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1
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Gupta S, Silveira DA, Mombach JC, Hashimoto RF. Targeting NSCLC drug resistance: Systems biology insights into the MALAT1/miR-145-5p axis and Wip1 in regulating ferroptosis and apoptosis. J R Soc Interface 2025; 22:20240852. [PMID: 40425041 DOI: 10.1098/rsif.2024.0852] [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: 11/29/2024] [Revised: 02/26/2025] [Accepted: 05/01/2025] [Indexed: 05/29/2025] Open
Abstract
The long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (lncRNA MALAT1) and microRNA-145-5p (miR-145) axis play a pivotal role in regulating drug resistance, apoptosis and senescence in non-small cell lung cancer (NSCLC). MALAT1 drives drug resistance by suppressing miR-145 and activating MUC1, thereby inhibiting ferroptosis; however, its precise role in regulating ferroptosis in NSCLC remains unclear. Therefore, we propose a computational modelling approach to unravel the impact of the MALAT1/miR-145 axis on ferroptosis and drug resistance, to identify potential therapeutic strategies that promote ferroptosis. Using Boolean logic and a stochastic updating scheme, we developed and validated a robust regulatory model that encompasses ferroptosis, apoptosis, senescence and drug resistance pathways. The model, based on extensive literature and validated through gain- and loss-of-function perturbations, demonstrated strong alignment with observed clinical data that were not included in its construction. Our analysis identified three previously unreported feedback loops, miR-145/Wip1/p53, miR-145/Myc/MALAT1 and miR-145/MUC1/BMI1, establishing miR-145 as a central regulator in NSCLC. Perturbations targeting MALAT1 and wild-type p53-induced phosphatase 1 (Wip1) revealed potential therapeutic opportunities, with miR-145 activation emerging as a promising strategy to induce ferroptosis and overcome drug resistance. These findings highlight the MALAT1/miR-145 axis as a transformative therapeutic target, presenting a computational foundation to advance NSCLC treatment strategies.
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MESH Headings
- MicroRNAs/metabolism
- MicroRNAs/genetics
- RNA, Long Noncoding/metabolism
- RNA, Long Noncoding/genetics
- Carcinoma, Non-Small-Cell Lung/metabolism
- Carcinoma, Non-Small-Cell Lung/genetics
- Carcinoma, Non-Small-Cell Lung/drug therapy
- Carcinoma, Non-Small-Cell Lung/pathology
- Humans
- Drug Resistance, Neoplasm
- Ferroptosis
- Lung Neoplasms/metabolism
- Lung Neoplasms/drug therapy
- Lung Neoplasms/genetics
- Lung Neoplasms/pathology
- Apoptosis
- Protein Phosphatase 2C/metabolism
- Protein Phosphatase 2C/genetics
- Models, Biological
- Gene Expression Regulation, Neoplastic
- RNA, Neoplasm/metabolism
- RNA, Neoplasm/genetics
- Neoplasm Proteins/metabolism
- Neoplasm Proteins/genetics
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Affiliation(s)
- Shantanu Gupta
- Department of Computer Science, University of Sao Paulo, Sao Paulo, Brazil
| | | | - José Carlos Mombach
- Department of Physics, Federal University of Santa Maria, Santa Maria, Rio Grande do Sul, Brazil
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2
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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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3
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Liu L, Pang W, Liu J, Xu S, Zhang Z, Hao R, Wan J, Xie W, Tao X, Yang P, Zhao L, Zhai Z, Wang C. Inhibition of heterogeneous nuclear ribonucleoproteins A1 and oxidative stress reduces glycolysis via pyruvate kinase M2 in chronic thromboembolic pulmonary hypertension. J Transl Int Med 2024; 12:437-451. [PMID: 39360158 PMCID: PMC11444468 DOI: 10.2478/jtim-2022-0051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/19/2023] Open
Abstract
Background and Objective Chronic thromboembolic pulmonary hypertension (CTEPH) is a lethal complication of pulmonary embolism involving pulmonary artery occlusion and microvascular disease. The glucose metabolism and reactive oxygen species (ROS) production may be perturbed in CTEPH, but the precise mechanisms are unclear. This study investigated glucose metabolism in CTEPH employing pulmonary endarterectomy (PEA)-derived pulmonary artery smooth muscle cells (PASMCs) and characterized the roles of pyruvate kinase M2 (PKM2) and its regulation by heterogeneous nuclear ribonucleoproteins A1 (hnRNPA1) and ROS in CTEPH. Methods PEA tissues and blood samples of CTEPH patients were collected to study the levels of PKM2. Primary PASMCs were isolated from PEA tissues. We used small interfering RNAs to knock down PKM2 and hnRNPAI, and applied antioxidant N-acetylcysteine (NAC) and mito-TEMPO to reduce ROS production. The expression of glucometabolic genes, ROS production, glycolysis rate and proliferative and migratory activities were analyzed in PEA-derived PASMCs. Results PKM2 levels in serum and PEA tissues of CTEPH patients were higher than that of the healthy controls. Compared to the control PASMCs, PEA-derived PASMCs showed increased PKM2 expression and ROS production. The rates of glycolysis, proliferation and migration were increased in PEA-PASMCs and could be mitigated by PKM2 downregulation through hnRNPA1 or ROS inhibition. Conclusions Increased glycolysis and PKM2 expression were found in PEA-PASMCs. Inhibition of hnRNPA1 or ROS corrected the aberrant glycolysis, cell proliferation and migration by downregulating PKM2. Regulation of the hnRNPA1/PKM2 axis represents a potential therapeutic target for the treatment of CTEPH.
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Affiliation(s)
- Lianhua Liu
- Department of Pulmonary and Critical Care Medicine, Peking University China-Japan Friendship School of Clinical Medicine, Beijing 100029, China
- Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing 100029, China
- Department of Pulmonary and Critical Care Medicine, Beijing Jishuitan Hospital, Beijing 100035, China
| | - Wenyi Pang
- Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing 100029, China
- Department of Pulmonary and Critical Care Medicine, Beijing Jishuitan Hospital, Beijing 100035, China
- Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Jixiang Liu
- Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing 100029, China
- Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Shiqing Xu
- Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing 100029, China
- National Center for Respiratory Medicine, Beijing 100029, China
| | - Zhu Zhang
- Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing 100029, China
- National Center for Respiratory Medicine, Beijing 100029, China
- Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing 100029, China
- National Clinical Research Center for Respiratory Diseases, Beijing 100029, China
| | - Risheng Hao
- Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing 100029, China
| | - Jun Wan
- Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing 100029, China
- National Center for Respiratory Medicine, Beijing 100029, China
- National Clinical Research Center for Respiratory Diseases, Beijing 100029, China
- Department of Pulmonary and Critical Care Medicine, Beijing Anzhen Hospital, Beijing 100029, China
| | - Wanmu Xie
- Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing 100029, China
- National Center for Respiratory Medicine, Beijing 100029, China
- National Clinical Research Center for Respiratory Diseases, Beijing 100029, China
| | - Xincao Tao
- Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing 100029, China
- Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing 100029, China
- National Clinical Research Center for Respiratory Diseases, Beijing 100029, China
| | - Peiran Yang
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, China
| | - Lan Zhao
- National Heart and Lung Institute (NHLI), Imperial College London, Hammersmith Hospital, London W12 0HS, UK
| | - Zhenguo Zhai
- Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing 100029, China
- Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
- National Center for Respiratory Medicine, Beijing 100029, China
- Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing 100029, China
- National Clinical Research Center for Respiratory Diseases, Beijing 100029, China
| | - Chen Wang
- Department of Pulmonary and Critical Care Medicine, Peking University China-Japan Friendship School of Clinical Medicine, Beijing 100029, China
- Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing 100029, China
- National Center for Respiratory Medicine, Beijing 100029, China
- Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing 100029, China
- National Clinical Research Center for Respiratory Diseases, Beijing 100029, China
- Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, China
- Department of Respiratory Medicine, Capital Medical University, Beijing 100069, China
- WHO Collaboration Center for Tobacco Cessation and Respiratory Diseases Prevention, Beijing 100029, China
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4
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Ni X, Lu CP, Xu GQ, Ma JJ. Transcriptional regulation and post-translational modifications in the glycolytic pathway for targeted cancer therapy. Acta Pharmacol Sin 2024; 45:1533-1555. [PMID: 38622288 PMCID: PMC11272797 DOI: 10.1038/s41401-024-01264-1] [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: 10/19/2023] [Accepted: 03/08/2024] [Indexed: 04/17/2024]
Abstract
Cancer cells largely rely on aerobic glycolysis or the Warburg effect to generate essential biomolecules and energy for their rapid growth. The key modulators in glycolysis including glucose transporters and enzymes, e.g. hexokinase 2, enolase 1, pyruvate kinase M2, lactate dehydrogenase A, play indispensable roles in glucose uptake, glucose consumption, ATP generation, lactate production, etc. Transcriptional regulation and post-translational modifications (PTMs) of these critical modulators are important for signal transduction and metabolic reprogramming in the glycolytic pathway, which can provide energy advantages to cancer cell growth. In this review we recapitulate the recent advances in research on glycolytic modulators of cancer cells and analyze the strategies targeting these vital modulators including small-molecule inhibitors and microRNAs (miRNAs) for targeted cancer therapy. We focus on the regulation of the glycolytic pathway at the transcription level (e.g., hypoxia-inducible factor 1, c-MYC, p53, sine oculis homeobox homolog 1, N6-methyladenosine modification) and PTMs (including phosphorylation, methylation, acetylation, ubiquitination, etc.) of the key regulators in these processes. This review will provide a comprehensive understanding of the regulation of the key modulators in the glycolytic pathway and might shed light on the targeted cancer therapy at different molecular levels.
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Affiliation(s)
- Xuan Ni
- Department of Pharmacy, The Fourth Affiliated Hospital of Soochow University, Suzhou Dushu Lake Hospital, Medical Center of Soochow University, Suzhou, 215123, China
| | - Cheng-Piao Lu
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou Key Laboratory of Drug Research for Prevention and Treatment of Hyperlipidemic Diseases, Soochow University, Suzhou, 215123, China
| | - Guo-Qiang Xu
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou Key Laboratory of Drug Research for Prevention and Treatment of Hyperlipidemic Diseases, Soochow University, Suzhou, 215123, China.
- Suzhou International Joint Laboratory for Diagnosis and Treatment of Brain Diseases, College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China.
- MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Medical College of Soochow University, Suzhou, 215123, China.
| | - Jing-Jing Ma
- Department of Pharmacy, The Fourth Affiliated Hospital of Soochow University, Suzhou Dushu Lake Hospital, Medical Center of Soochow University, Suzhou, 215123, China.
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Xiao X, Li C, Huang X, Chen G, Huang X, Song F, Zhou Y, Liu X, Zhou X, Meng J, Bellou A, Zhong L, Li X. Single-cell RNA sequencing reveals that NRF2 regulates vascular smooth muscle cell phenotypic switching in abdominal aortic aneurysm. FASEB J 2024; 38:e23707. [PMID: 38995239 DOI: 10.1096/fj.202400001rr] [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: 01/01/2024] [Revised: 05/10/2024] [Accepted: 05/15/2024] [Indexed: 07/13/2024]
Abstract
Abdominal aortic aneurysm (AAA) is a life-threatening disease characterized by extensive membrane destruction in the vascular wall that is closely associated with vascular smooth muscle cell (VSMC) phenotypic switching. A thorough understanding of the changes in regulatory factors during VSMC phenotypic switching is essential for managing AAA therapy. In this study, we revealed the impact of NRF2 on the modulation of VSMC phenotype and the development of AAA based on single-cell RNA sequencing analysis. By utilizing a murine model of VSMC-specific knockout of nuclear factor E2-related factor 2 (NRF2), we observed that the absence of NRF2 in VSMCs exacerbated AAA formation in an angiotensin II-induced AAA model. The downregulation of NRF2 promoted VSMC phenotypic switching, leading to an enhanced inflammatory response. Through genome-wide transcriptome analysis and loss- or gain-of-function experiments, we discovered that NRF2 upregulated the expression of VSMC contractile phenotype-specific genes by facilitating microRNA-145 (miR-145) expression. Our data identified NRF2 as a novel regulator involved in maintaining the VSMC contractile phenotype while also influencing AAA formation through an miR-145-dependent regulatory mechanism.
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MESH Headings
- Aortic Aneurysm, Abdominal/metabolism
- Aortic Aneurysm, Abdominal/genetics
- Aortic Aneurysm, Abdominal/pathology
- Aortic Aneurysm, Abdominal/chemically induced
- Animals
- NF-E2-Related Factor 2/metabolism
- NF-E2-Related Factor 2/genetics
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/pathology
- Mice
- MicroRNAs/genetics
- MicroRNAs/metabolism
- Male
- Myocytes, Smooth Muscle/metabolism
- Myocytes, Smooth Muscle/pathology
- Phenotype
- Mice, Knockout
- Single-Cell Analysis
- Mice, Inbred C57BL
- Angiotensin II/pharmacology
- Sequence Analysis, RNA
- Disease Models, Animal
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Affiliation(s)
- Xiaoyong Xiao
- Department of Emergency Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Chenglin Li
- Department of Emergency Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Xiaojia Huang
- Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Guona Chen
- Department of Emergency Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Xiaoran Huang
- Department of Emergency Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Feier Song
- Department of Emergency Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Yu Zhou
- Division of Vascular Surgery, National-Local Joint Engineering Laboratory of Vascular Disease Treatment, Engineering and Technology Center for Diagnosis and Treatment of Vascular Diseases, Guangdong Engineering Laboratory of Diagnosis and Treatment of Vascular Disease, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Xincheng Liu
- Department of Emergency Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Xueke Zhou
- School of Medicine, South China University of Technology, Guangzhou, China
| | - Jinxiu Meng
- Department of Emergency Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Abdelouahab Bellou
- Department of Emergency Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Lintao Zhong
- Department of Cardiovascular Medicine Department, Zhuhai People's Hospital, Zhuhai, China
| | - Xin Li
- Department of Emergency Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
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Abolhasanzadeh N, Sarabandi S, Dehghan B, Karamad V, Avci CB, Shademan B, Nourazarian A. Exploring the intricate relationship between miRNA dysregulation and breast cancer development: insights into the impact of environmental chemicals. Front Immunol 2024; 15:1333563. [PMID: 38807590 PMCID: PMC11130376 DOI: 10.3389/fimmu.2024.1333563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Accepted: 04/03/2024] [Indexed: 05/30/2024] Open
Abstract
Breast cancer stands as the most prevalent form of cancer among women globally, influenced by a combination of genetic and environmental factors. Recent studies have investigated changes in microRNAs (miRNAs) during breast cancer progression and the potential impact of environmental chemicals on miRNA expression. This review aims to provide an updated overview of miRNA alterations in breast cancer and to explore their potential association with environmental chemicals. We will discuss the current knowledge on dysregulated miRNAs in breast cancer, including both upregulated and downregulated miRNAs. Additionally, we will review the influence of environmental chemicals, such as endocrine-disrupting compounds, heavy metals, and air pollutants, on miRNA expression and their potential contribution to breast cancer development. This review aims to advance our understanding of the complex molecular mechanisms underlying miRNA dysregulation in breast cancer by comprehensively examining miRNA alterations and their association with environmental chemicals. This knowledge is crucial for the development of targeted therapies and preventive measures. Furthermore, identifying specific miRNAs affected by environmental chemicals may allow the prediction of individual susceptibility to breast cancer and the design of personalized intervention strategies.
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Affiliation(s)
- Narges Abolhasanzadeh
- Department of Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Sajed Sarabandi
- Department of Computer Science Leiden University, Leiden, Netherlands
| | - Bahar Dehghan
- Department of Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Vahidreza Karamad
- Department of Medical Biology, Ege University Medical School, Izmir, Türkiye
| | - Cigir Biray Avci
- Department of Medical Biology, Ege University Medical School, Izmir, Türkiye
| | - Behrouz Shademan
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Alireza Nourazarian
- Department of Basic Medical Sciences, Khoy University of Medical Sciences, Khoy, Iran
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7
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Armstrong L, Willoughby CE, McKenna DJ. The Suppression of the Epithelial to Mesenchymal Transition in Prostate Cancer through the Targeting of MYO6 Using MiR-145-5p. Int J Mol Sci 2024; 25:4301. [PMID: 38673886 PMCID: PMC11050364 DOI: 10.3390/ijms25084301] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 04/09/2024] [Accepted: 04/11/2024] [Indexed: 04/28/2024] Open
Abstract
Aberrant expression of miR-145-5p has been observed in prostate cancer where is has been suggested to play a tumor suppressor role. In other cancers, miR-145-5p acts as an inhibitor of epithelial-to-mesenchymal transition (EMT), a key molecular process for tumor progression. However, the interaction between miR-145-5p and EMT remains to be elucidated in prostate cancer. In this paper the link between miR-145-5p and EMT in prostate cancer was investigated using a combination of in silico and in vitro analyses. miR-145-5p expression was significantly lower in prostate cancer cell lines compared to normal prostate cells. Bioinformatic analysis of The Cancer Genome Atlas prostate adenocarcinoma (TCGA PRAD) data showed significant downregulation of miR-145-5p in prostate cancer, correlating with disease progression. Functional enrichment analysis significantly associated miR-145-5p and its target genes with EMT. MYO6, an EMT-associated gene, was identified and validated as a novel target of miR-145-5p in prostate cancer cells. In vitro manipulation of miR-145-5p levels significantly altered cell proliferation, clonogenicity, migration and expression of EMT-associated markers. Additional TCGA PRAD analysis suggested miR-145-5p tumor expression may be useful predictor of disease recurrence. In summary, this is the first study to report that miR-145-5p may inhibit EMT by targeting MYO6 in prostate cancer cells. The findings suggest miR-145-5p could be a useful diagnostic and prognostic biomarker for prostate cancer.
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Affiliation(s)
| | | | - Declan J. McKenna
- Genomic Medicine Research Group, Ulster University, Cromore Road, Coleraine BT52 1SA, UK; (L.A.); (C.E.W.)
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8
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Gupta S, Silveira DA, Piedade GP, Ostrowski MP, Mombach JCM, Hashimoto RF. A dynamic Boolean network reveals that the BMI1 and MALAT1 axis is associated with drug resistance by limiting miR-145-5p in non-small cell lung cancer. Noncoding RNA Res 2024; 9:185-193. [PMID: 38125755 PMCID: PMC10730431 DOI: 10.1016/j.ncrna.2023.10.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 10/17/2023] [Accepted: 10/18/2023] [Indexed: 12/23/2023] Open
Abstract
Patients with non-small cell lung cancer (NSCLC) are often treated with chemotherapy. Poor clinical response and the onset of chemoresistance limit the anti-tumor benefits of drugs such as cisplatin. According to recent research, metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a long non-coding RNA related to cisplatin resistance in NSCLC. Furthermore, MALAT1 targets microRNA-145-5p (miR-145), which activates Krüppel-like factor 4 (KLF4) in associated cell lines. B lymphoma Mo-MLV insertion region 1 homolog (BMI1), on the other hand, inhibits miR-145 expression, which stimulates Specificity protein 1 (Sp1) to trigger the epithelial-mesenchymal transition (EMT) process in pemetrexed-resistant NSCLC cells. The interplay between these molecules in drug resistance is still unclear. Therefore, we propose a dynamic Boolean network that can encapsulate the complexity of these drug-resistant molecules. Using published clinical data for gain or loss-of-function perturbations, our network demonstrates reasonable agreement with experimental observations. We identify four new positive circuits: miR-145/Sp1/MALAT1, BMI1/miR-145/Myc, KLF4/p53/miR-145, and miR-145/Wip1/p38MAPK/p53. Notably, miR-145 emerges as a central player in these regulatory circuits, underscoring its pivotal role in NSCLC drug resistance. Our circuit perturbation analysis further emphasizes the critical involvement of these new circuits in drug resistance for NSCLC. In conclusion, targeting MALAT1 and BMI1 holds promise for overcoming drug resistance, while activating miR-145 represents a potential strategy to significantly reduce drug resistance in NSCLC.
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Affiliation(s)
- Shantanu Gupta
- Instituto de Matemática e Estatística, Departamento de Ciência da Computação, Universidade de São Paulo, Rua do Matão 1010, 05508-090, São Paulo, SP, Brazil
| | - Daner A. Silveira
- Children's Cancer Institute, Porto Alegre, Rio Grande do Sul, Brazil
| | - Gabriel P.S. Piedade
- Instituto de Matemática e Estatística, Departamento de Ciência da Computação, Universidade de São Paulo, Rua do Matão 1010, 05508-090, São Paulo, SP, Brazil
| | - Miguel P. Ostrowski
- Instituto de Matemática e Estatística, Departamento de Ciência da Computação, Universidade de São Paulo, Rua do Matão 1010, 05508-090, São Paulo, SP, Brazil
| | - José Carlos M. Mombach
- Departamento de Física, Universidade Federal de Santa Maria, Santa Maria, 97105-900, RS, Brazil
| | - Ronaldo F. Hashimoto
- Instituto de Matemática e Estatística, Departamento de Ciência da Computação, Universidade de São Paulo, Rua do Matão 1010, 05508-090, São Paulo, SP, Brazil
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9
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Yildirim BA, Gedikli S, Kordali S, Kucukaydin S. Apoptotic and antiproliferative effects of Inula viscosa L. water extract in the expression of microRnas on HCT 116 cell line: an in vitro study. INTERNATIONAL JOURNAL OF ENVIRONMENTAL HEALTH RESEARCH 2024; 34:1076-1087. [PMID: 36998228 DOI: 10.1080/09603123.2023.2197641] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Accepted: 03/27/2023] [Indexed: 06/19/2023]
Abstract
In this study, the antiproliferative and apoptotic effects of Inula viscosa L. water extract (IVE) on HCT 116 has been examined, and the change in the expression of miRNAs. Phenolic compounds of IVE were determined as µg/g extract using by HPLC-DAD. Quantitative determination of apoptosis, cell viability, IC50 values and miRNAs of the cells were determined during 24, and 48 hours. IVE contain coumarin, rosmarinic acid and chlorogenic acid. According to the findings of our study, the expression of miR-21 and miR-135a1 was upregulated, and miR-145 was downregulated in HCT 116 cells (Control). Additionally, IVE was found to have significant potential in regulating miRNAs, downregulating miR-21, miR-31 and miR-135a1, and upregulating miR-145 in HCT-116 cells. All these results show that the anticancer effect of IVE via regulating miRNAs' expression has been demonstrated for the first time, and may be candidate biomarkers in colorectal cancer.
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Affiliation(s)
| | - Semin Gedikli
- Department of Histology embryology, Veterinary Faculty, Ataturk University, Erzurum, Turkey
| | - Saban Kordali
- Faculty of Agriculture, Department of Plant Protection, Mugla Sitki Kocman University, Fethiye, Mugla, Turkey
| | - Selcuk Kucukaydin
- Department of Medical Services and Techniques, Koycegiz Vocational School of Health Services, Mugla Sitki Kocman University, Fethiye, Mugla, Turkey
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10
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Yan M, Kang W, Liu X, Yang B, Sun N, Yang Y, Wang W. Prognostic value of plasma microRNAs for non-small cell lung cancer based on data mining models. BMC Cancer 2024; 24:52. [PMID: 38200421 PMCID: PMC10777550 DOI: 10.1186/s12885-024-11830-9] [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: 10/11/2023] [Accepted: 01/03/2024] [Indexed: 01/12/2024] Open
Abstract
BACKGROUND As biomarkers, microRNAs (miRNAs) are closely associated with the occurrence, progression, and prognosis of non-small cell lung cancer (NSCLC). However, the prognostic predictive value of miRNAs in NSCLC has rarely been explored. In this study, the value in prognosis prediction of NSCLC was mined based on data mining models using clinical data and plasma miRNAs biomarkers. METHODS A total of 69 patients were included in this prospective cohort study. After informed consent, they filled out questionnaires and had their peripheral blood collected. The expressions of plasma miRNAs were examined by quantitative polymerase chain reaction (qPCR). The Whitney U test was used to analyze non-normally distributed data. Kaplan-Meier was used to plot the survival curve, the log-rank test was used to compare with the overall survival curve, and the Cox proportional hazards model was used to screen the factors related to the prognosis of lung cancer. Data mining techniques were utilized to predict the prognostic status of patients. RESULTS We identified that smoking (HR = 2.406, 95% CI = 1.256-4.611), clinical stage III + IV (HR = 5.389, 95% CI = 2.290-12.684), the high expression group of miR-20a (HR = 4.420, 95% CI = 1.760-11.100), the high expression group of miR-197 (HR = 3.828, 95% CI = 1.778-8.245), the low expression group of miR-145 ( HR = 0.286, 95% CI = 0.116-0.709), and the low expression group of miR-30a (HR = 0.307, 95% CI = 0.133-0.706) was associated with worse prognosis. Among the five data mining models, the decision trees (DT) C5.0 model performs the best, with accuracy and Area Under Curve (AUC) of 93.75% and 0.929 (0.685, 0.997), respectively. CONCLUSION The results showed that the high expression level of miR-20a and miR-197, the low expression level of miR-145 and miR-30a were strongly associated with poorer prognosis in NSCLC patients, and the DT C5.0 model may serve as a novel, accurate, method for predicting prognosis of NSCLC.
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Affiliation(s)
- Mengqing Yan
- Department of Occupational and Environmental Health, College of Public Health, Zhengzhou University, Zhengzhou, China
- The Key Laboratory of Nanomedicine and Health Inspection of Zhengzhou, Zhengzhou University, Zhengzhou, China
| | - Wenjun Kang
- Zhuji People's Hospital of Zhejiang Province, Shaoxing, China
| | - Xiaohua Liu
- Department of Occupational and Environmental Health, College of Public Health, Zhengzhou University, Zhengzhou, China
- The Key Laboratory of Nanomedicine and Health Inspection of Zhengzhou, Zhengzhou University, Zhengzhou, China
| | - Bin Yang
- Department of Occupational and Environmental Health, College of Public Health, Zhengzhou University, Zhengzhou, China
- The Key Laboratory of Nanomedicine and Health Inspection of Zhengzhou, Zhengzhou University, Zhengzhou, China
| | - Na Sun
- Department of Epidemiology and Biostatistics, College of Public Health, Zhengzhou University, Zhengzhou, China
| | - Yongli Yang
- Department of Epidemiology and Biostatistics, College of Public Health, Zhengzhou University, Zhengzhou, China.
| | - Wei Wang
- Department of Occupational and Environmental Health, College of Public Health, Zhengzhou University, Zhengzhou, China.
- The Key Laboratory of Nanomedicine and Health Inspection of Zhengzhou, Zhengzhou University, Zhengzhou, China.
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11
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Jia Q, Cao Y, Zhang M, Xing Y, Xia T, Guo Y, Yue Y, Li X, Liu X, Zhang Y, Li D, Li Z, Tian Y, Kang X, Li H. miR-19b-3p regulated by estrogen controls lipid synthesis through targeting MSMO1 and ELOVL5 in LMH cells. Poult Sci 2024; 103:103200. [PMID: 37939591 PMCID: PMC10665931 DOI: 10.1016/j.psj.2023.103200] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 09/10/2023] [Accepted: 10/12/2023] [Indexed: 11/10/2023] Open
Abstract
miR-19b-3p is reported to undertake various biological role, while its function and action mechanism in chicken hepatic lipid metabolism is unclear. Conservation analysis and tissue expression pattern of miR-19b-3p and its target gene were evaluated, respectively. Dual luciferase reporter system and Western blot technologies were adopted to validate miR-19b-3p target gene. Overexpression and knockdown assays were done to explore the biological functions of miR-19b-3p and target gene in Leghorn Male Hepatoma cell line (LMH). Regulatory approaches of estrogen on miR-19b-3p and target gene expressions are analyzed through site-directed mutation combined with estrogen receptors antagonist treatment assays. The results showed that chicken miR-19b-3p mature sequences are highly conserved among Capra hircus, Columba livia, Rattus norvegicus, Mus musculus, Cricetulus griseus, Danio rerio, Danio novaehollandiae, Orycodylus porosus, Crocodylus porosus, Gadus morhua, and widely expressed in lung, ovary, spleen, duodenum, kidney, heart, liver, leg muscle, and pectoral muscle tissues. miR-19b-3p could significantly increase intracellular triglyceride (TG) content and decrease intracellular cholesterol (TC) content via targeting methylsterol monooxygenase 1 (MSMO1) and elongase of very long chain fatty acids 5 (ELOVL5), which are highly conserved among species, in both mRNA and protein levels. Estrogen could inhibit miR-19b-3p expression, but directly promoted MSMO1 transcription via estrogen receptor α (ERα) and indirectly regulated ELOVL5 expression at the transcription level. Meanwhile, estrogen could also upregulate MSMO1 and ELOVL5 expression through inhibiting miR-19b-3p expression at the post-transcription level. Taken together, these results highlight the role and regulatory mechanism of miR-19b-3p in hepatic lipid metabolism in chicken, and might produce useful comparative information for human obesity studies and biomedical research.
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Affiliation(s)
- Qihui Jia
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China
| | - Yuzhu Cao
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China
| | - Mengmeng Zhang
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China
| | - Yuxin Xing
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China
| | - Tian Xia
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China
| | - Yulong Guo
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China
| | - Yaxin Yue
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China
| | - Xin Li
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China
| | - Xiaojun Liu
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China; Henan Key Laboratory for Innovation and Utilization of Chicken Germplasm Resources, Zhengzhou 450046, China; International Joint Research Laboratory for Poultry Breeding of Henan, Zhengzhou 450046, China
| | - Yanhua Zhang
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China; Henan Key Laboratory for Innovation and Utilization of Chicken Germplasm Resources, Zhengzhou 450046, China; International Joint Research Laboratory for Poultry Breeding of Henan, Zhengzhou 450046, China
| | - Donghua Li
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China; Henan Key Laboratory for Innovation and Utilization of Chicken Germplasm Resources, Zhengzhou 450046, China; International Joint Research Laboratory for Poultry Breeding of Henan, Zhengzhou 450046, China
| | - Zhuanjian Li
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China; Henan Key Laboratory for Innovation and Utilization of Chicken Germplasm Resources, Zhengzhou 450046, China; International Joint Research Laboratory for Poultry Breeding of Henan, Zhengzhou 450046, China
| | - Yadong Tian
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China; Henan Key Laboratory for Innovation and Utilization of Chicken Germplasm Resources, Zhengzhou 450046, China; International Joint Research Laboratory for Poultry Breeding of Henan, Zhengzhou 450046, China
| | - Xiangtao Kang
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China; Henan Key Laboratory for Innovation and Utilization of Chicken Germplasm Resources, Zhengzhou 450046, China; International Joint Research Laboratory for Poultry Breeding of Henan, Zhengzhou 450046, China
| | - Hong Li
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China; Henan Key Laboratory for Innovation and Utilization of Chicken Germplasm Resources, Zhengzhou 450046, China; International Joint Research Laboratory for Poultry Breeding of Henan, Zhengzhou 450046, China.
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12
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Ning Z, Wu J, Ding Y, Wang Y, Peng Q, Fu L. BertNDA: A Model Based on Graph-Bert and Multi-Scale Information Fusion for ncRNA-Disease Association Prediction. IEEE J Biomed Health Inform 2023; 27:5655-5664. [PMID: 37669210 DOI: 10.1109/jbhi.2023.3311808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/07/2023]
Abstract
Non-coding RNAs (ncRNAs) are a class of RNA molecules that lack the ability to encode proteins in human cells, but play crucial roles in various biological process. Understanding the interactions between different ncRNAs and their impact on diseases can significantly contribute to diagnosis, prevention, and treatment of diseases. However, predicting tertiary interactions between ncRNAs and diseases based on structural information in multiple scales remains a challenging task. To address this challenge, we propose a method called BertNDA, aiming to predict potential relationships between miRNAs, lncRNAs, and diseases. The framework identifies the local information through connectionless subgraph, which aggregate neighbor nodes' feature. And global information is extracted by leveraging Laplace transform of graph structures and WL (Weisfeiler-Lehman) absolute role coding. Additionally, an EMLP (Element-wise MLP) structure is designed to fuse pairwise global information. The transformer-encoder is employed as the backbone of our approach, followed by a prediction-layer to output the final correlation score. Extensive experiments demonstrate that BertNDA outperforms state-of-the-art methods in prediction assignment and exhibits significant potential for various biological applications. Moreover, we develop an online prediction platform that incorporates the prediction model, providing users with an intuitive and interactive experience. Overall, our model offers an efficient, accurate, and comprehensive tool for predicting tertiary associations between ncRNAs and diseases.
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13
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Silveira DA, Gupta S, da Cunha Jaeger M, Brunetto de Farias C, Mombach JCM, Sinigaglia M. A logical model of Ewing sarcoma cell epithelial-to-mesenchymal transition supports the existence of hybrid cellular phenotypes. FEBS Lett 2023; 597:2446-2460. [PMID: 37597508 DOI: 10.1002/1873-3468.14724] [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: 07/20/2023] [Accepted: 08/04/2023] [Indexed: 08/21/2023]
Abstract
Ewing sarcoma (ES) is a highly aggressive pediatric tumor driven by the RNA-binding protein EWS (EWS)/friend leukemia integration 1 transcription factor (FLI1) chimeric transcription factor, which is involved in epithelial-mesenchymal transition (EMT). EMT stabilizes a hybrid cell state, boosting metastatic potential and drug resistance. Nevertheless, the mechanisms underlying the maintenance of this hybrid phenotype in ES remain elusive. Our study proposes a logical EMT model for ES, highlighting zinc finger E-box-binding homeobox 2 (ZEB2), miR-145, and miR-200 circuits that maintain hybrid states. The model aligns with experimental findings and reveals a previously unknown circuit supporting the mesenchymal phenotype. These insights emphasize the role of ZEB2 in the maintenance of the hybrid state in ES.
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Affiliation(s)
- Daner A Silveira
- Children's Cancer Institute, Porto Alegre, Brazil
- National Science and Technology Institute for Children's Cancer Biology and Pediatric Oncology - INCT BioOncoPed, Porto Alegre, Brazil
| | | | - Mariane da Cunha Jaeger
- Children's Cancer Institute, Porto Alegre, Brazil
- National Science and Technology Institute for Children's Cancer Biology and Pediatric Oncology - INCT BioOncoPed, Porto Alegre, Brazil
| | - Caroline Brunetto de Farias
- Children's Cancer Institute, Porto Alegre, Brazil
- National Science and Technology Institute for Children's Cancer Biology and Pediatric Oncology - INCT BioOncoPed, Porto Alegre, Brazil
| | | | - Marialva Sinigaglia
- Children's Cancer Institute, Porto Alegre, Brazil
- National Science and Technology Institute for Children's Cancer Biology and Pediatric Oncology - INCT BioOncoPed, Porto Alegre, Brazil
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14
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Roshani M, Molavizadeh D, Sadeghi S, Jafari A, Dashti F, Mirazimi SMA, Ahmadi Asouri S, Rajabi A, Hamblin MR, Anoushirvani AA, Mirzaei H. Emerging roles of miR-145 in gastrointestinal cancers: A new paradigm. Biomed Pharmacother 2023; 166:115264. [PMID: 37619484 DOI: 10.1016/j.biopha.2023.115264] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 07/25/2023] [Accepted: 07/31/2023] [Indexed: 08/26/2023] Open
Abstract
Gastrointestinal (GI) carcinomas are a group of cancers affecting the GI tract and digestive organs, such as the gastric, liver, bile ducts, pancreas, small intestine, esophagus, colon, and rectum. MicroRNAs (miRNAs) are small functional non-coding RNAs (ncRNAs) which are involved in regulating the expression of multiple target genes; mainly at the post-transcriptional level, via complementary binding to their 3'-untranslated region (3'-UTR). Increasing evidence has shown that miRNAs have critical roles in modulating of various physiological and pathological cellular processes and regulating the occurrence and development of human malignancies. Among them, miR-145 is recognized for its anti-oncogenic properties in various cancers, including GI cancers. MiR-145 has been implicated in diverse biological processes of cancers through the regulation of target genes or signaling, including, proliferation, differentiation, tumorigenesis, angiogenesis, apoptosis, metastasis, and therapy resistance. In this review, we have summarized the role of miR-145 in selected GI cancers and also its downstream molecules and cellular processes targets, which could lead to a better understanding of the miR-145 in these cancers. In conclusion, we reveal the potential diagnostic, prognostic, and therapeutic value of miR-145 in GI cancer, and hope to provide new ideas for its application as a biomarker as well as a therapeutic target for the treatment of these cancer.
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Affiliation(s)
- Mohammad Roshani
- Internal Medicine and Gastroenterology, Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Danial Molavizadeh
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran; Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Sara Sadeghi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran; Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Ameneh Jafari
- Proteomics Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fatemeh Dashti
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran; Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Seyed Mohammad Ali Mirazimi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran; Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Sahar Ahmadi Asouri
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for BasicSciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Ali Rajabi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran; Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Michael R Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein, South Africa
| | - Ali Arash Anoushirvani
- Department of Internal Medicine, Firoozgar Hospital, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
| | - Hamed Mirzaei
- Proteomics Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Internal Medicine, Firoozgar Hospital, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
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15
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Raczkowska J, Bielska A, Krętowski A, Niemira M. Extracellular circulating miRNAs as potential non-invasive biomarkers in non-small cell lung cancer patients. Front Oncol 2023; 13:1209299. [PMID: 37546401 PMCID: PMC10401434 DOI: 10.3389/fonc.2023.1209299] [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: 04/20/2023] [Accepted: 06/28/2023] [Indexed: 08/08/2023] Open
Abstract
Non-small cell lung cancer (NSCLC) comprises 85% of all lung cancers and is a malignant condition resistant to advanced-stage treatment. Despite the advancement in detection and treatment techniques, the disease is taking a deadly toll worldwide, being the leading cause of cancer death every year. Current diagnostic methods do not ensure the detection of the disease at an early stage, nor can they predict the risk of its development. There is an urgent need to identify biomarkers that can help predict an individual's risk of developing NSCLC, distinguish NSCLC subtype, allow monitor disease and treatment progression which can improve patient survival. Micro RNAs (miRNAs) represent the class of small and non-coding RNAs involved in gene expression regulation, influencing many biological processes such as proliferation, differentiation, and carcinogenesis. Research reports significant differences in miRNA profiles between healthy and neoplastic tissues in NSCLC. Its abundant presence in biofluids, such as serum, blood, urine, and saliva, makes them easily detectable and does not require invasive collection techniques. Many studies support miRNAs' importance in detecting, predicting, and prognosis of NSCLC, indicating their utility as a promising biomarker. In this work, we reviewed up-to-date research focusing on biofluid miRNAs' role as a diagnostic tool in NSCLC cases. We also discussed the limitations of applying miRNAs as biomarkers and highlighted future areas of interest.
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Affiliation(s)
- Justyna Raczkowska
- Clinical Research Centre, Medical University of Białystok, Białystok, Poland
| | - Agnieszka Bielska
- Clinical Research Centre, Medical University of Białystok, Białystok, Poland
| | - Adam Krętowski
- Clinical Research Centre, Medical University of Białystok, Białystok, Poland
- Department of Endocrinology, Diabetology and Internal Medicine, Medical University of Białystok, Białystok, Poland
| | - Magdalena Niemira
- Clinical Research Centre, Medical University of Białystok, Białystok, Poland
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16
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Fariha A, Hami I, Tonmoy MIQ, Akter S, Al Reza H, Bahadur NM, Rahaman MM, Hossain MS. Cell cycle associated miRNAs as target and therapeutics in lung cancer treatment. Heliyon 2022; 8:e11081. [PMID: 36303933 PMCID: PMC9593298 DOI: 10.1016/j.heliyon.2022.e11081] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2022] [Revised: 08/17/2022] [Accepted: 10/10/2022] [Indexed: 11/06/2022] Open
Abstract
Lung cancer is the primary cause of cancer related deaths worldwide. Limited therapeutic options and resistance to existing drugs are the major hindrances to the clinical success of this cancer. In the past decade, several studies showed the role of microRNA (miRNA) driven cell cycle regulation in lung cancer progression. Therefore, these small nucleotide molecules could be utilized as promising tools in lung cancer therapy. In this review, we highlighted the recent advancements in lung cancer therapy using cell cycle linked miRNAs. By highlighting the roles of the specific cell cycle core regulators affiliated miRNAs in lung cancer, we further outlined how these miRNAs can be explored in early diagnosis and treatment strategies to prevent lung cancer. With the provided information from our review, more medical efforts can ensure a potential breakthrough in miRNA-based lung cancer therapy.
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Affiliation(s)
- Atqiya Fariha
- Department of Biotechnology & Genetic Engineering, Noakhali Science and Technology University, Noakhali, Bangladesh
| | - Ithmam Hami
- Department of Biotechnology & Genetic Engineering, Noakhali Science and Technology University, Noakhali, Bangladesh
| | | | - Shahana Akter
- Department of Biotechnology & Genetic Engineering, Noakhali Science and Technology University, Noakhali, Bangladesh
| | - Hasan Al Reza
- Department of Genetic Engineering and Biotechnology, University of Dhaka, Dhaka, Bangladesh
| | - Newaz Mohammed Bahadur
- Department of Applied Chemistry and Chemical Engineering, Noakhali Science and Technology University, Noakhali, Bangladesh
| | - Md. Mizanur Rahaman
- Department of Microbiology, University of Dhaka, Dhaka, Bangladesh,Corresponding author.
| | - Md Shahadat Hossain
- Department of Biotechnology & Genetic Engineering, Noakhali Science and Technology University, Noakhali, Bangladesh,Corresponding author.
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17
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MicroRNA-143 act as a tumor suppressor microRNA in human lung cancer cells by inhibiting cell proliferation, invasion, and migration. Mol Biol Rep 2022; 49:7637-7647. [PMID: 35717476 DOI: 10.1007/s11033-022-07580-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 04/30/2022] [Accepted: 05/06/2022] [Indexed: 10/18/2022]
Abstract
BACKGROUND/AIM MicroRNAs play crucial roles in controlling cellular biological processes. miR-143 expression is usually downregulated in different cancers. In this study, we focused on exploring the role of miR143 in NSCLC development. METHODS Bioinformatics analyses were used to detect the expression level of miR-143 in lung tumors. The cells were transfected by pCMV-miR-143 vectors. The efficacy of transfection was verified by Flow cytometry. The influence of miR-143 replacement on NSCLC cells migration, proliferation, and apoptosis was detected using wound-healing assay, MTT assay, and DAPI staining, respectively. RESULTS MTT assay revealed that overexpression of miR143 inhibited cell growth and proliferation. Scratch assay results demonstrated that restoration of miR143 suppressed cell migration. The qRT-PCR assay was further used to detect the assumed relationship between miR143 and apoptotic and metastatic-related genes. CONCLUSION The findings showed that miR-143 could reduce cell proliferation, invasion, and migration by reducing CXCR4, Vimentin, MMP-1, Snail-1, C-myc expression level, and increasing E-cadherin expression levels in lung cancer cells and might be a potential target in NSCLC's targeted therapy.
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18
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MiR-145-5p Inhibits the Invasion of Prostate Cancer and Induces Apoptosis by Inhibiting WIP1. JOURNAL OF ONCOLOGY 2021; 2021:4412705. [PMID: 34899906 PMCID: PMC8660234 DOI: 10.1155/2021/4412705] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 10/21/2021] [Accepted: 10/25/2021] [Indexed: 11/26/2022]
Abstract
Prostate cancer (PCa) is a common malignant tumor of the male genitourinary system that seriously affects the quality of life of patients. Studying the pathogenesis and therapeutic targets of PCa is important. In this study, we investigated the role of miR-145-5p in PCa and its potential molecular mechanisms. The expression levels of miR-145-5p in PCa tissues and adjacent control tissues were detected by real-time quantitative polymerase chain reaction. The effects of miR-145-5p overexpression on PCa were studied using cell proliferation, migration, and invasion experiments. Furthermore, WIP1 was the target gene of miR-145-5p through the bioinformatics website and dual-luciferase reporter gene experiment. Further studies found that WIP1 downregulation could inhibit the proliferation, invasion, and cloning of PCa cells. Overexpression of WIP1 reversed the anticancer effects of miR-145. The anticancer effect of miR-145 was achieved by inhibiting the PI3K/AKT signaling pathway and upregulating ChK2 and p-p38MAPK. Taken together, these results confirmed that miR-145-5p inhibited the growth and metastasis of PCa cells by inhibiting the expression of proto-oncogene WIP1, thereby playing a role in tumor suppression in PCa and may become a potential therapeutic target for the treatment of PCa.
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Geater SL, Chaniad P, Trakunram K, Keeratichananont W, Buya S, Thongsuksai P, Raungrut P. Diagnostic and prognostic value of serum miR-145 and vascular endothelial growth factor in non-small cell lung cancer. Oncol Lett 2021; 23:12. [PMID: 34820011 PMCID: PMC8607352 DOI: 10.3892/ol.2021.13130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Accepted: 10/12/2021] [Indexed: 11/06/2022] Open
Abstract
Previous studies have reported the diagnostic and prognostic value of serum microRNA (miR)-145 and vascular endothelial growth factor (VEGF) levels in various types of cancer; however, their clinical use in non-small cell lung cancer (NSCLC) remains unclear. The present study included 215 patients, 106 with NSCLC and 109 with other lung diseases (OLDs). miR-145 expression levels were determined using reverse transcription-quantitative PCR (RT-qPCR) and VEGF levels were measured using an ELISA. The diagnostic performance was assessed using a receiver operating characteristic curve and area under the curve (AUC) analysis. A Kaplan-Meier survival curve and Cox regression analysis were employed to evaluate the prognostic significance of the markers. The biological function of miR-145 was examined in A549 and H1792 cell lines. The effects of miR-145 on cell proliferation of NSCLC cells were evaluated by flow cytometry, and the expression levels of miR-145 and cell cycle-related genes were determined by RT-qPCR. The results revealed that miR-145 and VEGF exhibited fair diagnostic performance [AUC, 0.61 (95% CI, 0.55-0.68) and AUC, 0.64 (95% CI, 0.57-0.71), respectively]. Combining age and smoking status with miR-145 and VEGF provided the best model for differentiating patients with NSCLC from those with OLDs (AUC, 0.76; 95% CI, 0.69-0.83). Furthermore, low serum miR-145 levels were associated with poor overall survival [hazard ratio (HR), 0.48; 95% CI, 0.27-0.85], whereas high VEGF levels were not associated with poor overall survival (HR, 1.47; 95% CI, 0.81-2.68). In addition, the results of the in vitro experiments indicated that miR-145 decreased cell proliferation via the induction of cell cycle arrest. In conclusion, the findings of the present study suggested that combining miR-145 and VEGF levels with clinical risk factors may be a potential diagnostic scheme for NSCLC. In addition, serum miR-145 may be used as a prognostic marker. These results indicated that miR-145 may function as a tumor suppressor in NSCLC.
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Affiliation(s)
- Sarayut Lucien Geater
- Department of Internal Medicine, Songklanagarind Hospital, Faculty of Medicine, Prince of Songkla University, Songkhla 90110, Thailand
| | - Pichitpon Chaniad
- Department of Biomedical Sciences and Biomedical Engineering, Songklanagarind Hospital, Faculty of Medicine, Prince of Songkla University, Songkhla 90110, Thailand
| | - Keson Trakunram
- Department of Biomedical Sciences and Biomedical Engineering, Songklanagarind Hospital, Faculty of Medicine, Prince of Songkla University, Songkhla 90110, Thailand
| | - Warangkana Keeratichananont
- Department of Internal Medicine, Songklanagarind Hospital, Faculty of Medicine, Prince of Songkla University, Songkhla 90110, Thailand
| | - Suhaimee Buya
- Medical Data Center for Research and Innovation, Songklanagarind Hospital, Faculty of Medicine, Prince of Songkla University, Songkhla 90110, Thailand
| | - Paramee Thongsuksai
- Department of Pathology, Songklanagarind Hospital, Faculty of Medicine, Prince of Songkla University, Songkhla 90110, Thailand
| | - Pritsana Raungrut
- Department of Biomedical Sciences and Biomedical Engineering, Songklanagarind Hospital, Faculty of Medicine, Prince of Songkla University, Songkhla 90110, Thailand
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Daks A, Shuvalov O, Fedorova O, Petukhov A, Lezina L, Zharova A, Baidyuk E, Khudiakov A, Barlev NA. p53-Independent Effects of Set7/9 Lysine Methyltransferase on Metabolism of Non-Small Cell Lung Cancer Cells. Front Oncol 2021; 11:706668. [PMID: 34692483 PMCID: PMC8528242 DOI: 10.3389/fonc.2021.706668] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Accepted: 09/14/2021] [Indexed: 11/13/2022] Open
Abstract
Set7/9 is a lysine-specific methyltransferase, which regulates the functioning of both the histone and non-histone substrates, thereby significantly affecting the global gene expression landscape. Using microarray expression profiling, we have identified several key master regulators of metabolic networks, including c-Myc, that were affected by Set7/9 status. Consistent with this observation, c-Myc transcriptional targets-genes encoding the glycolytic enzymes hexokinase (HK2), aldolase (ALDOB), and lactate dehydrogenase (LDHA)-were upregulated upon Set7/9 knockdown (Set7/9KD). Importantly, we showed the short hairpin RNA (shRNA)-mediated attenuation of Set7/9 augmented c-Myc, GLUT1, HK2, ALDOA, and LDHA expression in non-small cell lung cancer (NSCLC) cell lines, not only at the transcriptional but also at the protein level. In line with this observation, Set7/9KD significantly augmented the membrane mitochondrial potential (MMP), glycolysis, respiration, and the proliferation rate of NSCLC cells. Importantly, all these effects of Set7/9 on cell metabolism were p53-independent. Bioinformatic analysis has shown a synergistic impact of Set7/9 together with either GLUT1, HIF1A, HK2, or LDHA on the survival of lung cancer patients. Based on these evidence, we hypothesize that Set7/9 can be an important regulator of energy metabolism in NSCLC.
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Affiliation(s)
- Alexandra Daks
- Institute of Cytology, Russian Academy of Sciences, St Petersburg, Russia
| | - Oleg Shuvalov
- Institute of Cytology, Russian Academy of Sciences, St Petersburg, Russia
| | - Olga Fedorova
- Institute of Cytology, Russian Academy of Sciences, St Petersburg, Russia
| | - Alexey Petukhov
- Institute of Cytology, Russian Academy of Sciences, St Petersburg, Russia.,Institute of Molecular Biology and Genetics, Almazov National Medical Research Centre, St Petersburg, Russia
| | - Larissa Lezina
- Regulation of Cell Signaling Laboratory, Moscow Institute of Physics and Technology, Dolgoprudny, Russia
| | - Arsenia Zharova
- Institute of Cytology, Russian Academy of Sciences, St Petersburg, Russia
| | - Ekaterina Baidyuk
- Institute of Cytology, Russian Academy of Sciences, St Petersburg, Russia
| | - Alexander Khudiakov
- Institute of Molecular Biology and Genetics, Almazov National Medical Research Centre, St Petersburg, Russia
| | - Nickolai A Barlev
- Institute of Cytology, Russian Academy of Sciences, St Petersburg, Russia.,Regulation of Cell Signaling Laboratory, Moscow Institute of Physics and Technology, Dolgoprudny, Russia
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21
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Tuo Z, Liang L, Zhou R. LINC00852 is associated with poor prognosis in non-small cell lung cancer patients and its inhibition suppresses cancer cell proliferation and chemoresistance via the hsa-miR-145-5p/KLF4 axis. J Gene Med 2021; 23:e3384. [PMID: 34342374 DOI: 10.1002/jgm.3384] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 07/28/2021] [Accepted: 07/29/2021] [Indexed: 11/11/2022] Open
Abstract
BACKGROUND Emerging evidence shows that long non-coding RNAs (lncRNAs) play important roles in human cancer. In the present study, we examined the expression, prognostic implications and functional roles of a lncRNA, LINC00852 in non-small cell lung cancer (NSCLC). METHODS LINC00852 expression was examined by quantitative real-time PCR (qRT-PCR) in both NSCLC clinical samples and in vitro NSCLC cell lines. In patients with NSCLC, postoperative overall survival was estimated according to endogenous LINC00852 expression in their cancerous lung tissues. In NSCLC cell line SW900 and H441 cells, LINC00852 was down-regulated to examine its effects on cancer proliferation, cisplatin chemoresistance and cell-cycle transition in vitro, as well as tumorigenicity in vivo. The potential downstream target of LINC00852, the axis of human microRNA-145-5p (hsa-miR-145-5p) and Kruppel-like factor 4 (KLF4) gene, was investigated in NSCLC, by dual-luciferase assay, qRT-PCR and genetic knockdown functional assays. RESULTS LINC00852 is up-regulated in both NSCLC tumors and NSCLC cell lines. High LINC00852 expression was significantly correlated with NSCLC patients' short overall survival. In NSCLC cell lines, LINC00852 down-regulation had anti-cancer effects by suppressing cancer cell proliferation, cisplatin chemoresistance and cell-cycle transition in vitro, as well as explant growth in vivo. Moreover, the hsa-miR-145-5p/KLF4 axis was demonstrated to be directly regulated by LINC00852 in NSCLC. Inhibiting hsa-miR-145-5p or overexpressing KLF4 could reverse the LINC00852-down-regulation-induced anti-cancer effects on NSCLC cancer cell proliferation and chemoresistance. CONCLUSIONS LINC00852 may be a prognostic biomarker for NSCLC. The epigenetic signaling pathway of LINC00852/hsa-miR-145-5p/KLF4 may be considered as a novel molecular target for fighting NSCLC.
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Affiliation(s)
- Zineng Tuo
- Department of Respiratory Medicine, Gaozhou People's Hospital, Maoming, Guangdong Province, China
| | - Li Liang
- Department of Respiratory Medicine, Gaozhou People's Hospital, Maoming, Guangdong Province, China
| | - Rongmei Zhou
- Department of Respiratory Medicine, Gaozhou People's Hospital, Maoming, Guangdong Province, China
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22
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The Role of Non-Coding RNAs in the Regulation of the Proto-Oncogene MYC in Different Types of Cancer. Biomedicines 2021; 9:biomedicines9080921. [PMID: 34440124 PMCID: PMC8389562 DOI: 10.3390/biomedicines9080921] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Revised: 07/25/2021] [Accepted: 07/28/2021] [Indexed: 01/17/2023] Open
Abstract
Alterations in the expression level of the MYC gene are often found in the cells of various malignant tumors. Overexpressed MYC has been shown to stimulate the main processes of oncogenesis: uncontrolled growth, unlimited cell divisions, avoidance of apoptosis and immune response, changes in cellular metabolism, genomic instability, metastasis, and angiogenesis. Thus, controlling the expression of MYC is considered as an approach for targeted cancer treatment. Since c-Myc is also a crucial regulator of many cellular processes in healthy cells, it is necessary to find ways for selective regulation of MYC expression in tumor cells. Many recent studies have demonstrated that non-coding RNAs play an important role in the regulation of the transcription and translation of this gene and some RNAs directly interact with the c-Myc protein, affecting its stability. In this review, we summarize current data on the regulation of MYC by various non-coding RNAs that can potentially be targeted in specific tumor types.
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23
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Amri J, Molaee N, Karami H, Baazm M. Combination of two miRNAs has a stronger effect on stimulating apoptosis, inhibiting cell growth, and increasing erlotinib sensitivity relative to single miRNA in A549 lung cancer cells. Biotechnol Appl Biochem 2021; 69:1383-1394. [PMID: 34081797 DOI: 10.1002/bab.2211] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 05/27/2021] [Indexed: 12/15/2022]
Abstract
Despite the dramatic efficacy of EGFR-TKIs, most of non-small cell lung cancer patients ultimately develop resistance to these agents. In this study, we explored the effects of miRNA-125a-5p and miRNA-145, alone or in combination, EGFR expression, cell growth and sensitivity of the NSCLC cells to erlotinib. The expression of EGFR was measured using RT-qPCR and Western blotting. The effect of miRNAs and erlotinib on cell growth and survival was assessed by trypan blue assay and MTT assay, respectively. Apoptosis was measured using ELISA cell death assay. We found that transfection of miRNA-125a-5p and miRNA-145 significantly inhibited the expression of EGFR mRNA and protein in a time-dependent manner (p < 0.05 vs. blank control or negative control miRNA). ANOVA and Bonferroni's test were used to ascertain significant differences between groups. Other experiments indicated that upregulation of each of miRNA-125a-5p or miRNA-145 inhibited cell growth, induced apoptosis, and markedly decreased the IC50 value of erlotinib in A549 lung cancer cells (p < 0.05). Moreover, the combination of two miRNAs showed a stronger effect on cells survival, apoptosis, and drug sensitivity, relative to single miRNA (p < 0.05). The results of our study indicate that the therapeutic delivery of miRNA-145 and miRNA-125a-5p to lung cancer may inhibit cell proliferation, trigger apoptosis, and sensitize lung cancer cells to EGFR-TKIs.
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Affiliation(s)
- Jamal Amri
- Traditional and Complementary Medicine Research Center, Arak University of Medical Sciences, Sardasht Street, Arak, Iran.,Students' Scientific Research Center (SSRC), Tehran University of Medical Sciences, Tehran, Iran.,Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Neda Molaee
- Department of Molecular Medicine and Biotechnology, Faculty of Medicine, Arak University of Medical Sciences, Sardasht Street, Arak, Iran
| | - Hadi Karami
- Traditional and Complementary Medicine Research Center, Arak University of Medical Sciences, Sardasht Street, Arak, Iran.,Department of Molecular Medicine and Biotechnology, Faculty of Medicine, Arak University of Medical Sciences, Sardasht Street, Arak, Iran
| | - Maryam Baazm
- Department of Anatomy, Faculty of Medicine, Arak University of Medical Sciences, Arak, Iran
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24
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Chianese A, Santella B, Ambrosino A, Stelitano D, Rinaldi L, Galdiero M, Zannella C, Franci G. Oncolytic Viruses in Combination Therapeutic Approaches with Epigenetic Modulators: Past, Present, and Future Perspectives. Cancers (Basel) 2021; 13:cancers13112761. [PMID: 34199429 PMCID: PMC8199618 DOI: 10.3390/cancers13112761] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2021] [Revised: 05/28/2021] [Accepted: 05/29/2021] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Cancer rates have been accelerating significantly in recent years. Despite notable advances having been made in cancer therapy, and numerous studies being currently conducted in clinical trials, research is always looking for new treatment. Novel and promising anticancer therapies comprise combinations of oncolytic viruses and epigenetic modulators, including chromatin modifiers, such as DNA methyltransferase and histone deacetylases, and microRNA. Combinatorial treatments have several advantages: they enhance viral entry, replication, and spread between proximal cells and, moreover, they strengthen the immune response. In this review we summarize the main combination of therapeutic approaches, giving an insight into past, present, and future perspectives. Abstract According to the World Cancer Report, cancer rates have been increased by 50% with 15 million new cases in the year 2020. Hepatocellular carcinoma (HCC) is the only one of the most common tumors to cause a huge increase in mortality with a survival rate between 40% and 70% at 5 years, due to the high relapse and limitations associated with current therapies. Despite great progress in medicine, oncological research is always looking for new therapies: different technologies have been evaluated in clinical trials and others have been already used in clinics. Among them, oncolytic virotherapy represents a therapeutic option with a widespread possibility of approaches and applications. Oncolytic viruses are naturally occurring, or are engineered, viruses characterized by the unique features of preferentially infecting, replicating, and lysing malignant tumor cells, as well as activating the immune response. The combination of oncolytic virotherapy and chemical drugs are arousing great interest in the tumor treatment. In this scenario, novel and promising anticancer therapies comprise combinations of oncolytic viruses and epigenetic modulators or inhibitors of the signalling pathways. Combination treatments are required to improve the immune response and allow viral entry, replication, and diffusion between proximal cells. In this review, we summarize all combination therapies associated with virotherapy, including co-administered inhibitors of chromatin modifiers (combination strategies) and inserted target sites for miRNAs (recombination or arming strategies).
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Affiliation(s)
- Annalisa Chianese
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (A.C.); (A.A.); (D.S.); (M.G.)
| | - Biagio Santella
- Section of Microbiology and Virology, University Hospital “Luigi Vanvitelli”, 80138 Naples, Italy;
| | - Annalisa Ambrosino
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (A.C.); (A.A.); (D.S.); (M.G.)
| | - Debora Stelitano
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (A.C.); (A.A.); (D.S.); (M.G.)
| | - Luca Rinaldi
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy;
| | - Massimiliano Galdiero
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (A.C.); (A.A.); (D.S.); (M.G.)
- Section of Microbiology and Virology, University Hospital “Luigi Vanvitelli”, 80138 Naples, Italy;
| | - Carla Zannella
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (A.C.); (A.A.); (D.S.); (M.G.)
- Correspondence: (C.Z.); (G.F.)
| | - Gianluigi Franci
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, 84081 Baronissi, Italy
- Correspondence: (C.Z.); (G.F.)
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25
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Cohn DE, Barros-Filho MC, Minatel BC, Pewarchuk ME, Marshall EA, Vucic EA, Sage AP, Telkar N, Stewart GL, Jurisica I, Reis PP, Robinson WP, Lam WL. Reactivation of Multiple Fetal miRNAs in Lung Adenocarcinoma. Cancers (Basel) 2021; 13:2686. [PMID: 34072436 PMCID: PMC8199175 DOI: 10.3390/cancers13112686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 05/25/2021] [Accepted: 05/26/2021] [Indexed: 11/16/2022] Open
Abstract
MicroRNAs (miRNAs) play vital roles in the regulation of normal developmental pathways. However, cancer cells can co-opt these miRNAs, and the pathways that they regulate, to drive pro-tumourigenic phenotypes. Characterization of the miRNA transcriptomes of fetal organs is essential for identifying these oncofetal miRNAs, but it has been limited by fetal sample availability. As oncofetal miRNAs are absent from healthy adult lungs, they represent ideal targets for developing diagnostic and therapeutic strategies. We conducted small RNA sequencing of a rare collection of 25 human fetal lung (FL) samples and compared them to two independent cohorts (n = 140, n = 427), each comprised of adult non-neoplastic lung (ANL) and lung adenocarcinoma (LUAD) samples. We identified 13 oncofetal miRNAs that were expressed in FL and LUAD but not in ANL. These oncofetal miRNAs are potential biomarkers for LUAD detection (AUC = 0.963). Five of these miRNAs are derived from the imprinted C14MC miRNA cluster at the 14q32 locus, which has been associated with cancer development and abnormal fetal and placental development. Additionally, we observed the pulmonary expression of 44 previously unannotated miRNAs. The sequencing of these fetal lung samples also provides a baseline resource against which aberrant samples can be compared.
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Affiliation(s)
- David E. Cohn
- British Columbia Cancer Research Centre, Vancouver, BC V5Z 1L3, Canada; (M.C.B.-F.); (B.C.M.); (M.E.P.); (E.A.M.); (E.A.V.); (A.P.S.); (N.T.); (G.L.S.); (W.L.L.)
| | - Mateus C. Barros-Filho
- British Columbia Cancer Research Centre, Vancouver, BC V5Z 1L3, Canada; (M.C.B.-F.); (B.C.M.); (M.E.P.); (E.A.M.); (E.A.V.); (A.P.S.); (N.T.); (G.L.S.); (W.L.L.)
- International Research Center, A.C. Camargo Cancer Center, São Paulo, SP 01525-001, Brazil
| | - Brenda C. Minatel
- British Columbia Cancer Research Centre, Vancouver, BC V5Z 1L3, Canada; (M.C.B.-F.); (B.C.M.); (M.E.P.); (E.A.M.); (E.A.V.); (A.P.S.); (N.T.); (G.L.S.); (W.L.L.)
| | - Michelle E. Pewarchuk
- British Columbia Cancer Research Centre, Vancouver, BC V5Z 1L3, Canada; (M.C.B.-F.); (B.C.M.); (M.E.P.); (E.A.M.); (E.A.V.); (A.P.S.); (N.T.); (G.L.S.); (W.L.L.)
| | - Erin A. Marshall
- British Columbia Cancer Research Centre, Vancouver, BC V5Z 1L3, Canada; (M.C.B.-F.); (B.C.M.); (M.E.P.); (E.A.M.); (E.A.V.); (A.P.S.); (N.T.); (G.L.S.); (W.L.L.)
| | - Emily A. Vucic
- British Columbia Cancer Research Centre, Vancouver, BC V5Z 1L3, Canada; (M.C.B.-F.); (B.C.M.); (M.E.P.); (E.A.M.); (E.A.V.); (A.P.S.); (N.T.); (G.L.S.); (W.L.L.)
- NYU Langone Medical Center, New York, NY 10016, USA
| | - Adam P. Sage
- British Columbia Cancer Research Centre, Vancouver, BC V5Z 1L3, Canada; (M.C.B.-F.); (B.C.M.); (M.E.P.); (E.A.M.); (E.A.V.); (A.P.S.); (N.T.); (G.L.S.); (W.L.L.)
| | - Nikita Telkar
- British Columbia Cancer Research Centre, Vancouver, BC V5Z 1L3, Canada; (M.C.B.-F.); (B.C.M.); (M.E.P.); (E.A.M.); (E.A.V.); (A.P.S.); (N.T.); (G.L.S.); (W.L.L.)
- British Columbia Children’s Hospital Research Institute, Vancouver, BC V5Z 4H4, Canada;
- Department of Medical Genetics, University of British Columbia, Vancouver, BC V6H 3N1, Canada
| | - Greg L. Stewart
- British Columbia Cancer Research Centre, Vancouver, BC V5Z 1L3, Canada; (M.C.B.-F.); (B.C.M.); (M.E.P.); (E.A.M.); (E.A.V.); (A.P.S.); (N.T.); (G.L.S.); (W.L.L.)
| | - Igor Jurisica
- Osteoarthritis Research Program, Division of Orthopedic Surgery, Schroeder Arthritis Institute, University Health Network, Toronto, ON M5T 0S8, Canada;
- Data Science Discovery Centre for Chronic Diseases, Krembil Research Institute, University Health Network, Toronto, ON M5T 0S8, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada
- Department of Computer Science, University of Toronto, Toronto, ON M5S 2E4, Canada
| | - Patricia P. Reis
- Faculty of Medicine, São Paulo State University (UNESP), Botucatu, SP 18618-687, Brazil;
| | - Wendy P. Robinson
- British Columbia Children’s Hospital Research Institute, Vancouver, BC V5Z 4H4, Canada;
- Department of Medical Genetics, University of British Columbia, Vancouver, BC V6H 3N1, Canada
| | - Wan L. Lam
- British Columbia Cancer Research Centre, Vancouver, BC V5Z 1L3, Canada; (M.C.B.-F.); (B.C.M.); (M.E.P.); (E.A.M.); (E.A.V.); (A.P.S.); (N.T.); (G.L.S.); (W.L.L.)
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26
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Zhong S, Golpon H, Zardo P, Borlak J. miRNAs in lung cancer. A systematic review identifies predictive and prognostic miRNA candidates for precision medicine in lung cancer. Transl Res 2021; 230:164-196. [PMID: 33253979 DOI: 10.1016/j.trsl.2020.11.012] [Citation(s) in RCA: 106] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2020] [Revised: 11/05/2020] [Accepted: 11/24/2020] [Indexed: 02/08/2023]
Abstract
Lung cancer (LC) is the leading cause of cancer-related death worldwide and miRNAs play a key role in LC development. To better diagnose LC and to predict drug treatment responses we evaluated 228 articles encompassing 16,697 patients and 12,582 healthy controls. Based on the criteria of ≥3 independent studies and a sensitivity and specificity of >0.8 we found blood-borne miR-20a, miR-10b, miR-150, and miR-223 to be excellent diagnostic biomarkers for non-small cell LC whereas miR-205 is specific for squamous cell carcinoma. The systematic review also revealed 38 commonly regulated miRNAs in tumor tissue and the circulation, thus enabling the prediction of histological subtypes of LC. Moreover, theranostic biomarker candidates with proven responsiveness to checkpoint inhibitor treatments were identified, notably miR-34a, miR-93, miR-106b, miR-181a, miR-193a-3p, and miR-375. Conversely, miR-103a-3p, miR-152, miR-152-3p, miR-15b, miR-16, miR-194, miR-34b, and miR-506 influence programmed cell death-ligand 1 and programmed cell death-1 receptor expression, therefore providing a rationale for the development of molecularly targeted therapies. Furthermore, miR-21, miR-25, miR-27b, miR-19b, miR-125b, miR-146a, and miR-210 predicted response to platinum-based treatments. We also highlight controversial reports on specific miRNAs. In conclusion, we report diagnostic miRNA biomarkers for in-depth clinical evaluation. Furthermore, in an effort to avoid unnecessary toxicity we propose predictive biomarkers. The biomarker candidates support personalized treatment decisions of LC patients and await their confirmation in randomized clinical trials.
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Affiliation(s)
- Shen Zhong
- Centre for Pharmacology and Toxicology, Hannover Medical School, Hannover, Germany
| | - Heiko Golpon
- Department of Pneumology, Hannover Medical School, Hannover, Germany
| | - Patrick Zardo
- Clinic for Cardiothoracic and Transplantation Surgery, Hannover Medical School, Hannover, Germany
| | - Jürgen Borlak
- Centre for Pharmacology and Toxicology, Hannover Medical School, Hannover, Germany.
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27
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Ding HM, Zhang H, Wang J, Zhou JH, Shen FR, Ji RN, Shi JY, Chen YG. miR‑302c‑3p and miR‑520a‑3p suppress the proliferation of cervical carcinoma cells by targeting CXCL8. Mol Med Rep 2021; 23:322. [PMID: 33760117 PMCID: PMC7974325 DOI: 10.3892/mmr.2021.11961] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Accepted: 11/09/2020] [Indexed: 01/03/2023] Open
Abstract
The aim of the present study was to identify the differentially expressed microRNAs (miRs) in cervical carcinoma (CC) tissues and cells and to explore the function of miR-302c-3p and miR-520a-3p in the proliferation of CC cells. Potential dysregulated miRNAs in CC tissues and tumour-adjacent tissues were detected. Reverse transcription-quantitative PCR (RT-qPCR) was performed to determine the expression of miR-302c-3p, miR-520a-3p and CXCL8 in CC tissues and cell lines. The target genes of the miRNAs were predicted using miRTarBase and verified by luciferase reporter assays. RT-qPCR and western blotting were performed to measure the expression of C-X-C motif ligand (CXCL)8 after transfection. The effect on proliferation was verified by Cell Counting Kit assay and ethynyl-2-deoxyuridine staining. Flow cytometry was utilised to assess the effect on apoptosis. In the present study, miR-302c-3p and miR-520a-3p were markedly downregulated in CC cell lines compared to the normal cervical cell line H8. Functionally, overexpression of miR-302c-3p and/or miR-520a-3p inhibited proliferation and promoted the apoptosis of CC cell lines in vitro, while the knockdown of miR-302c-3p and/or miR-520a-3p had the opposite effect. Furthermore, miR-302c-3p and miR-520a-3p could both bind to CXCL8. Inhibition of CXCL8 in combination with miR-302c-3p and/or miR-520a-3p overexpression exerted proliferation-suppressive and apoptosis-stimulating effects on CC cells, whereas restoring CXCL8 attenuated the miR-302c-3p- and miR-520a-3p-induced anti-proliferative and pro-apoptotic effects. miR-302c-3p and miR-520a-3p suppress the proliferation of CC cells by downregulating the expression of CXCL8, which may provide a novel target for the treatment of CC.
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Affiliation(s)
- Hong-Mei Ding
- Department of Obstetrics and Gynaecology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Hong Zhang
- Department of Obstetrics and Gynaecology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Juan Wang
- Department of Obstetrics and Gynaecology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Jin-Hua Zhou
- Department of Obstetrics and Gynaecology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Fang-Rong Shen
- Department of Obstetrics and Gynaecology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Ru-Ning Ji
- Department of Medical Engineering, Suzhou Municipal Hospital, Suzhou, Jiangsu 215008, P.R. China
| | - Jia-Yin Shi
- Department of Dermatology, Suzhou Municipal Hospital, Suzhou, Jiangsu 215008, P.R. China
| | - You-Guo Chen
- Department of Obstetrics and Gynaecology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
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28
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Zhu W, Wang JZ, Wei JF, Lu C. Role of m6A methyltransferase component VIRMA in multiple human cancers (Review). Cancer Cell Int 2021; 21:172. [PMID: 33731118 PMCID: PMC7968318 DOI: 10.1186/s12935-021-01868-1] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Accepted: 03/06/2021] [Indexed: 12/18/2022] Open
Abstract
N6-Methyladenosine (m6A) modification is one of the most widely distributed RNA modifications in eukaryotes. It participates in various RNA functions and plays vital roles in tissue development, stem cell formation and differentiation, heat shock response control, and circadian clock controlling, particularly during tumor development. The reversible regulation of m6A modification is affected by the so-called ‘reader’, ‘writer’ and ‘eraser’. As a required component and the largest methyltransferase, vir-like m6A methyltransferase associated (VIRMA) can promote the progression of cancer and is associated with poor survival in multiple types of cancer. The present review investigated the role of VIRMA in various types of cancer. In an m6A-dependent or -independent manner, VIRMA can play an oncogenic role by regulating cancer cell proliferation, migration and invasion, metastasis, apoptosis resistance and tumor growth in different pathways by targeting stem factors, CCAT1/2, ID2, GATA3, CDK1, c-Jun, etc. VIRMA can also predict better prognosis in kidney renal clear cell carcinoma (KIRC), kidney renal papillary cell carcinoma (KIRP) and papillary thyroid carcinoma by TCGA analysis. The obvious oncogenic roles of VIRMA observed in different types of cancer and the mechanisms of VIRMA promoting cancers provided the basis for potential therapeutic targeting for cancer treatments.
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Affiliation(s)
- Wei Zhu
- Precision Medicine Center, First Affiliated Hospital of Gannan Medical University, 128 Jinling Road, Ganzhou, 341000, China.,Research Division of Clinical Pharmacology, The First Affiliated Hospital of Nanjing Medical University (Jiangsu Province Hospital), 300 Guangzhou Road, Nanjing, 210029, Jiangsu, China
| | - Jing-Zi Wang
- Department of Urology, Children's Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing, 210029, Jiangsu, China
| | - Ji-Fu Wei
- Precision Medicine Center, First Affiliated Hospital of Gannan Medical University, 128 Jinling Road, Ganzhou, 341000, China. .,Research Division of Clinical Pharmacology, The First Affiliated Hospital of Nanjing Medical University (Jiangsu Province Hospital), 300 Guangzhou Road, Nanjing, 210029, Jiangsu, China.
| | - Chen Lu
- Precision Medicine Center, First Affiliated Hospital of Gannan Medical University, 128 Jinling Road, Ganzhou, 341000, China.
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Zhang W, Hu C, Zhang C, Luo C, Zhong B, Yu X. MiRNA-132 regulates the development of osteoarthritis in correlation with the modulation of PTEN/PI3K/AKT signaling. BMC Geriatr 2021; 21:175. [PMID: 33691628 PMCID: PMC7945330 DOI: 10.1186/s12877-021-02046-8] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Accepted: 01/21/2021] [Indexed: 12/18/2022] Open
Abstract
Background Osteoarthritis (OA) is a commonly known prevalent joint disease, with limited therapeutic methods. This study aimed to investigate the functions of miRNA-132 (miR-132) in the modulation of PTEN/PI3K/AKT signaling pathway in the development and progression of osteoarthritis. Methods Eight male osteoarthritic patients and eight healthy males were recruited. Male Sprague Dawley (SD) rats were used for cellular experiments. QRT-PCR was performed to detect the expression levels of miR-132, PTEN, PI3K and AKT. MTT assay and apoptosis assay were carried out to measure the cell proliferation rate and cell apoptosis rate, respectively. Western blotting was employed to detect the protein expression of related RNAs and inflammatory factors. Results In osteoarthritic patients, the expression level of miR-132 was decreased, compared with that in the normal group. Over-expression of miR-132 elevated cell proliferation and decreased apoptosis of chondrocytes. Down-regulation of miR-132 decreased cell proliferation and induced apoptosis in chondrocytes. In addition, down-regulation of miR-132 promoted the expression of Bax protein and activated caspase-3/9, increased inflammation divisors. PTEN inhibitor antagonized the destructive effect of the miR-132 inhibitor on cell proliferation of chondrocytes. PI3K inhibitor increased the destructive effect of the miR-132 inhibitor on osteoarthritis. Conclusion In conclusion, miR-132 is an important regulator of osteoarthritis in chondrocytes through the PTEN/PI3K/AKT signaling pathway.
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Affiliation(s)
- Wei Zhang
- Department of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No. 600 Yishan Road, Shanghai, 200233, China
| | - Chengfang Hu
- Department of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No. 600 Yishan Road, Shanghai, 200233, China
| | - Chi Zhang
- Department of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No. 600 Yishan Road, Shanghai, 200233, China
| | - Congfeng Luo
- Department of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No. 600 Yishan Road, Shanghai, 200233, China
| | - Biao Zhong
- Department of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No. 600 Yishan Road, Shanghai, 200233, China
| | - Xiaowei Yu
- Department of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No. 600 Yishan Road, Shanghai, 200233, China.
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30
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Barlak N, Capik O, Kilic A, Sanli F, Aytatli A, Yazici A, Karatas EA, Ortucu S, Karatas OF. MicroRNA-145 transcriptionally regulates Semaphorin 3A expression in prostate cancer cells. Cell Biol Int 2021; 45:1082-1090. [PMID: 33501702 DOI: 10.1002/cbin.11554] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Accepted: 01/24/2021] [Indexed: 12/25/2022]
Abstract
Prostate cancer (PCa) is one of the most prevalent cancer types among males. Differential expression of microRNAs is associated with various cancers including PCa. Although mature microRNAs are preferentially located in the cytoplasm, several studies identified mature human microRNAs in purified nuclei and miR-145 has been found to be predominantly expressed in the nuclei of benign tissues compared to tumor lesions. However, the nuclear functions of miR-145 are yet limited. Here, we aimed at investigating the inductive role of miR-145 on the expression of Semaphorin 3A (SEMA3A) in PCa cell lines. To study the regulatory potential of miR-145 in the transcriptional level in PCa, we overexpressed miR-145 in PC3 and DU145 cells, and confirmed its upregulation by quantitative-real-time-PCR. Then we investigated the tumor suppressor potential of miR-145 upon inducing SEMA3A expression using cell viability assay, western blot analysis, Chromatin Immunoprecipitation assay and luciferase reporter assay. Our results revealed that p53, miR-145, and SEMA3A expressions are significantly downregulated in PC3 and DU145 cells compared to nontumorigenic prostate epithelial PNT1a cells. miR-145 overexpression in PCa cells induced the expression of SEMA3A at both messenger RNA and protein levels. Furthermore, increased miR-145 expression enriched RNA Pol-II antibody on the promoter of SEMA3A and induced luciferase activity controlled by SEMA3A promoter. In this study, we showed that the functions of miR-145 are not limited to gene silencing, and found that it may lead to changes in gene expression in the transcriptional level.
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Affiliation(s)
- Neslisah Barlak
- Department of Molecular Biology and Genetics, Erzurum Technical University, Erzurum, Turkey.,Molecular Cancer Biology Laboratory, High Technology Application and Research Center, Erzurum Technical University, Erzurum, Turkey
| | - Ozel Capik
- Department of Molecular Biology and Genetics, Erzurum Technical University, Erzurum, Turkey.,Molecular Cancer Biology Laboratory, High Technology Application and Research Center, Erzurum Technical University, Erzurum, Turkey
| | - Ahsen Kilic
- Department of Molecular Biology and Genetics, Erzurum Technical University, Erzurum, Turkey.,Molecular Cancer Biology Laboratory, High Technology Application and Research Center, Erzurum Technical University, Erzurum, Turkey
| | - Fatma Sanli
- Department of Molecular Biology and Genetics, Erzurum Technical University, Erzurum, Turkey.,Molecular Cancer Biology Laboratory, High Technology Application and Research Center, Erzurum Technical University, Erzurum, Turkey
| | - Abdulmelik Aytatli
- Department of Molecular Biology and Genetics, Erzurum Technical University, Erzurum, Turkey.,Molecular Cancer Biology Laboratory, High Technology Application and Research Center, Erzurum Technical University, Erzurum, Turkey
| | - Aysenur Yazici
- Department of Molecular Biology and Genetics, Erzurum Technical University, Erzurum, Turkey.,Molecular Cancer Biology Laboratory, High Technology Application and Research Center, Erzurum Technical University, Erzurum, Turkey
| | - Elanur Aydin Karatas
- Department of Molecular Biology and Genetics, Erzurum Technical University, Erzurum, Turkey.,Molecular Cancer Biology Laboratory, High Technology Application and Research Center, Erzurum Technical University, Erzurum, Turkey
| | - Serkan Ortucu
- Department of Molecular Biology and Genetics, Erzurum Technical University, Erzurum, Turkey.,Molecular Cancer Biology Laboratory, High Technology Application and Research Center, Erzurum Technical University, Erzurum, Turkey
| | - Omer Faruk Karatas
- Department of Molecular Biology and Genetics, Erzurum Technical University, Erzurum, Turkey.,Molecular Cancer Biology Laboratory, High Technology Application and Research Center, Erzurum Technical University, Erzurum, Turkey
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31
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Ferragut Cardoso AP, Udoh KT, States JC. Arsenic-induced changes in miRNA expression in cancer and other diseases. Toxicol Appl Pharmacol 2020; 409:115306. [PMID: 33127375 PMCID: PMC7772821 DOI: 10.1016/j.taap.2020.115306] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Revised: 10/20/2020] [Accepted: 10/26/2020] [Indexed: 02/06/2023]
Abstract
miRNAs (miRNA) are essential players regulating gene expression affecting cellular processes contributing to disease development. Dysregulated miRNA expression has been observed in numerous diseases including hepatitis, cardiovascular diseases and cancers. In cardiovascular diseases, several miRNAs function as mediators of pathogenic stress-related signaling pathways that may lead to an excessive extracellular matrix production and collagen deposition causing cardiac stress resulting in fibrosis. In cancers, many miRNAs function as oncogenes or tumor suppressors facilitating tumor growth, invasion and angiogenesis. Furthermore, the association between distinct miRNA profile and tumor development, progression and treatment response has identified miRNAs as potential biomarkers for disease diagnosis and prognosis. Growing evidence demonstrates changes in miRNA expression levels in experimental settings or observational studies associated with environmental chemical exposures such as arsenic. Arsenic is one of the most well-known human carcinogens. Long-term exposure through drinking water increases risk of developing skin, lung and urinary bladder cancers, as well as cardiovascular disease. The mechanism(s) by which arsenic causes disease remains elusive. Proposed mechanisms include miRNA dysregulation. Epidemiological studies identified differential miRNA expression between arsenic-exposed and non-exposed individuals from India, Bangladesh, China and Mexico. In vivo and in vitro studies have shown that miRNAs are critically involved in arsenic-induced malignant transformation. Few studies analyzed miRNAs in other diseases associated with arsenic exposure. Importantly, there is no consensus on a consistent miRNA profile for arsenic-induced cancers because most studies analyze only particular miRNAs. Identifying miRNA expression changes common among humans, rodents and cell lines might guide future miRNA investigations.
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Affiliation(s)
- Ana P Ferragut Cardoso
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA
| | - Karen T Udoh
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA
| | - J Christopher States
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA.
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32
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Sawant D, Lilly B. MicroRNA-145 targets in cancer and the cardiovascular system: evidence for common signaling pathways. VASCULAR BIOLOGY 2020; 2:R115-R128. [PMID: 33283158 PMCID: PMC7709916 DOI: 10.1530/vb-20-0012] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Accepted: 10/23/2020] [Indexed: 12/01/2022]
Abstract
miRNAs are small regulatory RNAs which govern gene expression post-transcriptionally by primarily binding to the 3'-UTR of mRNA target genes. miR-145 is a well-studied miRNA that has been implicated in controlling a range of biological processes. miR-145 is expressed in a variety of tissues and cell types and acts as a tumor-suppressor by regulating target gene signaling pathways involved in different aspects of tumor growth and progression. There is also strong evidence that highlights the important functions of miR-145 in the cardiovascular system. Here, we review the mechanisms of miR-145 in tumorigenesis and cancer progression and compare and contrast with the roles of miR-145 in cardiovascular development and disease. We discuss the important targets of miR-145 in cancer and their possible link to the cardiovascular system.
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Affiliation(s)
- Dwitiya Sawant
- Center for Cardiovascular Research and The Heart Center, Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Brenda Lilly
- Center for Cardiovascular Research and The Heart Center, Nationwide Children's Hospital, Columbus, Ohio, USA.,Department of Pediatrics, The Ohio State University, Columbus, Ohio, USA
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33
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Zeinali T, Karimi L, Hosseinahli N, Shanehbandi D, Mansoori B, Mohammadi A, Hajiasgharzadeh K, Babaloo Z, Majidi-Zolbanin J, Baradaran B. Overexpression of miRNA-145 induces apoptosis and prevents proliferation and migration of MKN-45 gastric cancer cells. EXCLI JOURNAL 2020; 19:1446-1458. [PMID: 33250681 PMCID: PMC7689247 DOI: 10.17179/excli2020-2777] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Accepted: 10/28/2020] [Indexed: 12/11/2022]
Abstract
MiR-145 is a tumor suppressor miRNA that its ubiquitously expressed in the body but in numerous types of cancers such as GC, its expression became reduced or sometimes ceased in many subjects. This study aimed at restoring the function of the miR-145 in MKN-45 cells and investigating the function of this miRNA in proliferation, apoptosis, and migration of GC cells. MKN-45 cells were transfected using the PCMV-miR-145 plasmid vector. The MTT, DAPI staining, and wound healing assays were applied to estimate the impacts of ectopic expression of miR-145 in vitro. Moreover, alterations in the expression levels of K-Ras, c-Myc, caspase-3, caspase-9, Bax, Bcl-2, and MMP-9 mRNA were measured by qRT-PCR analysis. The findings designated that high expression of miR-145 reduced the proliferation and migration and increased the apoptosis of the MKN-45 cells. These effects occur with concurrent suppression of c-Myc, K-Ras, Bcl-2, and MMP-9 as well as induction of caspase-3, caspase-9, and Bax expression. Exogenous miR-145 influences multiple oncogenic pathways and can be regarded as a promising avenue of future therapeutic interventions for GC therapy.
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Affiliation(s)
- Tahereh Zeinali
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Gastrointestinal and Liver Diseases Research Center, Guilan University of Medical Sciences, Rasht, Iran
| | - Leila Karimi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Nayer Hosseinahli
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Dariush Shanehbandi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Mansoori
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Mohammadi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Zohreh Babaloo
- Department of Immunology, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, Tabriz University of Medical Sciences, Tabriz, Iran
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34
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Sharma PC, Gupta A. MicroRNAs: potential biomarkers for diagnosis and prognosis of different cancers. Transl Cancer Res 2020; 9:5798-5818. [PMID: 35117940 PMCID: PMC8798648 DOI: 10.21037/tcr-20-1294] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Accepted: 06/12/2020] [Indexed: 12/14/2022]
Abstract
A thorough understanding of the tumor environment and underlying genetic factors helps in the better formulation of cancer management strategies. Availability of efficient diagnostic and prognostic biomarkers facilitates early detection and progression of the disease. MicroRNAs affect different biological processes participating in tumorigenesis through regulation of their target genes. An expanding list of unique RNAs and understanding of their regulatory role has opened up a new field in cancer research. Based on a comprehensive literature search, we identified 728 miRNAs dysregulated in sixteen cancer types namely bladder cancer (BC), breast cancer (BrC), cervical cancer (CC), colorectal cancer (CRC), esophageal cancer (EC), endometrial cancer (EnC), gastric cancer (GC), hepatocellular cancer (HCC), head and neck squamous cell cancer (HNSCC), lung cancer (LC), ovarian cancer (OC), pancreatic cancer (PC), prostate cancer (PrC), renal cell cancer (RCC), skin cancer (SC), and thyroid cancer (TC). Expression of 43 miRNAs was either upregulated or downregulated in six or more of these cancers. Finally, seven miRNAs namely mir-18a, mir-21, mir-143/145, mir-210, mir-218, mir-221, showing maximum dysregulation, either up- or down-regulation in the majority of cancers, were selected for a detailed presentation of their expression and evaluation of their potential as biomarkers in the diagnosis and prognosis of different cancers.
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Affiliation(s)
- Prakash Chand Sharma
- University School of Biotechnology, Guru Gobind Singh Indraprastha University, New Delhi, India
| | - Alisha Gupta
- University School of Biotechnology, Guru Gobind Singh Indraprastha University, New Delhi, India
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35
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Gu H, Cheng X, Xu J, Zhou K, Bian C, Chen G, Yin X. Circular RNA circFAT1(e2) Promotes Osteosarcoma Progression and Metastasis by Sponging miR-181b and Regulating HK2 Expression. BIOMED RESEARCH INTERNATIONAL 2020; 2020:3589871. [PMID: 32733938 PMCID: PMC7378629 DOI: 10.1155/2020/3589871] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Accepted: 06/17/2020] [Indexed: 01/14/2023]
Abstract
As a subclass of noncoding RNAs, circular RNAs (circRNAs) have been demonstrated to play a critical role in regulating gene expression in eukaryotes. Recent studies have revealed the pivotal functions of circRNAs in cancer progression. Nevertheless, how circRNAs participate in osteosarcoma (OS) development and progression are not well understood. In the present study, we identified a circRNA circFAT1(e2) with an upregulated expression level in OS tissues. By functional experiments, we found that circFAT1(e2) depletion significantly suppressed the proliferation and reduced migration in OS. In terms of mechanism, we found that circFAT1(e2) inhibited miR-181b, while miR-181b targeted HK2. By releasing the inhibition of miR-181b on HK2 expression, leading to attenuated OS progression. Mechanistic investigations suggested that circFAT1(e2) served as a competing endogenous RNA (ceRNA) of miR-181b to enhance HK2 expression. On the whole, our study indicated that circFAT1(e2) exerted oncogenic roles in OS and suggested the circFAT1(e2)/miR-181b/HK2 axis might be a potential therapeutic target.
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Affiliation(s)
- Huijie Gu
- Department of Orthopaedics, Minhang Hospital, Fudan University, 170 Xin-Song Road, Shanghai 201199, China
| | - Xiangyang Cheng
- Department of Orthopaedics, Minhang Hospital, Fudan University, 170 Xin-Song Road, Shanghai 201199, China
| | - Jun Xu
- Department of Orthopaedics, Minhang Hospital, Fudan University, 170 Xin-Song Road, Shanghai 201199, China
| | - Kaifeng Zhou
- Department of Orthopaedics, Minhang Hospital, Fudan University, 170 Xin-Song Road, Shanghai 201199, China
| | - Chong Bian
- Department of Orthopaedics, Minhang Hospital, Fudan University, 170 Xin-Song Road, Shanghai 201199, China
| | - Guangnan Chen
- Department of Orthopaedics, Minhang Hospital, Fudan University, 170 Xin-Song Road, Shanghai 201199, China
| | - Xiaofan Yin
- Department of Orthopaedics, Minhang Hospital, Fudan University, 170 Xin-Song Road, Shanghai 201199, China
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36
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Cristóbal I, Luque M, Sanz-Alvarez M, Rojo F, García-Foncillas J. Clinical Impact and Regulation of the circCAMSAP1/ miR-328-5p/E2F1 Axis in Colorectal Cancer. Mol Ther 2020; 28:1387-1388. [PMID: 32413279 DOI: 10.1016/j.ymthe.2020.05.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Affiliation(s)
- Ion Cristóbal
- Cancer Unit for Research on Novel Therapeutic Targets, Oncohealth Institute, IIS-Fundación Jiménez Díaz-UAM, Madrid, Spain; Translational Oncology Division, Oncohealth Institute, IIS-Fundación Jiménez Díaz-UAM, Madrid, Spain.
| | - Melani Luque
- Pathology Department, IIS-Fundación Jiménez Díaz-UAM, Madrid, Spain
| | | | - Federico Rojo
- Pathology Department, IIS-Fundación Jiménez Díaz-UAM, Madrid, Spain
| | - Jesús García-Foncillas
- Cancer Unit for Research on Novel Therapeutic Targets, Oncohealth Institute, IIS-Fundación Jiménez Díaz-UAM, Madrid, Spain; Translational Oncology Division, Oncohealth Institute, IIS-Fundación Jiménez Díaz-UAM, Madrid, Spain.
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37
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Hu MH, Wu TY, Huang Q, Jin G. New substituted quinoxalines inhibit triple-negative breast cancer by specifically downregulating the c-MYC transcription. Nucleic Acids Res 2020; 47:10529-10542. [PMID: 31584090 PMCID: PMC6846596 DOI: 10.1093/nar/gkz835] [Citation(s) in RCA: 74] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2019] [Revised: 08/25/2019] [Accepted: 09/28/2019] [Indexed: 12/18/2022] Open
Abstract
Conventional chemotherapy remains the primary treatment option for triple-negative breast cancer (TNBC). However, the current chemotherapeutic drugs have limited effects on TNBC, and often lead to serious side effects as well as drug resistance. Thus, more effective therapeutic options are sorely needed. As c-MYC oncogene is highly expressed during TNBC pathogenesis, inhibiting c-MYC expression would be an alternative anti-TNBC strategy. In this study, we designed and synthesized a serial of quinoxaline analogs that target c-MYC promoter G-quadruplex (G4), which is believed to be a repressor of c-MYC transcription. Among them, a difluoro-substituted quinoxaline QN-1 was identified as the most promising G4-stabilizing ligand with high selectivity to c-MYC G4 over other G4s, which is distinguished from many other reported ligands. Intracellular studies indicated that QN-1 induced cell cycle arrest and apoptosis, repressed metastasis and inhibited TNBC cell growth, primarily due to the downregulation of c-MYC transcription by a G4-dependent mechanism. Notably, inhibition by QN-1 was significantly greater for c-MYC than other G4-driven genes. Cancer cells with c-MYC overexpression were more sensitive to QN-1, relative to normal cells. Furthermore, QN-1 effectively suppressed tumor growth in a TNBC mouse model. Accordingly, this work provides an alternative strategy for treating TNBC.
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Affiliation(s)
- Ming-Hao Hu
- School of Pharmaceutical Sciences, Shenzhen University Health Science Center, Shenzhen 518060, China
| | - Tian-Ying Wu
- School of Pharmaceutical Sciences, Shenzhen University Health Science Center, Shenzhen 518060, China
| | - Qiong Huang
- School of Pharmaceutical Sciences, Shenzhen University Health Science Center, Shenzhen 518060, China
| | - Guangyi Jin
- School of Pharmaceutical Sciences, Shenzhen University Health Science Center, Shenzhen 518060, China.,International Cancer Center, Shenzhen University Health Science Center, Shenzhen 518060, China
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38
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VIRMA-Dependent N6-Methyladenosine Modifications Regulate the Expression of Long Non-Coding RNAs CCAT1 and CCAT2 in Prostate Cancer. Cancers (Basel) 2020; 12:cancers12040771. [PMID: 32218194 PMCID: PMC7226055 DOI: 10.3390/cancers12040771] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Revised: 03/18/2020] [Accepted: 03/24/2020] [Indexed: 01/26/2023] Open
Abstract
RNA methylation at position N6 in adenosine (m6A) and its associated methyltransferase complex (MTC) are involved in tumorigenesis. We aimed to explore m6A biological function for long non-coding RNAs (lncRNAs) in prostate cancer (PCa) and its clinical significance. m6A and MTC levels in PCa cells were characterized by ELISA and western blot. Putative m6A-regulated lncRNAs were identified and validated by lncRNA profiler qPCR array and bioinformatics analysis, followed by m6A/RNA co-immunoprecipitation. Impact of m6A depletion on RNA stability was assessed by Actinomycin D assay. The association of m6A-levels with PCa prognosis was examined in clinical samples. Higher m6A-levels and VIRMA overexpression were detected in metastatic castration-resistant PCa (mCRPC) cells (p < 0.05). VIRMA knockdown in PC-3 cells significantly decreased m6A-levels (p = 0.0317), attenuated malignant phenotype and suppressed the expression of oncogenic lncRNAs CCAT1 and CCAT2 (p < 0.00001). VIRMA depletion and m6A reduction decreased the stability and abundance of CCAT1/2 transcripts. Higher expression of VIRMA, CCAT1, and CCAT2 as a group variable was an independent predictor of poor prognosis (HR = 9.083, CI95% 1.911–43.183, p = 0.006). VIRMA is a critical factor sustaining m6A-levels in PCa cells. VIRMA downregulation attenuates the aggressive phenotype of PCa by overall reduction of m6A-levels decreasing stability and abundance of oncogenic lncRNAs.
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39
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The Microrna-143/145 Cluster in Tumors: A Matter of Where and When. Cancers (Basel) 2020; 12:cancers12030708. [PMID: 32192092 PMCID: PMC7140083 DOI: 10.3390/cancers12030708] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 03/13/2020] [Accepted: 03/15/2020] [Indexed: 01/06/2023] Open
Abstract
The establishment and spreading of cancer involve the acquirement of many biological functions including resistance to apoptosis, enhanced proliferation and the ability to invade the surrounding tissue, extravasate from the primary site, survive in circulating blood, and finally extravasate and colonize distant organs giving origin to metastatic lesions, the major cause of cancer deaths. Dramatic changes in the expression of protein coding genes due to altered transcription factors activity or to epigenetic modifications orchestrate these events, intertwining with a microRNA regulatory network that is often disrupted in cancer cells. microRNAs-143 and -145 represent puzzling players of this game, with apparently contradictory functions. They were at first classified as tumor suppressive due to their frequently reduced levels in tumors, correlating with cell survival, proliferation, and migration. More recently, pro-oncogenic roles of these microRNAs have been described, challenging their simplistic definition as merely tumor-suppressive. Here we review their known activities in tumors, whether oncogenic or onco-suppressive, and highlight how their expression and functions are strongly dependent on their complex regulation downstream and upstream of cytokines and growth factors, on the cell type of expression and on the specific tumor stage.
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40
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A triple-combination nanotechnology platform based on multifunctional RNA hydrogel for lung cancer therapy. Sci China Chem 2020. [DOI: 10.1007/s11426-019-9673-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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41
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Zuberi M, Mir R, Khan I, Javid J, Guru SA, Bhat M, Sumi MP, Ahmad I, Masroor M, Yadav P, Vishnubhatla S, Saxena A. The Promising Signatures of Circulating microRNA-145 in Epithelial Ovarian Cancer Patients. Microrna 2020; 9:49-57. [PMID: 30799804 DOI: 10.2174/2211536608666190225111234] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2018] [Revised: 11/09/2018] [Accepted: 02/13/2019] [Indexed: 06/09/2023]
Abstract
BACKGROUND Epithelial ovarian cancer continues to be a deleterious threat to women as it is asymptomatic and is typically detected in advanced stages. Cogent non-invasive biomarkers are therefore needed which are effective in apprehending the disease in early stages. Recently, miRNA deregulation has shown a promising magnitude in ovarian cancer tumorigenesis. miRNA-145(miR- 145) is beginning to be understood for its possible role in cancer development and progression. In this study, we identified the clinicopathological hallmarks altered owing to the downexpression of serum miR-145 in EOC. METHODS 70 serum samples from histopathologically confirmed EOC patients and 70 controls were collected. Total RNA from serum was isolated by Trizol method, polyadenylated and reverse transcribed into cDNA. Expression level of miR-145 was detected by miRNA qRT-PCR using RNU6B snRNA as reference. RESULTS The alliance of miR-145 profiling amongst patients and controls established itself to be conspicuous with a significant p-value (p<0.0001). A positive conglomeration (p=0.04) of miR-145 profiling was manifested with histopathological grade. Receiver Operating Characteristic (ROC) curve highlights the diagnostic potential and makes it imminent with a robust Area Under the curve (AUC). A positive correlation with the ROC curve was also noted for histological grade, FIGO stage, distant metastasis, lymph node status and survival. CONCLUSION Our results propose that miR-145 down-regulation might be a possible touchstone for disease progression and be identified as a diagnostic marker and predict disease outcome in EOC patients.
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Affiliation(s)
- Mariyam Zuberi
- Department of Biochemistry, Maulana Azad Medical College and Associated Hospitals, New Delhi-110002, India
| | - Rashid Mir
- Prince Fahd Bin Sultan Research Chair, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk, Saudi Arabia
| | - Imran Khan
- Department of Cell and Molecular Pharmacology & Experimental Therapeutics, Hollings Cancer Center, Medical University of South Carolina, Columbia, SC, United States
| | - Jamsheed Javid
- Prince Fahd Bin Sultan Research Chair, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk, Saudi Arabia
| | - Sameer Ahmad Guru
- Department of Biochemistry, Maulana Azad Medical College and Associated Hospitals, New Delhi-110002, India
| | - Musadiq Bhat
- Department of Biochemistry, Maulana Azad Medical College and Associated Hospitals, New Delhi-110002, India
| | - Mamta Pervin Sumi
- Department of Biochemistry, Maulana Azad Medical College and Associated Hospitals, New Delhi-110002, India
| | - Imtiyaz Ahmad
- Department of Biochemistry, Maulana Azad Medical College and Associated Hospitals, New Delhi-110002, India
| | - Mirza Masroor
- Department of Biochemistry, Maulana Azad Medical College and Associated Hospitals, New Delhi-110002, India
| | - Prasant Yadav
- Department of Biochemistry, Maulana Azad Medical College and Associated Hospitals, New Delhi-110002, India
| | | | - Alpana Saxena
- Department of Biochemistry, Maulana Azad Medical College and Associated Hospitals, New Delhi-110002, India
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Aravindan N, Subramanian K, Somasundaram DB, Herman TS, Aravindan S. MicroRNAs in neuroblastoma tumorigenesis, therapy resistance, and disease evolution. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2019; 2:1086-1105. [PMID: 31867575 PMCID: PMC6924638 DOI: 10.20517/cdr.2019.68] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Neuroblastoma (NB) deriving from neural crest cells is the most common extra-cranial solid cancer at infancy. NB originates within the peripheral sympathetic ganglia in adrenal medulla and along the midline of the body. Clinically, NB exhibits significant heterogeneity stretching from spontaneous regression to rapid progression to therapy resistance. MicroRNAs (miRNAs, miRs) are small (19-22 nt in length) non-coding RNAs that regulate human gene expression at the post-transcriptional level and are known to regulate cellular signaling, growth, differentiation, death, stemness, and maintenance. Consequently, the function of miRs in tumorigenesis, progression and resistance is of utmost importance for the understanding of dysfunctional cellular pathways that lead to disease evolution, therapy resistance, and poor clinical outcomes. Over the last two decades, much attention has been devoted to understanding the functional roles of miRs in NB biology. This review focuses on highlighting the important implications of miRs within the context of NB disease progression, particularly miRs’ influences on NB disease evolution and therapy resistance. In this review, we discuss the functions of both the “oncomiRs” and “tumor suppressor miRs” in NB progression/therapy resistance. These are the critical components to be considered during the development of novel miR-based therapeutic strategies to counter therapy resistance.
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Affiliation(s)
- Natarajan Aravindan
- Department of Radiation Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Karthikeyan Subramanian
- Department of Radiation Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Dinesh Babu Somasundaram
- Department of Radiation Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Terence S Herman
- Department of Radiation Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
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Petrek H, Yu A. MicroRNAs in non-small cell lung cancer: Gene regulation, impact on cancer cellular processes, and therapeutic potential. Pharmacol Res Perspect 2019; 7:e00528. [PMID: 31859460 PMCID: PMC6923806 DOI: 10.1002/prp2.528] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Revised: 09/16/2019] [Accepted: 09/18/2019] [Indexed: 12/29/2022] Open
Abstract
Lung cancer remains the most lethal cancer among men and women in the United States and worldwide. The majority of lung cancer cases are classified as non-small cell lung cancer (NSCLC). Developing new therapeutics on the basis of better understanding of NSCLC biology is critical to improve the treatment of NSCLC. MicroRNAs (miRNAs or miRs) are a superfamily of genome-derived, small noncoding RNAs that govern posttranscriptional gene expression in cells. Functional miRNAs are commonly dysregulated in NSCLC, caused by genomic deletion, methylation, or altered processing, which may lead to the changes of many cancer-related pathways and processes, such as growth and death signaling, metabolism, angiogenesis, cell cycle, and epithelial to mesenchymal transition, as well as sensitivity to current therapies. With the understanding of miRNA biology in NSCLC, there are growing interests in developing new therapeutic strategies, namely restoration of tumor suppressive miRNAs and inhibition of tumor promotive miRNAs, to combat against NSCLC. In this article, we provide an overview on the molecular features of NSCLC and current treatment options with a focus on pharmacotherapy and personalized medicine. By illustrating the roles of miRNAs in the control of NSCLC tumorigenesis and progression, we highlight the latest efforts in assessing miRNA-based therapies in animal models and discuss some critical challenges in developing RNA therapeutics.
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Affiliation(s)
- Hannah Petrek
- Department of Biochemistry & Molecular MedicineUC Davis School of MedicineSacramentoCAUSA
| | - Ai‐Ming Yu
- Department of Biochemistry & Molecular MedicineUC Davis School of MedicineSacramentoCAUSA
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Liu WJ, Du Y, Wen R, Yang M, Xu J. Drug resistance to targeted therapeutic strategies in non-small cell lung cancer. Pharmacol Ther 2019; 206:107438. [PMID: 31715289 DOI: 10.1016/j.pharmthera.2019.107438] [Citation(s) in RCA: 125] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Accepted: 11/06/2019] [Indexed: 02/07/2023]
Abstract
Rapidly developing molecular biology techniques have been employed to identify cancer driver genes in specimens from patients with non-small cell lung cancer (NSCLC). Inhibitors and antibodies that specifically target driver gene-mediated signaling pathways to suppress tumor growth and progression are expected to extend the survival time and further improve the quality of life of patients. However, the health of patients with advanced and metastatic NSCLC presents significant challenges due to treatment resistance, mediated by cancer driver gene alteration, epigenetic alteration, and tumor heterogeneity. In this review, we discuss two different resistance mechanisms in NSCLC targeted therapies, namely changes in the targeted oncogenes (on-target resistance) and changes in other related signaling pathways (off-target resistance) in tumor cells. We highlight the conventional mechanisms of drug resistance elicited by the complex heterogeneous microenvironment of NSCLC during targeted therapy, including mutations in epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), the receptor tyrosine kinase ROS proto-oncogene 1 (ROS1), and the serine/threonine-protein kinase BRAF (v-Raf murine sarcoma viral oncogene homolog B). We also discuss the mechanism of action of less common oncoproteins, as in-depth understanding of these molecular mechanisms is important for optimizing treatment strategies.
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Affiliation(s)
- Wen-Juan Liu
- Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, China
| | - Yue Du
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Ru Wen
- Department of Medicine, Stanford University School of Medicine, California, USA
| | - Ming Yang
- Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, China.
| | - Jian Xu
- Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
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Zheng TL, Li DP, He ZF, Zhao S. miR-145 sensitizes esophageal squamous cell carcinoma to cisplatin through directly inhibiting PI3K/AKT signaling pathway. Cancer Cell Int 2019; 19:250. [PMID: 31582906 PMCID: PMC6767650 DOI: 10.1186/s12935-019-0943-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2019] [Accepted: 08/18/2019] [Indexed: 12/20/2022] Open
Abstract
Background Esophageal squamous cell carcinoma (ESCC) is the eighth most common cancer worldwide and is one of the most lethal malignancies. Cisplatin (DDP) is a key drug for ESCC treatment, but the presence of chemotherapy resistance limits the use of DDP. To enhance chemosensitivity to DDP is important for ESCC treatment. Methods qRT-PCR and Western blotting detected mRNA and protein expression in ESCC tissues and cells. Luciferase reporter assay assessed the interaction between miR-145 and AKT3. Cell cycle, apoptosis and proliferation were investigated with flow cytometry and MTT assay, respectively. Nude mice xenograft model was established, and immunohistochemistry (IHC) and TUNEL assay were conducted to detect Ki-67 level and apoptosis in xenograft tumor. Results Down-regulated miR-145 and up-regulated AKT3 were observed in ESCC tissues and cells. Luciferase reporter assay revealed that miR-145 negatively regulated AKT3 through binding to its 3′-UTR. Overexpression of miR-145 or knockdown of AKT3 promoted DDP-induced cell cycle arrest and apoptosis, as well as reduced IC50 of DDP treatment, which was reversed by AKT3 overexpression. The expression level of MRP1, P-gp, CyclinD1, c-Myc and anti-apoptotic protein Bcl-2 were down-regulated, while pro-apoptotic protein Bax was up-regulated by miR-145. Furthermore, overexpression of miR-145 enhanced the DDP-induced tumor growth suppression in vivo. Conclusion miR-145 increased the sensitivity of ESCC to DDP, and facilitated DDP-induced apoptosis, cycle arrest by directly inhibiting PI3K/AKT signaling pathway to decrease multidrug resistance-associated proteins MRP1 and P-gp expression. Improving the efficacy of DDP by boosting the miR-145 level provides a new strategy for treatment of ESCC.
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Affiliation(s)
- Tian-Liang Zheng
- 1Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, No. 1, East Jianshe Road, Erqi District, Zhengzhou, 450000 Henan Province People's Republic of China
| | - De-Ping Li
- Department of Acupuncture and Moxibustion, Zhengzhou Hospital of Traditional Chinese Medicine, Zhengzhou, 450000 People's Republic of China
| | - Zhan-Feng He
- 1Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, No. 1, East Jianshe Road, Erqi District, Zhengzhou, 450000 Henan Province People's Republic of China
| | - Song Zhao
- 1Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, No. 1, East Jianshe Road, Erqi District, Zhengzhou, 450000 Henan Province People's Republic of China
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Amri J, Molaee N, Baazm M, Karami H. Targeting Epidermal Growth Factor Receptor by MiRNA-145 Inhibits Cell Growth and Sensitizes NSCLC Cells to Erlotinib. Asian Pac J Cancer Prev 2019; 20:2781-2787. [PMID: 31554377 PMCID: PMC6976848 DOI: 10.31557/apjcp.2019.20.9.2781] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Accepted: 08/29/2019] [Indexed: 11/25/2022] Open
Abstract
Background: Despite effective activity of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), such as erlotinib, all non-small cell lung cancer (NSCLC) patients eventually acquire resistance to these agents. Studies have demonstrated that down-regulation of miRNA-145 leads to enhancement of EGFR expression, cell proliferation and metastasis. The aim of this study was to investigate the effect of miRNA-145 on sensitivity of the A549 NSCLC cells to erlotinib. Methods: Quantitative real-time PCR was used to examine the effect of miRNA-145 on EGFR expression. The effect of miRNA-145 on cell growth and sensitivity the lung cancer cells to erlotinib was examined by trypan blue and MTT assays, respectively. The combination index was calculated using the non-constant method of Chou-Talalay. Apoptosis was determined by ELISA cell death assay. Results: We found that miRNA-145 was markedly suppressed the expression of EGFR and inhibited the cancer cell growth, relative to blank control and negative control miRNA (p<0.05). Pretreatment with miRNA-145 synergistically enhanced the sensitivity of the lung cancer cells to erlotinib. Results of apoptosis assay revealed that miRNA-145 can induce apoptosis and increase the erlotinib-mediated apoptosis. Conclusions: Our data demonstrate that miRNA-145 play a critical role in the lung cancer cell growth, survival and EGFR-TKIs resistance possibly by regulation of EGFR. Therefore, miRNA-145 replacement therapy can become a new therapeutic strategy in lung cancer.
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Affiliation(s)
- Jamal Amri
- Molecular and Medicine Research Center, Faculty of Medicine, Arak University of Medical Sciences, Arak, Iran
- Traditional and Complementary Medicine Research Center, Faculty of Medicine, Arak University of Medical Sciences, Arak, Iran
| | - Neda Molaee
- Department of Molecular Medicine and Biotechnology, Faculty of Medicine, Arak University of Medical Sciences, Arak, Iran.
| | - Maryam Baazm
- Department of Anatomy, Faculty of Medicine, Arak University of Medical Sciences, Arak, Iran
| | - Hadi Karami
- Molecular and Medicine Research Center, Faculty of Medicine, Arak University of Medical Sciences, Arak, Iran
- Department of Molecular Medicine and Biotechnology, Faculty of Medicine, Arak University of Medical Sciences, Arak, Iran.
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Liu H, Xiong W, Liu F, Lin F, He J, Liu C, Lin Y, Dong S. Significant role and mechanism of microRNA-143-3p/KLLN axis in the development of coronary heart disease. Am J Transl Res 2019; 11:3610-3619. [PMID: 31312371 PMCID: PMC6614641] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2019] [Accepted: 05/11/2019] [Indexed: 06/10/2023]
Abstract
Cardiovascular disease predominantly includes coronary heart disease (CHD) and stroke, results in high morbidity and mortality. MicroRNA-143-3p (miR-143-3p) is a tumor suppressor and is involved in many cancers. However, the role and mechanism of miR-143-3p in coronary heart disease is still unclear. In this study, we identified that miR-143-3p was up-regulated in rabbit CHD model. The results of TargetScan and the dual luciferase reporter assay indicated that KLLN (killin, p53 regulated DNA replication inhibitor) was a direct target of miR-143-3p. Besides, we revealed that KLLN was down-regulated in rabbit coronary heart disease model. In addition, we found that the related-markers of CHD such as TC (total cholesterol), TG (triglyceride), and LDLC (low-density lipoprotein cholesterol) in the model group were significantly increased than that in the control group. And compared with the model group, miR-143-3p inhibitor significantly reduced TC, TG, LDLC expression, while miR-143-3p mimic further increased the expression of TC, TG, and LDLC. We next found that miR-143-3p mimic promoted cell viability and migration of vascular smooth muscle cells, inhibited apoptosis; and these changes were reversed by KLLN-plasmid. And miR-143-3p inhibitor had the counter effects. Our study provided a new target for the treatment of CHD and deserves further study.
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Affiliation(s)
- Huadong Liu
- Department of Cardiovascular, The Second Clinical Medical College (Shenzhen People's Hospital), Jinan University, Shenzhen Cardiovascular Minimal Invasive Engineering Center Shenzhen 518000, China
| | - Wei Xiong
- Department of Cardiovascular, The Second Clinical Medical College (Shenzhen People's Hospital), Jinan University, Shenzhen Cardiovascular Minimal Invasive Engineering Center Shenzhen 518000, China
| | - Feng Liu
- Department of Cardiovascular, The Second Clinical Medical College (Shenzhen People's Hospital), Jinan University, Shenzhen Cardiovascular Minimal Invasive Engineering Center Shenzhen 518000, China
| | - Feng Lin
- Department of Cardiovascular, The Second Clinical Medical College (Shenzhen People's Hospital), Jinan University, Shenzhen Cardiovascular Minimal Invasive Engineering Center Shenzhen 518000, China
| | - Junbo He
- Department of Cardiovascular, The Second Clinical Medical College (Shenzhen People's Hospital), Jinan University, Shenzhen Cardiovascular Minimal Invasive Engineering Center Shenzhen 518000, China
| | - Cheng Liu
- Department of Cardiovascular, The Second Clinical Medical College (Shenzhen People's Hospital), Jinan University, Shenzhen Cardiovascular Minimal Invasive Engineering Center Shenzhen 518000, China
| | - Yaowang Lin
- Department of Cardiovascular, The Second Clinical Medical College (Shenzhen People's Hospital), Jinan University, Shenzhen Cardiovascular Minimal Invasive Engineering Center Shenzhen 518000, China
| | - Shaohong Dong
- Department of Cardiovascular, The Second Clinical Medical College (Shenzhen People's Hospital), Jinan University, Shenzhen Cardiovascular Minimal Invasive Engineering Center Shenzhen 518000, China
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Zhang Y, Zhang L, Wang R, Wang B, Hua P, Li J. LncRNA Erbb4‐IR promotes esophageal squamous cell carcinoma (ESCC) by downregulating miR‐145. J Cell Biochem 2019; 120:17566-17572. [PMID: 31119810 DOI: 10.1002/jcb.29023] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Revised: 04/19/2019] [Accepted: 04/29/2019] [Indexed: 11/12/2022]
Affiliation(s)
- Yan Zhang
- Department of Thoracic Surgery The Second Hospital of Jilin University Changchun Jilin China
| | - Li Zhang
- Department of Anesthesiology The Second Hospital of Jilin University Changchun Jilin China
| | - Ruimin Wang
- Department of Operating Room The Second Hospital of Jilin University Changchun Jilin China
| | - Bin Wang
- Department of Thoracic Surgery The Second Hospital of Jilin University Changchun Jilin China
| | - Peiyan Hua
- Department of Thoracic Surgery The Second Hospital of Jilin University Changchun Jilin China
| | - Jindong Li
- Department of Thoracic Surgery The Second Hospital of Jilin University Changchun Jilin China
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Liu Q, Chen J, Wang B, Zheng Y, Wan Y, Wang Y, Zhou L, Liu S, Li G, Yan Y. Retracted: miR-145 modulates epithelial-mesenchymal transition and invasion by targeting ZEB2 in non-small cell lung cancer cell lines. J Cell Biochem 2019; 120:8409-8418. [PMID: 30525209 DOI: 10.1002/jcb.28126] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Accepted: 10/31/2018] [Indexed: 01/24/2023]
Abstract
Lung cancer is the leading cause of cancer-related deaths worldwide. Epithelial-mesenchymal transition (EMT) is a major event that drives cancer progression. Here we aim to investigate the role of microRNA, miR-145, in regulating EMT of the highly invasive non-small cell lung cancer (NSCLC). Quantitative real-time polymerase chain reaction analysis indicated that miR-145 was downregulated in cancer tissue compared with that in adjacent normal tissue. NSCLC cell lines, namely H1299, PC7, and SPCA-1, also demonstrated miR-145 downregulation, which is correlated well with their invasive ability, assessed by the Matrigel invasion assay. miR-145 overexpression resulted in downregulation of N-cadherin, and downregulation of vimentin and E-cadherin, suggesting a decreased EMT activity. TargetScan analysis predicted that a binding site exists between miR-145 and an oncogene, ZEB2, which was verified using the dual-luciferase assay. Alteration of miR-145 expression also induced inverse effects on ZEB2 expression, and a negative correlation exists between ZEB2 and miR-145 in human tissues. ZEB2 and miR-145 also exerted antagonizing effects on the invasion of NSCLC cells. Therefore, miR-145 is an important molecule in NSCLC that regulates cancer EMT through targeting ZEB2.
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Affiliation(s)
- Qun Liu
- Medical Ward 20, Lianshui County People's Hospital, Huai'an, Jiangsu, China
| | - Jianhui Chen
- Tongji University School of Medicine, Shanghai, China
- Department of Respiratory and Critical Care Medicine, Huai'an Second People's Hospital and The Affiliated Huai'an Hospital of Xuzhou Medical University, Huai'an, Jiangsu, China
| | - Baolan Wang
- Department of Respiratory Medicine, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, Jiangsu, China
| | - Yulong Zheng
- Department of Respiratory and Critical Care Medicine, Huai'an Second People's Hospital and The Affiliated Huai'an Hospital of Xuzhou Medical University, Huai'an, Jiangsu, China
| | - Yufeng Wan
- Department of Respiratory and Critical Care Medicine, Huai'an Second People's Hospital and The Affiliated Huai'an Hospital of Xuzhou Medical University, Huai'an, Jiangsu, China
| | - Yi Wang
- Department of Respiratory and Critical Care Medicine, Huai'an Second People's Hospital and The Affiliated Huai'an Hospital of Xuzhou Medical University, Huai'an, Jiangsu, China
| | - Liyang Zhou
- Department of Respiratory and Critical Care Medicine, Huai'an Second People's Hospital and The Affiliated Huai'an Hospital of Xuzhou Medical University, Huai'an, Jiangsu, China
| | - Shu Liu
- Department of Respiratory and Critical Care Medicine, Huai'an Second People's Hospital and The Affiliated Huai'an Hospital of Xuzhou Medical University, Huai'an, Jiangsu, China
| | - Gang Li
- Department of Respiratory and Critical Care Medicine, Huai'an Second People's Hospital and The Affiliated Huai'an Hospital of Xuzhou Medical University, Huai'an, Jiangsu, China
| | - Yi Yan
- Department of Respiratory Medicine, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
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MicroRNA in Lung Cancer Metastasis. Cancers (Basel) 2019; 11:cancers11020265. [PMID: 30813457 PMCID: PMC6406837 DOI: 10.3390/cancers11020265] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Revised: 02/17/2019] [Accepted: 02/18/2019] [Indexed: 12/12/2022] Open
Abstract
Tumor metastasis is a hallmark of cancer, with distant metastasis frequently developing in lung cancer, even at initial diagnosis, resulting in poor prognosis and high mortality. However, available biomarkers cannot reliably predict cancer spreading sites. The metastatic cascade involves highly complicated processes including invasion, migration, angiogenesis, and epithelial-to-mesenchymal transition that are tightly controlled by various genetic expression modalities along with interaction between cancer cells and the extracellular matrix. In particular, microRNAs (miRNAs), a group of small non-coding RNAs, can influence the transcriptional and post-transcriptional processes, with dysregulation of miRNA expression contributing to the regulation of cancer metastasis. Nevertheless, although miRNA-targeted therapy is widely studied in vitro and in vivo, this strategy currently affords limited feasibility and a few miRNA-targeted therapies for lung cancer have entered into clinical trials to date. Advances in understanding the molecular mechanism of metastasis will thus provide additional potential targets for lung cancer treatment. This review discusses the current research related to the role of miRNAs in lung cancer invasion and metastasis, with a particular focus on the different metastatic lesions and potential miRNA-targeted treatments for lung cancer with the expectation that further exploration of miRNA-targeted therapy may establish a new spectrum of lung cancer treatments.
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