was down-regulated in lung cancer cells. RIP assay proved that miR-3175 bound LINC00312 and SEMA6A. The dual-luciferase assay showed that miR-3175 specifically targeted SEMA6A, suppressing the expression of SEMA6A. Overexpressing LINC00312 remarkably inhibited the binding between miR-3175 and SEMA6A. Overexpressing miR-3175 or silencing SEMA6A could hamper the effects of LINC00312 on lung cancer cells. LINC00312 inhibits lung cancer occurrence and progression via the miR-3175/SEMA6A axis.
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Affiliation(s)
- Xiangli Zhang
- Department of Respiratory and Critical Care, Shaanxi Provincial People's Hospital, Xi'an City 710068, China
| | - Qian Zhang
- Department of Pediatric Ward, Shaanxi Provincial People's Hospital, Xi'an City 710068, China
| | - Ting Li
- Department of Traditional Chinese Medicine, Shaanxi Provincial People's Hospital, Xi'an City 710068, China
| | - Lu Liu
- Department of Respiratory and Critical Care, Shaanxi Provincial People's Hospital, Xi'an City 710068, China
| | - Yi Miao
- Department of Respiratory and Critical Care, Shaanxi Provincial People's Hospital, Xi'an City 710068, China
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38
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Smok-Kalwat J, Mertowska P, Mertowski S, Smolak K, Kozińska A, Koszałka F, Kwaśniewski W, Grywalska E, Góźdź S. The Importance of the Immune System and Molecular Cell Signaling Pathways in the Pathogenesis and Progression of Lung Cancer. Int J Mol Sci 2023; 24:1506. [PMID: 36675020 PMCID: PMC9861992 DOI: 10.3390/ijms24021506] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 01/04/2023] [Accepted: 01/08/2023] [Indexed: 01/13/2023] Open
Abstract
Lung cancer is a disease that in recent years has become one of the greatest threats to modern society. Every year there are more and more new cases and the percentage of deaths caused by this type of cancer increases. Despite many studies, scientists are still looking for answers regarding the mechanisms of lung cancer development and progression, with particular emphasis on the role of the immune system. The aim of this literature review was to present the importance of disorders of the immune system and the accompanying changes at the level of cell signaling in the pathogenesis of lung cancer. The collected results showed that in the process of immunopathogenesis of almost all subtypes of lung cancer, changes in the tumor microenvironment, deregulation of immune checkpoints and abnormalities in cell signaling pathways are involved, which contribute to the multistage and multifaceted carcinogenesis of this type of cancer. We, therefore, suggest that in future studies, researchers should focus on a detailed analysis of tumor microenvironmental immune checkpoints, and to validate their validity, perform genetic polymorphism analyses in a wide range of patients and healthy individuals to determine the genetic susceptibility to lung cancer development. In addition, further research related to the analysis of the tumor microenvironment; immune system disorders, with a particular emphasis on immunological checkpoints and genetic differences may contribute to the development of new personalized therapies that improve the prognosis of patients.
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Affiliation(s)
- Jolanta Smok-Kalwat
- Department of Clinical Oncology, Holy Cross Cancer Centre, 3 Artwinskiego Street, 25-734 Kielce, Poland
| | - Paulina Mertowska
- Department of Experimental Immunology, Medical University of Lublin, 4a Chodzki Street, 20-093 Lublin, Poland
| | - Sebastian Mertowski
- Department of Experimental Immunology, Medical University of Lublin, 4a Chodzki Street, 20-093 Lublin, Poland
| | - Konrad Smolak
- Department of Experimental Immunology, Medical University of Lublin, 4a Chodzki Street, 20-093 Lublin, Poland
| | - Aleksandra Kozińska
- Student Research Group of Experimental Immunology, Medical University of Lublin, 4a Chodzki Street, 20-093 Lublin, Poland
| | - Filip Koszałka
- Student Research Group of Experimental Immunology, Medical University of Lublin, 4a Chodzki Street, 20-093 Lublin, Poland
| | - Wojciech Kwaśniewski
- Department of Gynecologic Oncology and Gynecology, Medical University of Lublin, 20-081 Lublin, Poland
| | - Ewelina Grywalska
- Department of Experimental Immunology, Medical University of Lublin, 4a Chodzki Street, 20-093 Lublin, Poland
| | - Stanisław Góźdź
- Department of Clinical Oncology, Holy Cross Cancer Centre, 3 Artwinskiego Street, 25-734 Kielce, Poland
- Institute of Medical Science, Collegium Medicum, Jan Kochanowski University of Kielce, IX Wieków Kielc 19A, 25-317 Kielce, Poland
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Zhang Y, Hu Y, Guo F. miR-21 Inhibits Non-Small Cell Lung Cancer Cell Proliferation and Promotes Apoptosis. J BIOMATER TISS ENG 2023. [DOI: 10.1166/jbt.2023.3214] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
This study assesses miR-21’s role in non-small cell lung cancer (NSCLC) cells. miR-21/PTEN RNA level in normal and NSCLC cell (A549) was detected by qPCR. After transfection of miR-21 and inhibitors, cell proliferation was assessed by MTT. PTEN, NF-κB, p53, BCL2,
BAX levels were measured after si-PTEN transfection. miR-21 was significantly lower and PTEN was higher in NSCLC cells than normal cells (P <0.001) and PTEN was negatively associated with miR-21. MTT assay showed that cell survival rate was decreased after miR-21 was inhibited and
increased after miR-21 was overexpressed. After inhibiting PTEN, protein expression of proliferation-related factors NF-κB and p53 was decreased. TUNEL experiment showed elevated cell apoptosis after miR-21 was inhibited and decreased apoptosis after miR-21 was overexpressed.
Inhibition of PTEN modulated Akt signaling as demonstrated by no changes of Akt expression and decreased p-Akt level along with downregulated BCL2 and BAX. In conclusion, miR-21/PTEN inhibits NSCLC cell proliferation and promotes cell apoptosis.
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Affiliation(s)
- Yi Zhang
- Department of Pulmonary and Critical Care Medicine, Xianning Central Hospital, The First Affiliated Hospital of Hubei University of Science and Technology, Xianning, Hubei, 437100, China
| | - Yiming Hu
- Department of Pulmonary and Critical Care Medicine, Xianning Central Hospital, The First Affiliated Hospital of Hubei University of Science and Technology, Xianning, Hubei, 437100, China
| | - Fen Guo
- National Demonstration Center for Experimental General Medicine Education (Hubei University of Science and Technology), Xianning, Hubei, 437100, China
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Ghareghomi S, Atabaki V, Abdollahzadeh N, Ahmadian S, Hafez Ghoran S. Bioactive PI3-kinase/Akt/mTOR Inhibitors in Targeted Lung Cancer Therapy. Adv Pharm Bull 2023; 13:24-35. [PMID: 36721812 PMCID: PMC9871280 DOI: 10.34172/apb.2023.003] [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: 06/04/2021] [Revised: 07/27/2021] [Accepted: 09/28/2021] [Indexed: 02/03/2023] Open
Abstract
One of the central signaling pathways with a regulatory effect on cell proliferation and survival is Akt/mTOR. In many human cancer types, for instance, lung cancer, the overexpression of Akt/mTOR has been reported. For this reason, either targeting cancer cells by synthetic or natural products affecting the Akt/mTOR pathway down-regulation is a useful strategy in cancer therapy. Direct inhibition of the signaling pathway or modulation of each related molecule could have significant feedback on the growth and proliferation of cancer cells. A variety of secondary metabolites has been identified to directly inhibit the AKT/mTOR signaling, which is important in the field of drug discovery. Naturally occurring nitrogenous and phenolic compounds can emerge as two pivotal classes of natural products possessing anticancer abilities. Herein, we have summarized the alkaloids and flavonoids for lung cancer treatment together with all the possible mechanisms of action relying on the Akt/mTOR pathway down-regulation. This review suggested that in search of new drugs, phytochemicals could be considered as promising scaffolds to be developed into efficient drugs for the treatment of cancer. In this review, the terms "Akt/mTOR", "Alkaloid", "flavonoid", and "lung cancer" were searched without any limitation in search criteria in Scopus, PubMed, Web of Science, and Google scholar engines.
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Affiliation(s)
- Somayyeh Ghareghomi
- Department of Biochemistry, Institute of Biochemistry and Biophysics (IBB), University of Tehran, Tehran, Iran
| | - Vahideh Atabaki
- Department of Pharmacognosy and Pharmaceutical Biotechnology, Faculty of Pharmacy, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Naseh Abdollahzadeh
- Neurophysiology Research Center, Cellular and Molecular Medicine Institute, Urmia University of Medical Sciences, Urmia, Iran
| | - Shahin Ahmadian
- Department of Biochemistry, Institute of Biochemistry and Biophysics (IBB), University of Tehran, Tehran, Iran.,Corresponding Authors: Salar Hafez Ghoran and Shahin Ahmadian, and
| | - Salar Hafez Ghoran
- Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran.,Corresponding Authors: Salar Hafez Ghoran and Shahin Ahmadian, and
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Dhuri K, Pradeep SP, Shi J, Anastasiadou E, Slack FJ, Gupta A, Zhong XB, Bahal R. Simultaneous Targeting of Multiple oncomiRs with Phosphorothioate or PNA-Based Anti-miRs in Lymphoma Cell Lines. Pharm Res 2022; 39:2709-2720. [PMID: 36071352 PMCID: PMC9879158 DOI: 10.1007/s11095-022-03383-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 08/27/2022] [Indexed: 01/29/2023]
Abstract
PURPOSE MicroRNAs (miRNAs) are short (~ 22 nts) RNAs that regulate gene expression via binding to mRNA. MiRNAs promoting cancer are known as oncomiRs. Targeting oncomiRs is an emerging area of cancer therapy. OncomiR-21 and oncomiR-155 are highly upregulated in lymphoma cells, which are dependent on these oncomiRs for survival. Targeting specific miRNAs and determining their effect on cancer cell progression and metastasis have been the focus of various studies. Inhibiting a single miRNA can have a limited effect, as there may be other overexpressed miRNAs present that may promote tumor proliferation. Herein, we target miR-21 and miR-155 simultaneously using nanoparticles delivered two different classes of antimiRs: phosphorothioates (PS) and peptide nucleic acids (PNAs) and compared their efficacy in lymphoma cell lines. METHODS Poly-Lactic-co-Glycolic acid (PLGA) nanoparticles (NPs) containing PS and PNA-based antimiR-21 and -155 were formulated, and comprehensive NP characterizations: morphology (scanning electron microscopy), size (differential light scattering), and surface charge (zeta potential) were performed. Cellular uptake analysis was performed using a confocal microscope and flow cytometry analysis. The oncomiR knockdown and the effect on downstream targets were confirmed by gene expression (real time-polymerase chain reaction) assay. RESULTS We demonstrated that simultaneous targeting with NP delivered PS and PNA-based antimiRs resulted in significant knockdown of miR-21 and miR-155, as well as their downstream target genes followed by reduced cell viability ex vivo. CONCLUSIONS This project demonstrated that targeting miRNA-155 and miR-21 simultaneously using nanotechnology and a diverse class of antisense oligomers can be used as an effective approach for lymphoma therapy.
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Affiliation(s)
- Karishma Dhuri
- Department of Pharmaceutical Science, University of Connecticut, Storrs, CT, 06269, USA
| | - Sai Pallavi Pradeep
- Department of Pharmaceutical Science, University of Connecticut, Storrs, CT, 06269, USA
| | - Jason Shi
- Department of Pharmaceutical Science, University of Connecticut, Storrs, CT, 06269, USA
| | - Eleni Anastasiadou
- HMS Initiative for RNA Medicine, Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02115, USA
| | - Frank J Slack
- HMS Initiative for RNA Medicine, Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02115, USA
| | - Anisha Gupta
- School of Pharmacy, University of Saint Joseph, West Hartford, CT, 06117, USA
| | - Xiao-Bo Zhong
- Department of Pharmaceutical Science, University of Connecticut, Storrs, CT, 06269, USA
| | - Raman Bahal
- Department of Pharmaceutical Science, University of Connecticut, Storrs, CT, 06269, USA.
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42
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Calvo-Lozano O, García-Aparicio P, Raduly LZ, Estévez MC, Berindan-Neagoe I, Ferracin M, Lechuga LM. One-Step and Real-Time Detection of microRNA-21 in Human Samples for Lung Cancer Biosensing Diagnosis. Anal Chem 2022; 94:14659-14665. [PMID: 36219565 PMCID: PMC9607850 DOI: 10.1021/acs.analchem.2c02895] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
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The rapid diagnosis
of cancer, especially in its early
stages,
is crucial for on-time medical treatment and for increasing the patient
survival rate. Lung cancer shows the highest mortality rate and the
lowest 5-year survival rate due to the late diagnosis in advanced
cancer stages. Providing rapid and reliable diagnostic tools is a
top priority to address the problem of a delayed cancer diagnosis.
We introduce a nanophotonic biosensor for the direct and real-time
detection in human plasma of the microRNA-21-5p biomarker related
to lung cancer. The biosensor employs a silicon photonic bimodal interferometric
waveguide that provides a highly sensitive detection in a label-free
format. We demonstrate a very competitive detectability for direct
microRNA-21-5p biomarker assays in human plasma samples (estimated
LOD: 25 pM). The diagnostic capability of our biosensor was validated
by analyzing 40 clinical samples from healthy individuals and lung
cancer patients, previously analyzed by reverse-transcription quantitative
polymerase chain reaction (qRT-PCR). We could successfully identify
and quantify the levels of microRNA in a one-step assay, without the
need for DNA extraction or amplification steps. The study confirmed
the significance of implementing this biosensor technique compared
to the benchmarking molecular analysis and showed excellent agreement
with previous results employing the traditional qRT-PCR. This work
opens new possibilities for the true implementation of point-of-care
biosensors that enable fast, simple, and efficient early diagnosis
of cancer diseases.
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Affiliation(s)
- Olalla Calvo-Lozano
- Nanobiosensors and Bioanalytical Applications Group (NanoB2A), Catalan Institute of Nanoscience and Nanotechnology (ICN2), CSIC, CIBER-BBN and BIST, Campus UAB, 08193 Bellaterra, Barcelona, Spain
| | - Pablo García-Aparicio
- Nanobiosensors and Bioanalytical Applications Group (NanoB2A), Catalan Institute of Nanoscience and Nanotechnology (ICN2), CSIC, CIBER-BBN and BIST, Campus UAB, 08193 Bellaterra, Barcelona, Spain
| | - Lajos-Zsolt Raduly
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, University of Medicine and Pharmacy "Iuliu Hatieganu", Gheorghe Marinescu 23, 400337 Cluj-Napoca, Romania
| | - Maria Carmen Estévez
- Nanobiosensors and Bioanalytical Applications Group (NanoB2A), Catalan Institute of Nanoscience and Nanotechnology (ICN2), CSIC, CIBER-BBN and BIST, Campus UAB, 08193 Bellaterra, Barcelona, Spain
| | - Ioana Berindan-Neagoe
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, University of Medicine and Pharmacy "Iuliu Hatieganu", Gheorghe Marinescu 23, 400337 Cluj-Napoca, Romania
| | - Manuela Ferracin
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Via S. Giacomo 14, 40126 Bologna, Italy
| | - Laura M Lechuga
- Nanobiosensors and Bioanalytical Applications Group (NanoB2A), Catalan Institute of Nanoscience and Nanotechnology (ICN2), CSIC, CIBER-BBN and BIST, Campus UAB, 08193 Bellaterra, Barcelona, Spain
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43
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Rhim J, Baek W, Seo Y, Kim JH. From Molecular Mechanisms to Therapeutics: Understanding MicroRNA-21 in Cancer. Cells 2022; 11:cells11182791. [PMID: 36139366 PMCID: PMC9497241 DOI: 10.3390/cells11182791] [Citation(s) in RCA: 79] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 08/30/2022] [Accepted: 09/01/2022] [Indexed: 11/29/2022] Open
Abstract
MicroRNAs (miRNAs) are small noncoding RNAs that play an important role in regulating gene expression at a posttranscriptional level. As one of the first discovered oncogenic miRNAs, microRNA-21 (miR-21) has been highlighted for its critical role in cancers, such as glioblastoma, pancreatic adenocarcinoma, non-small cell lung cancer, and many others. MiR-21 targets many vital components in a wide range of cancers and acts on various cellular processes ranging from cancer stemness to cell death. Expression of miR-21 is elevated within cancer tissues and circulating miR-21 is readily detectable in biofluids, making it valuable as a cancer biomarker with significant potential for use in diagnosis and prognosis. Advances in RNA-based therapeutics have revealed additional avenues by which miR-21 can be utilized as a promising target in cancer. The purpose of this review is to outline the roles of miR-21 as a key modulator in various cancers and its potential as a therapeutic target.
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Affiliation(s)
- Jiho Rhim
- Cancer Molecular Biology Branch, Division of Cancer Biology, Research Institute, National Cancer Center, Goyang 10408, Korea
- Department of Cancer Biomedical Science, National Cancer Center, Graduate School of Cancer Science and Policy, Goyang 10408, Korea
| | - Woosun Baek
- Cancer Molecular Biology Branch, Division of Cancer Biology, Research Institute, National Cancer Center, Goyang 10408, Korea
- Department of Cancer Biomedical Science, National Cancer Center, Graduate School of Cancer Science and Policy, Goyang 10408, Korea
| | - Yoona Seo
- Cancer Molecular Biology Branch, Division of Cancer Biology, Research Institute, National Cancer Center, Goyang 10408, Korea
- Department of Cancer Biomedical Science, National Cancer Center, Graduate School of Cancer Science and Policy, Goyang 10408, Korea
| | - Jong Heon Kim
- Cancer Molecular Biology Branch, Division of Cancer Biology, Research Institute, National Cancer Center, Goyang 10408, Korea
- Department of Cancer Biomedical Science, National Cancer Center, Graduate School of Cancer Science and Policy, Goyang 10408, Korea
- Correspondence: ; Tel.: +82-31-920-2204
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44
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Roles of microRNAs in Regulating Apoptosis in the Pathogenesis of Endometriosis. Life (Basel) 2022; 12:life12091321. [PMID: 36143357 PMCID: PMC9500848 DOI: 10.3390/life12091321] [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: 07/13/2022] [Revised: 08/22/2022] [Accepted: 08/23/2022] [Indexed: 11/24/2022] Open
Abstract
Endometriosis is a gynecologic disorder characterized by the presence of endometrial tissues outside the uterine cavity affecting reproductive-aged women. Previous studies have shown that microRNAs and their target mRNAs are expressed differently in endometriosis, suggesting that this molecule may play a role in the development and persistence of endometriotic lesions. microRNA (miRNA), a small non-coding RNA fragment, regulates cellular functions such as cell proliferation, differentiation, and apoptosis by the post-transcriptional modulation of gene expression. In this review, we focused on the dysregulated miRNAs in women with endometriosis and their roles in the regulation of apoptosis. The dysregulated miRNAs and their target genes in this pathophysiology were highlighted. Circulating miRNAs as potential biomarkers for the diagnosis of endometriosis have also been identified. As shown by various studies, miRNAs were reported to be a potent regulator of gene expression in endometriosis; thus, identifying the dysregulated miRNAs and their target genes could help discover new therapeutic targets for treating this disease. The goal of this review is to draw attention to the functions that miRNAs play in the pathophysiology of endometriosis, particularly those that govern cell death.
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45
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Celik N, Kim MH, Yeo M, Kamal F, Hayes DJ, Ozbolat IT. miRNA induced 3D bioprinted-heterotypic osteochondral interface. Biofabrication 2022; 14:10.1088/1758-5090/ac7fbb. [PMID: 35803212 PMCID: PMC9588307 DOI: 10.1088/1758-5090/ac7fbb] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Accepted: 07/08/2022] [Indexed: 11/12/2022]
Abstract
The engineering of osteochondral interfaces remains a challenge. MicroRNAs (miRs) have emerged as significant tools to regulate the differentiation and proliferation of osteogenic and chondrogenic formation in the human musculoskeletal system. Here, we describe a novel approach to osteochondral reconstruction based on the three-dimensional (3D) bioprinting of miR-transfected adipose-derived stem cell (ADSC) spheroids to produce a heterotypic interface that addresses the intrinsic limitations of the traditional approach to inducing zonal differentiation via the use of diffusible cytokines. We evaluated the delivery of miR-148b for osteogenic differentiation and the codelivery of miR-140 and miR-21 for the chondrogenic differentiation of ADSC spheroids. Our results demonstrated that miR-transfected ADSC spheroids exhibited upregulated expression of osteogenic and chondrogenic differentiation related gene and protein markers, and enhanced mineralization and cell proliferation compared to spheroids differentiated using a commercially-available differentiation medium. Upon confirmation of the osteogenic and chondrogenic potential of miR-transfected ADSC spheroids, using aspiration-assisted bioprinting, these spheroids were 3D bioprinted into a dual-layer heterotypic osteochondral interface with a stratified arrangement of distinct osteogenic and chondrogenic zones. The proposed approach holds great promise for the biofabrication of stratified tissues, not only for the osteochondral interfaces presented in this work, but also for other composite tissues and tissue interfaces, such as, but not limited to, the bone-tendon-muscle interface and craniofacial tissues.
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Affiliation(s)
- Nazmiye Celik
- Department of Engineering Science and Mechanics, Penn State University, 212 Earth-Engineering Sciences Bldg., University Park, PA 16802, USA
- The Huck Institutes of the Life Sciences, Penn State University, University Park, PA 16802, USA
| | - Myoung Hwan Kim
- The Huck Institutes of the Life Sciences, Penn State University, University Park, PA 16802, USA
- Department of Biomedical Engineering, Penn State University, Chemical and Biomedical Engineering Bldg., University Park, PA 16802, USA
| | - Miji Yeo
- Department of Engineering Science and Mechanics, Penn State University, 212 Earth-Engineering Sciences Bldg., University Park, PA 16802, USA
- The Huck Institutes of the Life Sciences, Penn State University, University Park, PA 16802, USA
| | - Fadia Kamal
- Center for Orthopedic Research and Translational Sciences, Department of Orthopedics and Re-Habilitation, Penn State University, Hershey, PA 17033, USA
| | - Daniel J. Hayes
- The Huck Institutes of the Life Sciences, Penn State University, University Park, PA 16802, USA
- Department of Biomedical Engineering, Penn State University, Chemical and Biomedical Engineering Bldg., University Park, PA 16802, USA
- Materials Research Institute, Penn State University, University Park, PA 16802, USA
| | - Ibrahim T. Ozbolat
- Department of Engineering Science and Mechanics, Penn State University, 212 Earth-Engineering Sciences Bldg., University Park, PA 16802, USA
- The Huck Institutes of the Life Sciences, Penn State University, University Park, PA 16802, USA
- Department of Biomedical Engineering, Penn State University, Chemical and Biomedical Engineering Bldg., University Park, PA 16802, USA
- Materials Research Institute, Penn State University, University Park, PA 16802, USA
- Department of Neurosurgery, Penn State College of Medicine, Hershey, PA 17033, USA
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46
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Fedorova O, Parfenyev S, Daks A, Shuvalov O, Barlev NA. The Role of PTEN in Epithelial–Mesenchymal Transition. Cancers (Basel) 2022; 14:cancers14153786. [PMID: 35954450 PMCID: PMC9367281 DOI: 10.3390/cancers14153786] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 07/31/2022] [Accepted: 08/02/2022] [Indexed: 11/23/2022] Open
Abstract
Simple Summary The PTEN phosphatase is a ubiquitously expressed tumor suppressor, which inhibits the PI3K/AKT pathway in the cell. The PI3K/AKT pathway is considered to be one of the main signaling pathways that drives the proliferation of cancer cells. Furthermore, the same pathway controls the epithelial–mesenchymal transition (EMT). EMT is an evolutionarily conserved developmental program, which, upon aberrant reactivation, is also involved in the formation of cancer metastases. Importantly, metastasis is the leading cause of cancer-associated deaths. In this review, we discuss the literature data that highlight the role of PTEN in EMT. Based on this knowledge, we speculate about new possible strategies for cancer treatment. Abstract Phosphatase and Tensin Homolog deleted on Chromosome 10 (PTEN) is one of the critical tumor suppressor genes and the main negative regulator of the PI3K pathway. PTEN is frequently found to be inactivated, either partially or fully, in various malignancies. The PI3K/AKT pathway is considered to be one of the main signaling cues that drives the proliferation of cells. Perhaps it is not surprising, then, that this pathway is hyperactivated in highly proliferative tumors. Importantly, the PI3K/AKT pathway also coordinates the epithelial–mesenchymal transition (EMT), which is pivotal for the initiation of metastases and hence is regarded as an attractive target for the treatment of metastatic cancer. It was shown that PTEN suppresses EMT, although the exact mechanism of this effect is still not fully understood. This review is an attempt to systematize the published information on the role of PTEN in the development of malignant tumors, with a main focus on the regulation of the PI3K/AKT pathway in EMT.
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47
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Padinharayil H, Varghese J, John MC, Rajanikant GK, Wilson CM, Al-Yozbaki M, Renu K, Dewanjee S, Sanyal R, Dey A, Mukherjee AG, Wanjari UR, Gopalakrishnan AV, George A. Non-small cell lung carcinoma (NSCLC): Implications on molecular pathology and advances in early diagnostics and therapeutics. Genes Dis 2022. [DOI: 10.1016/j.gendis.2022.07.023] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/09/2022] Open
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48
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Zhu Z, Zhang H, Dong X, Lin M, Yang C. Niosome-Assisted Delivery of DNA Fluorescent Probe with Optimized Strand Displacement for Intracellular MicroRNA21 Imaging. BIOSENSORS 2022; 12:557. [PMID: 35892454 PMCID: PMC9331323 DOI: 10.3390/bios12080557] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 07/15/2022] [Accepted: 07/21/2022] [Indexed: 06/15/2023]
Abstract
MicroRNAs play a vital role in cancer development and are considered as potential biomarkers for early prognostic assessment. Here, we propose a novel biosensing system to achieve fluorescence imaging of miRNA21 (miR21) in cancer cells. This system consists of two components: an optimized "off-on" double-stranded DNA (dsDNA) fluorescent for miR21 sensing by efficient strand-displacement reaction and a potent carrier vesicle, termed niosome (SPN), to facilitate the efficient intracellular delivery of the dsDNA probe. A series of dsDNA probes based on fluorescence energy resonance transfer (FRET) was assembled to target miR21. By optimizing the appropriate length of the reporter strand in the dsDNA probe, high accuracy and sensitivity for miR21 recognition are ensured. To overcome the cellular barrier, we synthesized SPN with the main components of a nonionic surfactant Span 80 and a cationic lipid DOTAP, which could efficiently load dsDNA probes via electrostatic interactions and potently deliver the dsDNA probes into cells with good biosafety. The SPN/dsDNA achieved efficient miR21 fluorescent imaging in living cells, and could discriminate cancer cells (MCF-7) from normal cells (L-02). Therefore, the proposed SPN/dsDNA system provides a powerful tool for intracellular miRNA biosensing, which holds great promise for early cancer diagnosis.
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49
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MiRNAs in Lung Cancer: Diagnostic, Prognostic, and Therapeutic Potential. Diagnostics (Basel) 2022; 12:diagnostics12071610. [PMID: 35885514 PMCID: PMC9322918 DOI: 10.3390/diagnostics12071610] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 04/13/2022] [Accepted: 04/17/2022] [Indexed: 12/24/2022] Open
Abstract
Lung cancer is the dominant emerging factor in cancer-related mortality around the globe. Therapeutic interventions for lung cancer are not up to par, mainly due to reoccurrence/relapse, chemoresistance, and late diagnosis. People are currently interested in miRNAs, which are small double-stranded (20–24 ribonucleotides) structures that regulate molecular targets (tumor suppressors, oncogenes) involved in tumorigeneses such as cell proliferation, apoptosis, metastasis, and angiogenesis via post-transcriptional regulation of mRNA. Many studies suggest the emerging role of miRNAs in lung cancer diagnostics, prognostics, and therapeutics. Therefore, it is necessary to intensely explore the miRNOME expression of lung tumors and the development of anti-cancer strategies. The current review focuses on the therapeutic, diagnostic, and prognostic potential of numerous miRNAs in lung cancer.
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50
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Zheng C, Hu X, Sun S, Zhu L, Wang N, Zhang J, Huang G, Wang Y, Huang X, Wang L, Shen Z. Hairpin allosteric molecular beacons-based cascaded amplification for effective detection of lung cancer-associated microRNA. Talanta 2022; 244:123412. [DOI: 10.1016/j.talanta.2022.123412] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 02/07/2022] [Accepted: 03/25/2022] [Indexed: 12/25/2022]
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