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Aloliqi AA, Alnuqaydan AM, Albutti A, Alharbi BF, Rahmani AH, Khan AA. Current updates regarding biogenesis, functions and dysregulation of microRNAs in cancer: Innovative approaches for detection using CRISPR/Cas13‑based platforms (Review). Int J Mol Med 2025; 55:90. [PMID: 40242952 PMCID: PMC12021393 DOI: 10.3892/ijmm.2025.5531] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2025] [Accepted: 03/04/2025] [Indexed: 04/18/2025] Open
Abstract
MicroRNAs (miRNAs) are short non‑coding RNAs, which perform a key role in cellular differentiation and development. Most human diseases, particularly cancer, are linked to miRNA functional dysregulation implicated in the expression of tumor‑suppressive or oncogenic targets. Cancer hallmarks such as continued proliferative signaling, dodging growth suppressors, invasion and metastasis, triggering angiogenesis, and avoiding cell death have all been demonstrated to be affected by dysregulated miRNAs. Thus, for the treatment of different cancer types, the detection and quantification of this type of RNA is significant. The classical and current methods of RNA detection, including northern blotting, reverse transcription‑quantitative PCR, rolling circle amplification and next‑generation sequencing, may be effective but differ in efficiency and accuracy. Furthermore, these approaches are expensive, and require special instrumentation and expertise. Thus, researchers are constantly looking for more innovative approaches for miRNA detection, which can be advantageous in all aspects. In this regard, an RNA manipulation tool known as the CRISPR and CRISPR‑associated sequence 13 (CRISPR/Cas13) system has been found to be more advantageous in miRNA detection. The Cas13‑based miRNA detection approach is cost effective and requires no special instrumentation or expertise. However, more research and validation are required to confirm the growing body of CRISPR/Cas13‑based research that has identified miRNAs as possible cancer biomarkers for diagnosis and prognosis, and as targets for treatment. In the present review, current updates regarding miRNA biogenesis, structural and functional aspects, and miRNA dysregulation during cancer are described. In addition, novel approaches using the CRISPR/Cas13 system as a next‑generation tool for miRNA detection are discussed. Furthermore, challenges and prospects of CRISPR/Cas13‑based miRNA detection approaches are described.
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Affiliation(s)
- Abdulaziz A. Aloliqi
- Department of Basic Health Sciences, College of Applied Medical Sciences, Qassim University, Buraydah, Al-Qassim 51452, Saudi Arabia
| | - Abdullah M. Alnuqaydan
- Department of Basic Health Sciences, College of Applied Medical Sciences, Qassim University, Buraydah, Al-Qassim 51452, Saudi Arabia
| | - Aqel Albutti
- Department of Basic Health Sciences, College of Applied Medical Sciences, Qassim University, Buraydah, Al-Qassim 51452, Saudi Arabia
| | - Basmah F. Alharbi
- Department of Basic Health Sciences, College of Applied Medical Sciences, Qassim University, Buraydah, Al-Qassim 51452, Saudi Arabia
| | - Arshad Husain Rahmani
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah, Al-Qassim 51452, Saudi Arabia
| | - Amjad Ali Khan
- Department of Basic Health Sciences, College of Applied Medical Sciences, Qassim University, Buraydah, Al-Qassim 51452, Saudi Arabia
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Yin H, Zhang M, Zhang Y, Zhang X, Zhang X, Zhang B. Liquid biopsies in cancer. MOLECULAR BIOMEDICINE 2025; 6:18. [PMID: 40108089 PMCID: PMC11923355 DOI: 10.1186/s43556-025-00257-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 02/14/2025] [Accepted: 02/23/2025] [Indexed: 03/22/2025] Open
Abstract
Cancer ranks among the most lethal diseases worldwide. Tissue biopsy is currently the primary method for the diagnosis and biological analysis of various solid tumors. However, this method has some disadvantages related to insufficient tissue specimen collection and intratumoral heterogeneity. Liquid biopsy is a noninvasive approach for identifying cancer-related biomarkers in peripheral blood, which allows for repetitive sampling across multiple time points. In the field of liquid biopsy, representative biomarkers include circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), and exosomes. Many studies have evaluated the prognostic and predictive roles of CTCs and ctDNA in various solid tumors. Although these studies have limitations, the results of most studies appear to consistently demonstrate the correlations of high CTC counts and ctDNA mutations with lower survival rates in cancer patients. Similarly, a reduction in CTC counts throughout therapy may be a potential prognostic indicator related to treatment response in advanced cancer patients. Moreover, the biochemical characteristics of CTCs and ctDNA can provide information about tumor biology as well as resistance mechanisms against targeted therapy. This review discusses the current clinical applications of liquid biopsy in cancer patients, emphasizing its possible utility in outcome prediction and treatment decision-making.
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Affiliation(s)
- Hang Yin
- The First Affiliated Hospital of Dalian Medical University, Dalian, 116000, China
| | - Manjie Zhang
- The First Affiliated Hospital of Dalian Medical University, Dalian, 116000, China
| | - Yu Zhang
- Dalian Medical University, Dalian, 116000, China
| | - Xuebing Zhang
- The First Affiliated Hospital of Dalian Medical University, Dalian, 116000, China
| | - Xia Zhang
- Dalian Fifth People's Hospital, Dalian, 116000, China.
| | - Bin Zhang
- The First Affiliated Hospital of Dalian Medical University, Dalian, 116000, China.
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Zavadil J, Juracek J, Cechova B, Rohan T, Husty J, Slaby O, Litschmannova M, Uher M, Goldberg SN, Andrasina T. Tumor Suppressor miR-34a: Potential Biomarker of TACE Response in HCC. Cardiovasc Intervent Radiol 2025; 48:26-37. [PMID: 39638971 DOI: 10.1007/s00270-024-03908-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2024] [Accepted: 10/24/2024] [Indexed: 12/07/2024]
Abstract
PURPOSE TACE induces variable systemic effects by producing factors that promote inflammation, oncogenesis, and angiogenesis. Here we compare concentrations of microRNAs (miR-21, miR-210 and miR-34a) and vascular endothelial growth factor (VEGF) in hepatocellular carcinoma (HCC) patients undergoing TACE with degradable (DSM) and nondegradable (DEB) particles and potential use of these biomarker changes for prediction of patient outcomes. MATERIALS AND METHODS Overall, 52 patients with HCC treated with DSM TACE (24 patients) and DEB TACE (28 patients) were included in this prospective study. Concentrations of studied biomarkers were measured from blood plasma preprocedurally, immediately (< 90 min) postprocedurally, and 24-h after TACE. Levels were compared between DSM and DEB TACE and correlated with treatment response six and 12 months after the first TACE. RESULTS Both DSM and DEB TACE elevated plasma levels of miR-21, miR-34a, and miR-210 at 24 h post-procedure compared to baseline levels (FC 1.25-4.0). MiR-34a elevation immediately after TACE was significantly associated with nonprogressive disease compared to those with progressive disease at both six months (FCa: p = 0.014) and 12 months (FCa: p = 0.029) post-TACE. No significant biomarker changes were found between the embolization particle groups. However, VEGF levels showed a decrease only in the DSM TACE group (FC24: p = < 0.001). CONCLUSION Embolization particle type did not significantly impact miRNA or VEGF changes post-TACE. However, miR-34a elevation immediately after the procedure predicts better patient outcome and may prove useful as a biomarkers for the monitoring of clinical outcomes. LEVEL OF EVIDENCE Level 3 Prospective cohort study.
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Affiliation(s)
- Jan Zavadil
- Department of Radiology and Nuclear Medicine, University Hospital Brno and Masaryk University Brno, Jihlavská 340/20, 625 00, Brno, Czechia
| | - Jaroslav Juracek
- Central European Institute of Technology, Kamenice 753/5, 625 00, Brno, Czechia
- CERIT-SC Centre, Institute of Computer Science, Masaryk University, Šumavská 416/15, 602 00, Brno, Czechia
| | - Barbora Cechova
- Department of Radiology and Nuclear Medicine, University Hospital Brno and Masaryk University Brno, Jihlavská 340/20, 625 00, Brno, Czechia
| | - Tomas Rohan
- Department of Radiology and Nuclear Medicine, University Hospital Brno and Masaryk University Brno, Jihlavská 340/20, 625 00, Brno, Czechia
| | - Jakub Husty
- Department of Radiology and Nuclear Medicine, University Hospital Brno and Masaryk University Brno, Jihlavská 340/20, 625 00, Brno, Czechia
| | - Ondrej Slaby
- Central European Institute of Technology, Kamenice 753/5, 625 00, Brno, Czechia
| | - Martina Litschmannova
- Department of Applied Mathematics, Faculty of Electrical Engineering and Computer Science, VSB-Technical University of Ostrava, 17. Listopadu 2172/15, 708 00, Ostrava, Czechia
| | - Michal Uher
- Masaryk Memorial Cancer Institute, Žlutý Kopec 543/7, 602 00, Brno, Czechia
| | - S Nahum Goldberg
- Hadassah Hebrew University Medical Center, Ein Karem, Jerusalem, Israel
| | - Tomas Andrasina
- Department of Radiology and Nuclear Medicine, University Hospital Brno and Masaryk University Brno, Jihlavská 340/20, 625 00, Brno, Czechia.
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Zhang X, Meng Z, Yang C, Wang C, Zhang K, Shi A, Guo J, Feng Y, Zeng Y. miR-210 loss leads to widespread phenotypic and gene expression changes in human 293T cells. Front Genet 2024; 15:1486252. [PMID: 39737000 PMCID: PMC11683127 DOI: 10.3389/fgene.2024.1486252] [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: 08/25/2024] [Accepted: 12/02/2024] [Indexed: 01/01/2025] Open
Abstract
Introduction Hypoxia responses are critical for myriad physiological and pathological processes, such as development, tissue repair, would healing, and tumorigenesis. microRNAs (miRNAs) are a class of small non-coding RNAs that exert their functions by inhibiting the expression of their target genes, and miR-210 is the miRNA universally and most conspicuously upregulated by hypoxia in mammalian systems. For its relationship to hypoxia, miR-210 has been studied extensively, yet no consensus exists on the roles and mechanisms of miR-210 in human physiological processes or diseases, and we know little about genuine miR-210 target genes in humans. Methods To better investigate the functions and mechanisms of human miR-210, therefore, we derived the human miR-210 gene knockout (KO) 293T cell lines using the CRISPR/Cas9 technology. We then examined the cellular phenotypes and gene expression profiles of 293T cells under normoxia and hypoxia conditions. Results and Discussion We found that the loss of miR-210 altered a variety of cellular phenotypes including proliferation and apoptosis. Subsequent global gene expression analyses identified plausible mechanisms underlying these phenotypic changes in 293T cells. In particular, we showed that miR-210 might target the expression of BNIP3L as a potential mechanism to suppress apoptosis. Surprisingly, the mRNA levels of most previously reported miR-210 target genes were not induced upon miR-210 KO, suggesting a need to reexamining and studying human miR-210 functions directly and comprehensively. Thus, our work established a human cellular system and opportunity to unravel the complexity of the regulatory networks by miR-210.
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Affiliation(s)
- Xiaoxiao Zhang
- Department of Zoology, College of Life Sciences, Nanjing Agricultural University, Nanjing, Jiangsu, China
| | - Zhen Meng
- Department of Zoology, College of Life Sciences, Nanjing Agricultural University, Nanjing, Jiangsu, China
| | - Chengyong Yang
- Department of Zoology, College of Life Sciences, Nanjing Agricultural University, Nanjing, Jiangsu, China
| | - Chenghao Wang
- Department of Zoology, College of Life Sciences, Nanjing Agricultural University, Nanjing, Jiangsu, China
| | - Kexin Zhang
- Department of Zoology, College of Life Sciences, Nanjing Agricultural University, Nanjing, Jiangsu, China
| | - Anxin Shi
- Department of Zoology, College of Life Sciences, Nanjing Agricultural University, Nanjing, Jiangsu, China
| | - Jingjing Guo
- Centre in Artificial Intelligence Driven Drug Discovery, Faculty of Applied Sciences, Macao Polytechnic University, Macao, China
| | - Yong Feng
- Institute of Medical Virology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei, China
| | - Yan Zeng
- Department of Zoology, College of Life Sciences, Nanjing Agricultural University, Nanjing, Jiangsu, China
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Mortoglou M, Lian M, Miralles F, Dart DA, Uysal-Onganer P. miR-210 Mediated Hypoxic Responses in Pancreatic Ductal Adenocarcinoma. ACS OMEGA 2024; 9:47872-47883. [PMID: 39651070 PMCID: PMC11618397 DOI: 10.1021/acsomega.4c08947] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Revised: 11/11/2024] [Accepted: 11/14/2024] [Indexed: 12/11/2024]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one among the most lethal malignancies due to its aggressive behavior and resistance to conventional therapies. Hypoxia significantly contributes to cancer progression and therapeutic resistance of PDAC. microRNAs (miRNAs/miRs) have emerged as critical regulators of various biological processes. miR-210 is known as the "hypoxamir" due to its prominent role in cellular responses to hypoxia. In this study, we investigated the multifaceted role of miR-210 in PDAC using miR-210 knockout (KO) cellular models to elucidate its functions under hypoxic conditions. Hypoxia-inducible factor-1α (HIF1-α), a key transcription factor activated in response to low oxygen levels, upregulates miR-210. miR-210 maintains cancer stem cell (CSC) phenotypes and promotes epithelial-mesenchymal transition (EMT), which is essential for tumor initiation, metastasis, and therapeutic resistance. Our findings demonstrate that miR-210 regulates the expression of CSC markers, such as CD24, CD44, and CD133, and EMT markers, including E-cadherin, Vimentin, and Snail. Specifically, depletion of miR-210 reversed EMT and CSC marker expression levels in hypoxic Panc-1 and MiaPaCa-2 PDAC cells. These regulatory actions facilitate a more invasive and treatment-resistant PDAC phenotype. Understanding the regulatory network involving miR-210 under hypoxic conditions may reveal new therapeutic targets for combating PDAC and improving patient outcomes. Our data suggest that miR-210 is a critical regulator of HIF1-α expression, EMT, and the stemness of PDAC cells in hypoxic environments.
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Affiliation(s)
- Maria Mortoglou
- Cancer
Mechanisms and Biomarkers Research Group, School of Life Sciences, University of Westminster, London W1W 6UW, U.K.
| | - Mutian Lian
- Cancer
Mechanisms and Biomarkers Research Group, School of Life Sciences, University of Westminster, London W1W 6UW, U.K.
| | - Francesc Miralles
- School
of Health and Medical Sciences, City St
George’s, University of London, Cranmer Terrace, London SW17 0RE, U.K.
| | - D. Alwyn Dart
- UCL
Cancer Institute, University College London, Paul O’Gorman Building, 72
Huntley Street, London WC1E 6DD, U.K.
| | - Pinar Uysal-Onganer
- Cancer
Mechanisms and Biomarkers Research Group, School of Life Sciences, University of Westminster, London W1W 6UW, U.K.
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Szymanska M, Basavaraja R, Meidan R. A tale of two endothelins: the rise and fall of the corpus luteum. Reprod Fertil Dev 2024; 37:RD24158. [PMID: 39680472 DOI: 10.1071/rd24158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Accepted: 11/28/2024] [Indexed: 12/18/2024] Open
Abstract
Endothelins are small 21 amino acid peptides that interact with G-protein-coupled receptors. They are highly conserved across species and play important roles in vascular biology as well as in disease development and progression. Endothelins, mainly endothelin-1 and endothelin-2, are intricately involved in ovarian function and metabolism. These two peptides differ only in two amino acids but are encoded by different genes, which suggests an independent regulation and a cell-specific mode of expression. This review aims to comprehensively discuss the distinct regulation and roles of endothelin-1 and endothelin-2 regarding corpus luteum function throughout its life span.
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Affiliation(s)
- Magdalena Szymanska
- Department of Animal Sciences, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot 7610001, Israel; and Present address: Department of Hormonal Action Mechanisms, Institute of Animal Reproduction and Food Research of the Polish Academy of Sciences, Olsztyn, Poland
| | - Raghavendra Basavaraja
- Department of Animal Sciences, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot 7610001, Israel; and Present address: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Rina Meidan
- Department of Animal Sciences, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot 7610001, Israel
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Lai Y, Fu Z, Gao Y, Ma N, Li L. Hypoxia-inducible factors (HIFs) in early pregnancy: implications for miscarriage†. Biol Reprod 2024; 111:987-999. [PMID: 39325972 DOI: 10.1093/biolre/ioae139] [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: 05/09/2024] [Revised: 09/07/2024] [Accepted: 09/25/2024] [Indexed: 09/28/2024] Open
Abstract
Miscarriage poses a significant threat to both maternal and fetal health. Its etiology remains unknown, and there are no established effective identification or prevention strategies. A low-oxygen environment in early pregnancy is a physiological necessity for embryonic and placental growth. Hypoxia-inducible factors are a family of classic hypoxia signaling molecules whose expression level may fluctuate abnormally because of an imbalance in oxygen levels. Its unusual fluctuations initiate multiple signaling pathways at the maternal womb. Hypoxia-inducible factors are a family of classic hypoxia-signaling molecules and immune tolerance. Notably, aberrant regulation of these processes may lead to miscarriage. This review aims to clarify how the hypoxia-inducible factor-1α mediates the aberrant regulation of biological processes, including autophagy, metabolic reprogramming, et al., and how these effects impact trophoblasts and other cells at the maternal-fetal interface. These findings provide new insights into potential therapeutic and preventive strategies for miscarriage.
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Affiliation(s)
- Yuxuan Lai
- Department of Social Medicine and Health Care Management, School of Public Health, Hebei Medical University, Shijiazhuang, China
| | - Zhiyu Fu
- Department of Social Medicine and Health Care Management, School of Public Health, Hebei Medical University, Shijiazhuang, China
| | - Yaxin Gao
- Department of Social Medicine and Health Care Management, School of Public Health, Hebei Medical University, Shijiazhuang, China
- Hebei Key Laboratory of Environment and Population Health, School of Public Health, Hebei Medical University, Shijiazhuang, China
| | - Ning Ma
- Department of Social Medicine and Health Care Management, School of Public Health, Hebei Medical University, Shijiazhuang, China
- Hebei Key Laboratory of Environment and Population Health, School of Public Health, Hebei Medical University, Shijiazhuang, China
| | - Lu Li
- Department of Social Medicine and Health Care Management, School of Public Health, Hebei Medical University, Shijiazhuang, China
- Hebei Key Laboratory of Environment and Population Health, School of Public Health, Hebei Medical University, Shijiazhuang, China
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8
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Jia L, Meng Q, Xu X. Autophagy-related miRNAs, exosomal miRNAs, and circRNAs in tumor progression and drug-and radiation resistance in colorectal cancer. Pathol Res Pract 2024; 263:155597. [PMID: 39426141 DOI: 10.1016/j.prp.2024.155597] [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: 04/13/2024] [Revised: 07/16/2024] [Accepted: 09/20/2024] [Indexed: 10/21/2024]
Abstract
Targeted therapies are often more tolerable than traditional cytotoxic ones. Nurses play a critical role in providing patients and caregivers with information about the disease, available therapies, and the kind, severity, and identification of any potential adverse events. By doing this, it may be possible to ensure that any adverse effects are managed quickly, maximizing the therapeutic benefit. In colorectal cancer (CRC), autophagy-related activities are significantly influenced by miRNAs and exosomal miRNAs. CRC development and treatment resistance have been associated with the cellular process of autophagy. miRNAs, which are short non-coding RNA molecules, have the ability to control the expression of genes by binding to the 3' untranslated region (UTR) of target mRNAs and either preventing or suppressing translation. It has been discovered that several miRNAs are significant regulators of CRC autophagy. By preventing autophagy, these miRNAs enhance the survival and growth of cancer cells. Exosomes are small membrane vesicles that are released by cells and include miRNAs among other bioactive compounds. Exosomes have the ability to modify recipient cells' biological processes by delivering their cargo, which includes miRNAs. It has been demonstrated that exosomal miRNAs control autophagy in CRC in both autocrine and paracrine ways. We will discuss the potential roles of miRNAs, exosomal miRNAs, and circRNAs in CRC autophagy processes and how nursing care can reduce unfavorable outcomes.
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Affiliation(s)
- Liting Jia
- Cardiovascular Center, Beijing Friendship Hospital, Capital Medical University, Beijing 102413, China
| | - Qingyun Meng
- Gastroenterology Department, Qingdao Municipal Hospital, Qingdao 266000, China
| | - Xiaofeng Xu
- Thoracic Surgery, Qingdao Municipal Hospital, Qingdao 266000, China.
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Helen H, Gunawan MC, Halim P, Dinata MR, Ahmed A, Dalimunthe A, Marianne M, Ribeiro RIMDA, Hasibuan PAZ, Nurkolis F, Hey-Hawkins E, Park MN, Harahap U, Kim SH, Kim B, Syahputra RA. Flavonoids as modulators of miRNA expression in pancreatic cancer: Pathways, Mechanisms, And Therapeutic Potential. Biomed Pharmacother 2024; 179:117347. [PMID: 39241569 DOI: 10.1016/j.biopha.2024.117347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Revised: 08/20/2024] [Accepted: 08/22/2024] [Indexed: 09/09/2024] Open
Abstract
Pancreatic cancer (PC) is a complex malignancy, distinguished by its aggressive characteristics and unfavorable prognosis. Recent developments in understanding the molecular foundations of this disease have brought attention to the noteworthy involvement of microRNAs (miRNAs) in disease development, advancement, and treatment resistance. The anticancer capabilities of flavonoids, which are a wide range of phytochemicals present in fruits and vegetables, have attracted considerable interest because of their ability to regulate miRNA expression. This review provides the effects of flavonoids on miRNA expression in PC, explains the underlying processes, and explores the possible therapeutic benefits of flavonoid-based therapies. Flavonoids inhibit PC cell proliferation, induce apoptosis, and enhance chemosensitivity via the modulation of miRNAs involved in carcinogenesis. Additionally, this review emphasizes the significance of certain miRNAs as targets of flavonoid action. These miRNAs have a role in regulating important signaling pathways such as the phosphoinositide-3-kinase-protein kinase B/Protein kinase B (Akt), mitogen activated protein kinase (MAPK), Janus kinase/signal transducers and activators of transcription (JAK/STAT), and Wnt/β-catenin pathways. This review aims to consolidate current knowledge on the interaction between flavonoids and miRNAs in PC, providing a comprehensive analysis of how flavonoid-mediated modulation of miRNA expression could influence cancer progression and therapy. It highlights the use of flavonoid nanoformulations to enhance stability, increase absorption, and maximize anti-PC activity, improving patient outcomes. The review calls for further research to optimize the use of flavonoid nanoformulations in clinical trials, leading to innovative treatment strategies and more effective approaches for PC.
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Affiliation(s)
- Helen Helen
- Department of Pharmacology, Faculty of Pharmacy, Universitas Sumatera Utara, Sumatera Utara, Indonesia
| | - Mega Carensia Gunawan
- Department of Pharmacology, Faculty of Pharmacy, Universitas Sumatera Utara, Sumatera Utara, Indonesia
| | - Princella Halim
- Department of Pharmacology, Faculty of Pharmacy, Universitas Sumatera Utara, Sumatera Utara, Indonesia
| | - Muhammad Riza Dinata
- Department of Pharmacology, Faculty of Pharmacy, Universitas Sumatera Utara, Sumatera Utara, Indonesia
| | - Amer Ahmed
- Department of Bioscience, Biotechnology and Environment, University of Bari, Bari, Italy
| | - Aminah Dalimunthe
- Department of Pharmacology, Faculty of Pharmacy, Universitas Sumatera Utara, Sumatera Utara, Indonesia
| | - Marianne Marianne
- Department of Pharmacology, Faculty of Pharmacy, Universitas Sumatera Utara, Sumatera Utara, Indonesia
| | - Rosy Iara Maciel De Azambuja Ribeiro
- Experimental Pathology Laboratory, Federal University of São João del Rei (UFSJ), 400, Sebastião Gonçalves Coelho, Chanadour, Divinópolis 35501-296, MG, Brazil
| | | | - Fahrul Nurkolis
- Biological Sciences, Faculty of Sciences and Technology, UIN Sunan Kalijaga, Yogyakarta, Indonesia
| | - Evamarie Hey-Hawkins
- Leipzig University, Faculty of Chemistry and Mineralogy, Centre for Biotechnology and Biomedicine (BBZ), Institute of Bioanalytical Chemistry, Deutscher Platz 5, 04103 Leipzig, Germany
| | - Moon Nyeo Park
- Department of Internal Medicine, College of Korean Medicine, Kyung Hee University, Seoul, 02447, Republic of Korea; College of Korean Medicine, Kyung Hee University, Hoegidong, Dongdaemungu, Seoul, 05253, Republic of Korea
| | - Urip Harahap
- Department of Pharmacology, Faculty of Pharmacy, Universitas Sumatera Utara, Sumatera Utara, Indonesia
| | - Sung-Hoon Kim
- Department of Internal Medicine, College of Korean Medicine, Kyung Hee University, Seoul, 02447, Republic of Korea
| | - Bonglee Kim
- Department of Internal Medicine, College of Korean Medicine, Kyung Hee University, Seoul, 02447, Republic of Korea; College of Korean Medicine, Kyung Hee University, Hoegidong, Dongdaemungu, Seoul, 05253, Republic of Korea
| | - Rony Abdi Syahputra
- Department of Pharmacology, Faculty of Pharmacy, Universitas Sumatera Utara, Sumatera Utara, Indonesia.
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Imamura T, Komatsu S, Nishibeppu K, Kiuchi J, Ohashi T, Konishi H, Shiozaki A, Yamamoto Y, Moriumura R, Ikoma H, Ochiai T, Otsuji E. Urinary microRNA-210-3p as a novel and non-invasive biomarker for the detection of pancreatic cancer, including intraductal papillary mucinous carcinoma. BMC Cancer 2024; 24:907. [PMID: 39069624 DOI: 10.1186/s12885-024-12676-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Accepted: 07/23/2024] [Indexed: 07/30/2024] Open
Abstract
BACKGROUND This study aims to explore novel microRNAs in urine for screening and predicting clinical characteristics in pancreatic cancer (PC) patients using a microRNA array-based approach. METHODS We used the Toray® 3D-Gene microRNA array-based approach to compare urinary levels between PC patients and healthy volunteers. RESULTS (1) Four oncogenic microRNAs (miR-744-5p, miR-572, miR-210-3p, and miR-575) that were highly upregulated in the urine of PC patients compared to healthy individuals were identified by comprehensive microRNA array analysis. (2) Test-scale analysis by quantitative RT-PCR for each group of 20 cases showed that miR-210-3p was significantly upregulated in the urine of PC patients compared to healthy individuals (P = 0.009). (3) Validation analysis (58 PC patients and 35 healthy individuals) confirmed that miR-210-3p was significantly upregulated in the urine of PC patients compared to healthy individuals (P < 0.001, area under the receiver operating characteristic curve = 0.79, sensitivity: 0.828, specificity: 0.743). We differentiated PC patients into invasive ductal carcinoma (IDCa) and intraductal papillary mucinous carcinoma (IPMC) groups. In addition to urinary miR-210-3p levels being upregulated in IDCa over healthy individuals (P = 0.009), urinary miR-210-3p levels were also elevated in IPMC over healthy individuals (P = 0.0018). Urinary miR-210-3p can differentiate IPMC from healthy individuals by a cutoff of 8.02 with an AUC value of 0.762, sensitivity of 94%, and specificity of 63%. (4) To test whether urinary miR210-3p levels reflected plasma miR-210-3p levels, we examined the correlation between urinary and plasma levels. Spearman's correlation analysis showed a moderate positive correlation (ρ = 0.64, P = 0.005) between miR-210-3p expression in plasma and urine. CONCLUSIONS Urinary miR-210-3p is a promising, non-invasive diagnostic biomarker of PC, including IPMC. TRIAL REGISTRATION Not applicable.
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MESH Headings
- Humans
- MicroRNAs/urine
- MicroRNAs/blood
- MicroRNAs/genetics
- Female
- Male
- Biomarkers, Tumor/urine
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/blood
- Pancreatic Neoplasms/urine
- Pancreatic Neoplasms/genetics
- Pancreatic Neoplasms/diagnosis
- Pancreatic Neoplasms/blood
- Middle Aged
- Aged
- Adenocarcinoma, Mucinous/urine
- Adenocarcinoma, Mucinous/genetics
- Adenocarcinoma, Mucinous/diagnosis
- ROC Curve
- Case-Control Studies
- Gene Expression Regulation, Neoplastic
- Adult
- Carcinoma, Pancreatic Ductal/urine
- Carcinoma, Pancreatic Ductal/genetics
- Carcinoma, Pancreatic Ductal/diagnosis
- Carcinoma, Pancreatic Ductal/blood
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Affiliation(s)
- Taisuke Imamura
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii- cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Shuhei Komatsu
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii- cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan.
| | - Keiji Nishibeppu
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii- cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Jun Kiuchi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii- cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Takuma Ohashi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii- cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Hirotaka Konishi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii- cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Atsushi Shiozaki
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii- cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Yusuke Yamamoto
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii- cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Ryo Moriumura
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii- cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Hisashi Ikoma
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii- cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Toshiya Ochiai
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii- cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Eigo Otsuji
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii- cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
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11
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Slawski J, Jaśkiewicz M, Barton A, Kozioł S, Collawn JF, Bartoszewski R. Regulation of the HIF switch in human endothelial and cancer cells. Eur J Cell Biol 2024; 103:151386. [PMID: 38262137 DOI: 10.1016/j.ejcb.2024.151386] [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: 10/25/2023] [Revised: 01/17/2024] [Accepted: 01/17/2024] [Indexed: 01/25/2024] Open
Abstract
Hypoxia-inducible factors (HIFs) are transcription factors that reprogram the transcriptome for cells to survive hypoxic insults and oxidative stress. They are important during embryonic development and reprogram the cells to utilize glycolysis when the oxygen levels are extremely low. This metabolic change facilitates normal cell survival as well as cancer cell survival. The key feature in survival is the transition between acute hypoxia and chronic hypoxia, and this is regulated by the transition between HIF-1 expression and HIF-2/HIF-3 expression. This transition is observed in many human cancers and endothelial cells and referred to as the HIF Switch. Here we discuss the mechanisms involved in the HIF Switch in human endothelial and cancer cells which include mRNA and protein levels of the alpha chains of the HIFs. A major continuing effort in this field is directed towards determining the differences between normal and tumor cell utilization of this important pathway, and how this could lead to potential therapeutic approaches.
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Affiliation(s)
- Jakub Slawski
- Department of Biophysics, Faculty of Biotechnology, University of Wroclaw, Wroclaw, Poland
| | - Maciej Jaśkiewicz
- International Research Agenda 3P, Medicine Laboratory, Medical University of Gdansk, Gdansk, Poland
| | - Anna Barton
- Department of Biophysics, Faculty of Biotechnology, University of Wroclaw, Wroclaw, Poland
| | - Sylwia Kozioł
- Department of Biophysics, Faculty of Biotechnology, University of Wroclaw, Wroclaw, Poland
| | - James F Collawn
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, USA
| | - Rafał Bartoszewski
- Department of Biophysics, Faculty of Biotechnology, University of Wroclaw, Wroclaw, Poland.
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12
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Nemours S, Armesto M, Arestín M, Manini C, Giustetto D, Sperga M, Pivovarcikova K, Pérez-Montiel D, Hes O, Michal M, López JI, Lawrie CH. Non-coding RNA and gene expression analyses of papillary renal neoplasm with reverse polarity (PRNRP) reveal distinct pathological mechanisms from other renal neoplasms. Pathology 2024; 56:493-503. [PMID: 38413252 DOI: 10.1016/j.pathol.2023.11.013] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Revised: 10/25/2023] [Accepted: 11/14/2023] [Indexed: 02/29/2024]
Abstract
Papillary renal neoplasm with reversed polarity (PRNRP) is a recently described rare renal neoplasm. Traditionally, it was considered a variant of papillary renal cell carcinoma (PRCC). However, several studies reported significant differences between PRNRP and PRCC in terms of clinical, morphological, immunohistochemical and molecular features. Nonetheless, PRNRP remains a poorly understood entity. We used microarray analysis to elucidate the non-coding RNA (ncRNA) and gene expression profiles of 10 PRNRP cases and compared them with other renal neoplasms. Unsupervised cluster analysis showed that PRNRP had distinct expression profiles from either clear cell renal cell carcinoma (ccRCC) or PRCC cases at the level of ncRNA but were less distinct at the level of gene expression. An integrated omic approach determined miRNA:gene interactions that distinguished PRNRP from PRCC and we validated 10 differentially expressed miRNAs and six genes by quantitative RT-PCR. We found that levels of the miRNAs, miR-148a, miR-375 and miR-429, were up-regulated in PRNRP cases compared to ccRCC and PRCC. miRNA target genes, including KRAS and VEGFA oncogenes, and CXCL8, which regulates VEGFA, were also differentially expressed between renal neoplasms. Gene set enrichment analysis (GSEA) determined different activation of metabolic pathways between PRNRP and PRCC cases. Overall, this study is by far the largest molecular study of PRNRP cases and the first to investigate either ncRNA expression or their gene expression by microarray assays.
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MESH Headings
- Humans
- Kidney Neoplasms/genetics
- Kidney Neoplasms/pathology
- Kidney Neoplasms/metabolism
- Carcinoma, Renal Cell/genetics
- Carcinoma, Renal Cell/pathology
- Carcinoma, Renal Cell/metabolism
- Middle Aged
- Female
- Male
- Aged
- RNA, Untranslated/genetics
- Gene Expression Profiling
- MicroRNAs/genetics
- MicroRNAs/metabolism
- Gene Expression Regulation, Neoplastic
- Adult
- Carcinoma, Papillary/pathology
- Carcinoma, Papillary/genetics
- Carcinoma, Papillary/metabolism
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
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Affiliation(s)
- Stéphane Nemours
- Biogipuzkoa Health Research Institute, Oncology Area, Molecular Oncology Group, San Sebastian, Spain
| | - María Armesto
- Biogipuzkoa Health Research Institute, Oncology Area, Molecular Oncology Group, San Sebastian, Spain
| | - María Arestín
- Biogipuzkoa Health Research Institute, Oncology Area, Molecular Oncology Group, San Sebastian, Spain
| | - Claudia Manini
- Department of Pathology, San Giovanni Bosco Hospital, ASL Città di Torino, Turin, Italy; Department of Sciences of Public Health and Pediatrics, University of Turin, Italy
| | - Doriana Giustetto
- Department of Pathology, Maria Victoria Hospital, ASL Città di Torino, Turin, Italy
| | - Maris Sperga
- Department of Pathology, Stradin's University, Riga, Latvia
| | - Kristyna Pivovarcikova
- Department of Pathology, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic
| | | | - Ondrej Hes
- Department of Pathology, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic
| | - Michal Michal
- Department of Pathology, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic; Bioptical Laboratory Ltd, Pilsen, Czech Republic
| | - José I López
- Biocruces-Bizkaia Health Research Institute, Barakaldo, Spain
| | - Charles H Lawrie
- Biogipuzkoa Health Research Institute, Oncology Area, Molecular Oncology Group, San Sebastian, Spain; IKERBASQUE, Basque Foundation for Science, Bilbao, Spain; Sino-Swiss Institute of Advanced Technology (SSIAT), University of Shanghai, Shanghai, China; Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
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13
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Billi M, De Marinis E, Gentile M, Nervi C, Grignani F. Nuclear miRNAs: Gene Regulation Activities. Int J Mol Sci 2024; 25:6066. [PMID: 38892257 PMCID: PMC11172810 DOI: 10.3390/ijms25116066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 05/29/2024] [Accepted: 05/29/2024] [Indexed: 06/21/2024] Open
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs which contribute to the regulation of many physiological and pathological processes. Conventionally, miRNAs perform their activity in the cytoplasm where they regulate gene expression by interacting in a sequence-specific manner with mature messenger RNAs. Recent studies point to the presence of mature miRNAs in the nucleus. This review summarizes current findings regarding the molecular activities of nuclear miRNAs. These molecules can regulate gene expression at the transcriptional level by directly binding DNA on the promoter or the enhancer of regulated genes. miRNAs recruit different protein complexes to these regions, resulting in activation or repression of transcription, through a number of molecular mechanisms. Hematopoiesis is presented as a paradigmatic biological process whereby nuclear miRNAs possess a relevant regulatory role. Nuclear miRNAs can influence gene expression by affecting nuclear mRNA processing and by regulating pri-miRNA maturation, thus impacting the biogenesis of miRNAs themselves. Overall, nuclear miRNAs are biologically active molecules that can be critical for the fine tuning of gene expression and deserve further studies in a number of physiological and pathological conditions.
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Affiliation(s)
- Monia Billi
- General Pathology and Department of Medicine, University of Perugia, 06132 Perugia, Italy;
| | - Elisabetta De Marinis
- Department of Medical-Surgical Sciences and Biotechnologies, University of Rome “La Sapienza”, 04100 Latina, Italy; (E.D.M.); (M.G.); (C.N.)
| | - Martina Gentile
- Department of Medical-Surgical Sciences and Biotechnologies, University of Rome “La Sapienza”, 04100 Latina, Italy; (E.D.M.); (M.G.); (C.N.)
| | - Clara Nervi
- Department of Medical-Surgical Sciences and Biotechnologies, University of Rome “La Sapienza”, 04100 Latina, Italy; (E.D.M.); (M.G.); (C.N.)
| | - Francesco Grignani
- General Pathology and Department of Medicine, University of Perugia, 06132 Perugia, Italy;
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14
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Dai Z, Zhan Z, Chen Y, Li J. MiRNA-210 is involved in cigarette smoke extract-induced apoptosis of MLE-12 via the Shh signaling pathway. Tob Induc Dis 2024; 22:TID-22-92. [PMID: 38813585 PMCID: PMC11135024 DOI: 10.18332/tid/186643] [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: 09/06/2022] [Revised: 11/19/2023] [Accepted: 03/29/2024] [Indexed: 05/31/2024] Open
Abstract
INTRODUCTION The aim of the study is the regulatory effect of MicroRNA-210 (MiR-210) on cigarette smoke extract (CSE)-induced mouse lung epithelial type II cells (MLE-12) apoptosis and determine whether the MiR-210 is involved in cigarette smoke extract-induced apoptosis of MLE-12 via Shh signaling pathway. METHODS Expression of MiR-210 in CSE-induced MLE-12 was assessed by qRT-PCR. The emphysema mouse model and MiR-210 knockdown mice were each established by inhaling cigarette smoke or intratracheal lentiviral vector instillation. The Sonic hedgehog (Shh), Ptch1, Gli1, B-cell lymphoma-2 (Bcl-2), and Caspase 3 protein expressions were detected by Western blotting. mRNA expressions of MiR-210, Shh, Ptch1, and Gli1 were measured using quantitative real-time polymerase chain reaction (qRT-PCR). Apoptotic ratios in mice and CSE-induced HPVEC were assessed using TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) assays and flow cytometry. RESULTS Our results showed that MiR-210 mRNA levels were significantly down-regulated in the CSE-induced MLE 12. MLE 12 apoptosis with down-regulated Shh, Ptch1, Gli1, and Bcl-2 expression, increased Caspase 3 expression in the emphysema mouse model and CSE-induced MLE 12. Knockdown MiR-210 can facilitate cell apoptosis and emphysema via the Shh signaling pathway in mice. In vitro, MiR-210 can attenuate the apoptosis of CSE-exposed MLE 12. Moreover, MiR-210 regulated the Shh pathway and promoted its expression. CONCLUSIONS MiRNA-210 is involved in cigarette smoke extract-induced apoptosis of MLE-12 via the Shh signaling pathway. The present study reveals that MiRNA-210 may be a key regulator of cellular apoptosis and could be explored as a potential therapeutic target in the future.
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Affiliation(s)
- Zhongshang Dai
- Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Zijie Zhan
- Department of Pulmonary and Critical Care Medicine, the Second Xiangya Hospital, Central South University, Changsha, China
| | - Yan Chen
- Department of Pulmonary and Critical Care Medicine, the Second Xiangya Hospital, Central South University, Changsha, China
- Research Unit of Respiratory Disease, Central South University, Changsha, China
- Clinical Medical Research Center for Pulmonary and Critical Care Medicine in Hunan Province, Changsha, China
- Diagnosis and Treatment Center of Respiratory Disease, Central South University, Changsha, China
| | - Jinhua Li
- Department of Pulmonary and Critical Care Medicine, the Second Xiangya Hospital, Central South University, Changsha, China
- Research Unit of Respiratory Disease, Central South University, Changsha, China
- Clinical Medical Research Center for Pulmonary and Critical Care Medicine in Hunan Province, Changsha, China
- Diagnosis and Treatment Center of Respiratory Disease, Central South University, Changsha, China
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15
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Valencia-Cervantes J, Sierra-Vargas MP. Regulation of Cancer-Associated miRNAs Expression under Hypoxic Conditions. Anal Cell Pathol (Amst) 2024; 2024:5523283. [PMID: 38766303 PMCID: PMC11101257 DOI: 10.1155/2024/5523283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2023] [Revised: 04/17/2024] [Accepted: 04/27/2024] [Indexed: 05/22/2024] Open
Abstract
Solid tumors frequently experience hypoxia or low O2 levels. In these conditions, hypoxia-inducible factor 1 alpha (HIF-1α) is activated and acts as a transcription factor that regulates cancer cell adaptation to O2 and nutrient deprivation. HIF-1α controls gene expression associated with various signaling pathways that promote cancer cell proliferation and survival. MicroRNAs (miRNAs) are 22-nucleotide noncoding RNAs that play a role in various biological processes essential for cancer progression. This review presents an overview of how hypoxia regulates the expression of multiple miRNAs in the progression of cancer cells.
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Affiliation(s)
- Jesús Valencia-Cervantes
- Departamento de Investigación en Toxicología y Medicina Ambiental, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City 14080, Mexico
- Estancias Posdoctorales por México 2022 (1), Consejo Nacional de Humanidades, Ciencias y Tecnologías CONAHCYT, Mexico City 03940, Mexico
| | - Martha Patricia Sierra-Vargas
- Departamento de Investigación en Toxicología y Medicina Ambiental, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City 14080, Mexico
- Subdirección de Investigación Clínica, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City 14080, Mexico
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16
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Monaci S, Coppola F, Filippi I, Falsini A, Carraro F, Naldini A. Targeting hypoxia signaling pathways in angiogenesis. Front Physiol 2024; 15:1408750. [PMID: 38725568 PMCID: PMC11079266 DOI: 10.3389/fphys.2024.1408750] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Accepted: 04/10/2024] [Indexed: 05/12/2024] Open
Abstract
Oxygen (O2) supply is constantly maintained by the vascular network for a proper tissue oxygenation. Hypoxia is the result of an increased O2 demand and/or decreased supply and is common in both physiological conditions and human diseases. Angiogenesis is one of the adaptive responses to hypoxia and is mainly regulated by the hypoxia-inducible factors, HIFs. These heterodimeric transcription factors are composed of one of three O2-dependent α subunits (HIF-1, HIF-2, and HIF-3) and a constitutively expressed O2-insensitive subunit (HIF-1β). Among them HIF-1α is the most characterized and its activity is tightly controlled. Under hypoxia, its intracellular accumulation triggers the transcription of several genes, involved in cell survival/proliferation, autophagy, apoptosis, cell metabolism, and angiogenesis. HIF pathway is also modulated by specific microRNAs (miRNAs), thus resulting in the variation of several cellular responses, including alteration of the angiogenic process. The pro-angiogenic activity of HIF-1α is not restricted to endothelial cells, as it also affects the behavior of other cell types, including tumor and inflammatory/immune cells. In this context, exosomes play a crucial role in cell-cell communication by transferring bio-active cargos such as mRNAs, miRNAs, and proteins (e.g., VEGFA mRNA, miR210, HIF-1α). This minireview will provide a synopsis of the multiple factors able to modulate hypoxia-induced angiogenesis especially in the tumor microenvironment context. Targeting hypoxia signaling pathways by up-to-date approaches may be relevant in the design of therapeutic strategies in those pathologies where angiogenesis is dysregulated.
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Affiliation(s)
- Sara Monaci
- Cellular and Molecular Physiology Unit, Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy
| | - Federica Coppola
- Cellular and Molecular Physiology Unit, Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy
| | - Irene Filippi
- Cellular and Molecular Physiology Unit, Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy
| | - Alessandro Falsini
- Cellular and Molecular Physiology Unit, Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy
| | - Fabio Carraro
- Department of Medical Biotechnologies, University of Siena, Siena, Italy
| | - Antonella Naldini
- Cellular and Molecular Physiology Unit, Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy
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17
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Engin AB, Engin A. Next-Cell Hypothesis: Mechanism of Obesity-Associated Carcinogenesis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1460:727-766. [PMID: 39287871 DOI: 10.1007/978-3-031-63657-8_25] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/19/2024]
Abstract
Higher body fat content is related to a higher risk of mortality, and obesity-related cancer represents approximately 40% of all cancer patients diagnosed each year. Furthermore, epigenetic mechanisms are involved in cellular metabolic memory and can determine one's predisposition to being overweight. Low-grade chronic inflammation, a well-established characteristic of obesity, is a central component of tumor development and progression. Cancer-associated adipocytes (CAA), which enhance inflammation- and metastasis-related gene sets within the cancer microenvironment, have pro-tumoral effects. Adipose tissue is a major source of the exosomal micro ribonucleic acids (miRNAs), which modulate pathways involved in the development of obesity and obesity-related comorbidities. Owing to their composition of cargo, exosomes can activate receptors at the target cell or transfer molecules to the target cells and thereby change the phenotype of these cells. Exosomes that are released into the extracellular environment are internalized with their cargo by neighboring cells. The tumor-secreted exosomes promote organ-specific metastasis of tumor cells that normally lack the capacity to metastasize to a specific organ. Therefore, the communication between neighboring cells via exosomes is defined as the "next-cell hypothesis." The reciprocal interaction between the adipocyte and tumor cell is realized through the adipocyte-derived exosomal miRNAs and tumor cell-derived oncogenic miRNAs. The cargo molecules of adipocyte-derived exosomes are important messengers for intercellular communication involved in metabolic responses and have very specific signatures that direct the metabolic activity of target cells. RNA-induced silencing regulates gene expression through various mechanisms. Destabilization of DICER enzyme, which catalyzes the conversion of primary miRNA (pri-miRNA) to precursor miRNA (pre-miRNA), is an important checkpoint in cancer development and progression. Interestingly, adipose tissue in obesity and tumors share similar pathogenic features, and the local hypoxia progress in both. While hypoxia in obesity leads to the adipocyte dysfunction and metabolic abnormalities, in obesity-related cancer cases, it is associated with worsened prognosis, increased metastatic potential, and resistance to chemotherapy. Notch-interleukin-1 (IL-1)-Leptin crosstalk outcome is referred to as "NILCO effect." In this chapter, obesity-related cancer development is discussed in the context of "next-cell hypothesis," miRNA biogenesis, and "NILCO effect."
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Affiliation(s)
- Ayse Basak Engin
- Faculty of Pharmacy, Department of Toxicology, Gazi University, Hipodrom, Ankara, Turkey.
| | - Atilla Engin
- Faculty of Medicine, Department of General Surgery, Gazi University, Besevler, Ankara, Turkey
- Mustafa Kemal Mah. 2137. Sok. 8/14, 06520, Cankaya, Ankara, Turkey
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18
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Pandey C, Tiwari P. Differential microRNAs Expression during Cancer Development, and Chemoprevention by Natural Compounds: A Comprehensive Review. J Environ Pathol Toxicol Oncol 2024; 43:65-80. [PMID: 39016142 DOI: 10.1615/jenvironpatholtoxicoloncol.2024050357] [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: 07/18/2024] Open
Abstract
MicroRNAs are short non-coding RNAs that inhibit gene expression at the post-transcriptional level. Abnormal microRNA expression has been associated with different human diseases, including cancer. Epigenetic changes, mutation, transcriptional deregulation, DNA copy number abnormalities, and defects in the biogenesis machinery play an important role in abnormal microRNA expression. Modulation of microRNAs by natural agents has emerged to enhance the efficacy of conventional chemotherapy through combinatorial therapeutic approach. This review summarizes the current understanding of abnormal microRNA expression in cancer, the different cellular mechanisms of microRNA, and their prevention by natural compounds. Understanding microRNA expression patterns during cancer development may help to identify stage-specific molecular markers. Natural compounds that exert regulatory effects by modulating microRNAs can be used in better cancer chemopreventive strategies by directly targeting microRNAs or as a way to increase sensitivity to existing chemotherapy regimens.
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Affiliation(s)
- Chhaya Pandey
- School of Environmental Biology, Awadhesh Pratap Singh University, Rewa-486001, Madhya Pradesh, India
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19
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Lian M, Mortoglou M, Uysal-Onganer P. Impact of Hypoxia-Induced miR-210 on Pancreatic Cancer. Curr Issues Mol Biol 2023; 45:9778-9792. [PMID: 38132457 PMCID: PMC10742176 DOI: 10.3390/cimb45120611] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 11/29/2023] [Accepted: 12/04/2023] [Indexed: 12/23/2023] Open
Abstract
Pancreatic cancer (PC) poses significant clinical challenges, with late-stage diagnosis and limited therapeutic options contributing to its dismal prognosis. A hallmark feature of PC is the presence of a profoundly hypoxic tumour microenvironment, resulting from various factors such as fibrotic stroma, rapid tumour cell proliferation, and poor vascularization. Hypoxia plays a crucial role in promoting aggressive cancer behaviour, therapeutic resistance, and immunosuppression. Previous studies have explored the molecular mechanisms behind hypoxia-induced changes in PC, focusing on the role of hypoxia-inducible factors (HIFs). Among the myriad of molecules affected by hypoxia, microRNA-210 (miR-210) emerges as a central player. It is highly responsive to hypoxia and regulated by HIF-dependent and HIF-independent pathways. miR-210 influences critical cellular processes, including angiogenesis, metastasis, and apoptosis, all of which contribute to PC progression and resistance to treatment. Understanding these pathways provides insights into potential therapeutic targets. Furthermore, investigating the role of miR-210 and its regulation in hypoxia sheds light on the potential development of early diagnostic strategies, which are urgently needed to improve outcomes for PC patients. This review delves into the complexities of PC and introduces the roles of hypoxia and miR-210 in the progression of PC.
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Affiliation(s)
| | | | - Pinar Uysal-Onganer
- Cancer Mechanisms and Biomarkers Research Group, School of Life Sciences, University of Westminster, London W1W 6UW, UK; (M.L.); (M.M.)
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20
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Mafi A, Mannani R, Khalilollah S, Hedayati N, Salami R, Rezaee M, Dehmordi RM, Ghorbanhosseini SS, Alimohammadi M, Akhavan-Sigari R. The Significant Role of microRNAs in Gliomas Angiogenesis: A Particular Focus on Molecular Mechanisms and Opportunities for Clinical Application. Cell Mol Neurobiol 2023; 43:3277-3299. [PMID: 37414973 PMCID: PMC11409989 DOI: 10.1007/s10571-023-01385-x] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Accepted: 06/25/2023] [Indexed: 07/08/2023]
Abstract
MicroRNAs (miRNAs) are non-coding RNAs with only 20-22 nucleic acids that inhibit gene transcription and translation by binding to mRNA. MiRNAs have a diverse set of target genes and can alter most physiological processes, including cell cycle checkpoints, cell survival, and cell death mechanisms, affecting the growth, development, and invasion of various cancers, including gliomas. So optimum management of miRNA expression is essential for preserving a normal biological environment. Due to their small size, stability, and capability of specifically targeting oncogenes, miRNAs have emerged as a promising marker and new biopharmaceutical targeted therapy for glioma patients. This review focuses on the most common miRNAs associated with gliomagenesis and development by controlling glioma-determining markers such as angiogenesis. We also summarized the recent research about miRNA effects on signaling pathways, their mechanistic role and cellular targets in the development of gliomas angiogenesis. Strategies for miRNA-based therapeutic targets, as well as limitations in clinical applications, are also discussed.
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Affiliation(s)
- Alireza Mafi
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
- Nutrition and Food Security Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Reza Mannani
- Department of Surgery, Faculty of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Shayan Khalilollah
- Department of Neurosurgery, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Neda Hedayati
- School of Medicine, Iran University of Medical Science, Tehran, Iran
| | - Raziyeh Salami
- Department of Clinical Biochemistry, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Malihe Rezaee
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Tehran Heart Center, Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Rohollah Mousavi Dehmordi
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
- Department of Clinical Biochemistry, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Seyedeh Sara Ghorbanhosseini
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mina Alimohammadi
- Student Research Committee, Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Reza Akhavan-Sigari
- Department of Neurosurgery, University Medical Center Tuebingen, Tübingen, Germany
- Department of Health Care Management and Clinical Research, Collegium Humanum Warsaw Management University Warsaw, Warsaw, Poland
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21
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Rezaei Z, Dastjerdi K, Allahyari A, ShahidSales S, Talebian S, Maharati A, Zangooie A, Zangouei AS, Sadri F, Sargazi S. Plasma microRNA-195, -34c, and - 1246 as novel biomarkers for the diagnosis of trastuzumab-resistant HER2-positive breast cancer patients. Toxicol Appl Pharmacol 2023; 475:116652. [PMID: 37557922 DOI: 10.1016/j.taap.2023.116652] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 08/04/2023] [Accepted: 08/05/2023] [Indexed: 08/11/2023]
Abstract
Recently, miRNAs have been regarded as potential candidates for mediating therapeutic functions by targeting genes related to drug response. In this study, we suggested that plasma miRNAs may be correlated with response to trastuzumab in HER2-positive breast cancer patients. To determine whether miR-195, miR-23b-3p, miR-1246, and miR-34c-3p are involved in trastuzumab resistance, we screened their expressions in the BT-474 cell line, which was followed by plasma analysis from 20 trastuzumab-resistant HER2-positive breast cancer patients and 20 nonresistance subjects. Then, TargetScan, Pictar, and miRDB were applied to find the possible targets of the selected miRNAs. In addition, the expression status of admitted targets was evaluated. Our results showed that in resistant BT-474 cells, miR-1246, and miR-23b-3p were significantly upregulated, and miR-195-5p and miR-34c-3p were downregulated. In plasma analysis, we found miR-195-5p, miR-34c-3p, and miR-1246 meaningfully diminished in the resistant group, while the expression of miR-23b-3p was not statistically different. The expression levels of confirmed targets by qRT-PCR showed that the expression of RAF1, AKT3, c-MET, CCND1, PHLPP2, MYB, MAP2K1, and PTEN was significantly upregulated, while the expression of CCNG2 was significantly downregulated. The networks of miRNAs with their confirmed targets improved comprehension of miRNA-mediated therapeutic responses to trastuzumab and might be proposed for more characterization of miRNA functions. Moreover, these data indicated that miR-195-5p, miR-34c-3p, and miR-1246 could be possible biomarkers for prognosis and early detection of the trastuzumab-resistant group from the sensitive group of HER2-positive breast cancer patients.
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Affiliation(s)
- Zohreh Rezaei
- Department of Biology, University of Sistan and Baluchestan, Zahedan, Iran; Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjnad, Iran
| | - Kazem Dastjerdi
- Department of Medical Biotechnology, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran; Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjnad, Iran.
| | - Abolghasem Allahyari
- Department of Hematology-Oncology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Sahar Talebian
- Cancer Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhosein Maharati
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Alireza Zangooie
- Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjnad, Iran; Student Research Committee, Birjand University of Medical Sciences, Birjand, Iran
| | - Amir Sadra Zangouei
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Farzad Sadri
- Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjnad, Iran; Student Research Committee, Birjand University of Medical Sciences, Birjand, Iran
| | - Saman Sargazi
- Cellular and Molecular Research Center, Zahedan University of Medical Sciences, Zahedan, Iran; Cellular and Molecular Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran
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22
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H. Al-Zuaini H, Rafiq Zahid K, Xiao X, Raza U, Huang Q, Zeng T. Hypoxia-driven ncRNAs in breast cancer. Front Oncol 2023; 13:1207253. [PMID: 37583933 PMCID: PMC10424730 DOI: 10.3389/fonc.2023.1207253] [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: 04/17/2023] [Accepted: 07/06/2023] [Indexed: 08/17/2023] Open
Abstract
Low oxygen tension, or hypoxia is the driving force behind tumor aggressiveness, leading to therapy resistance, metastasis, and stemness in solid cancers including breast cancer, which now stands as the leading cause of cancer-related mortality in women. With the great advancements in exploring the regulatory roles of the non-coding genome in recent years, the wide spectrum of hypoxia-responsive genome is not limited to just protein-coding genes but also includes multiple types of non-coding RNAs, such as micro RNAs, long non-coding RNAs, and circular RNAs. Over the years, these hypoxia-responsive non-coding molecules have been greatly implicated in breast cancer. Hypoxia drives the expression of these non-coding RNAs as upstream modulators and downstream effectors of hypoxia inducible factor signaling in the favor of breast cancer through a myriad of molecular mechanisms. These non-coding RNAs then contribute in orchestrating aggressive hypoxic tumor environment and regulate cancer associated cellular processes such as proliferation, evasion of apoptotic death, extracellular matrix remodeling, angiogenesis, migration, invasion, epithelial-to-mesenchymal transition, metastasis, therapy resistance, stemness, and evasion of the immune system in breast cancer. In addition, the interplay between hypoxia-driven non-coding RNAs as well as feedback and feedforward loops between these ncRNAs and HIFs further contribute to breast cancer progression. Although the current clinical implications of hypoxia-driven non-coding RNAs are limited to prognostics and diagnostics in breast cancer, extensive explorations have established some of these hypoxia-driven non-coding RNAs as promising targets to treat aggressive breast cancers, and future scientific endeavors hold great promise in targeting hypoxia-driven ncRNAs at clinics to treat breast cancer and limit global cancer burden.
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Affiliation(s)
| | - Kashif Rafiq Zahid
- Department of Medical Laboratory, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
- Department of Radiation Oncology, Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Xiangyan Xiao
- Department of Medical Laboratory, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
- Department of Medical Laboratory, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
| | - Umar Raza
- Department of Biological Sciences, National University of Medical Sciences (NUMS), Rawalpindi, Pakistan
| | - Qiyuan Huang
- Department of Clinical Biobank Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Tao Zeng
- Department of Medical Laboratory, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
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23
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Tsintarakis A, Papalouka C, Kontarini C, Zoumpourlis P, Karakostis K, Adamaki M, Zoumpourlis V. The Intricate Interplay between Cancer Stem Cells and Oncogenic miRNAs in Breast Cancer Progression and Metastasis. Life (Basel) 2023; 13:1361. [PMID: 37374142 DOI: 10.3390/life13061361] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 06/06/2023] [Accepted: 06/06/2023] [Indexed: 06/29/2023] Open
Abstract
Complex signaling interactions between cancer cells and their microenvironments drive the clonal selection of cancer cells. Opposing forces of antitumor and tumorigenic potential regulate the survival of the fittest clones, while key genetic and epigenetic alterations in healthy cells force them to transform, overcome cell senescence, and proliferate in an uncontrolled manner. Both clinical samples and cancer cell lines provide researchers with an insight into the complex structure and hierarchy of cancer. Intratumor heterogeneity allows for multiple cancer cell subpopulations to simultaneously coexist within tumors. One category of these cancer cell subpopulations is cancer stem cells (CSCs), which possess stem-like characteristics and are not easily detectable. In the case of breast cancer, which is the most prevalent cancer type among females, such subpopulations of cells have been isolated and characterized via specific stem cell markers. These stem-like cells, known as breast cancer stem cells (BCSCs), have been linked to major events during tumorigenesis including invasion, metastasis and patient relapse following conventional therapies. Complex signaling circuitries seem to regulate the stemness and phenotypic plasticity of BCSCs along with their differentiation, evasion of immunosurveillance, invasiveness and metastatic potential. Within these complex circuitries, new key players begin to arise, with one of them being a category of small non-coding RNAs, known as miRNAs. Here, we review the importance of oncogenic miRNAs in the regulation of CSCs during breast cancer formation, promotion and metastasis, in order to highlight their anticipated usage as diagnostic and prognostic tools in the context of patient stratification and precision medicine.
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Affiliation(s)
- Antonis Tsintarakis
- Biomedical Applications Unit, Institute of Chemical Biology, National Hellenic Research Foundation (NHRF), 11635 Athens, Greece
| | - Chara Papalouka
- Biomedical Applications Unit, Institute of Chemical Biology, National Hellenic Research Foundation (NHRF), 11635 Athens, Greece
| | - Christina Kontarini
- Biomedical Applications Unit, Institute of Chemical Biology, National Hellenic Research Foundation (NHRF), 11635 Athens, Greece
| | - Panagiotis Zoumpourlis
- Biomedical Applications Unit, Institute of Chemical Biology, National Hellenic Research Foundation (NHRF), 11635 Athens, Greece
| | - Konstantinos Karakostis
- Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain
| | - Maria Adamaki
- Biomedical Applications Unit, Institute of Chemical Biology, National Hellenic Research Foundation (NHRF), 11635 Athens, Greece
| | - Vassilis Zoumpourlis
- Biomedical Applications Unit, Institute of Chemical Biology, National Hellenic Research Foundation (NHRF), 11635 Athens, Greece
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24
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Silina MV, Dzhalilova DS, Makarova OV. Role of MicroRNAs in Regulation of Cellular Response to Hypoxia. BIOCHEMISTRY. BIOKHIMIIA 2023; 88:741-757. [PMID: 37748871 DOI: 10.1134/s0006297923060032] [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: 02/20/2023] [Revised: 04/13/2023] [Accepted: 04/13/2023] [Indexed: 09/27/2023]
Abstract
Hypoxia causes changes in transcription of the genes that contribute to adaptation of the cells to low levels of oxygen. The main mechanism regulating cellular response to hypoxia is activation of hypoxia-inducible transcription factors (HIF), which include several isoforms and control expression of more than a thousand genes. HIF activity is regulated at various levels, including by small non-coding RNA molecules called microRNAs (miRNAs). miRNAs regulate cellular response to hypoxia by influencing activation of HIF, its degradation, and translation of HIF-dependent proteins. At the same time, HIFs also affect miRNAs biogenesis. Data on the relationship of a particular HIF isoform with miRNAs are contradictory, since studies have been performed using different cell lines, various types of experimental animals and clinical material, as well as at different oxygen concentrations and durations of hypoxic exposure. In addition, HIF expression may be affected by the initial resistance of organisms to lack of oxygen, which has not been taken into account in the studies. This review analyzes the data on the effect of hypoxia on biogenesis and functioning of miRNAs, as well as on the effect of miRNAs on mRNAs of the genes involved in adaptation to oxygen deficiency. Understanding the mechanisms of relationship between HIF, hypoxia, and miRNA is necessary to develop new approaches to personalized therapy for diseases accompanied by oxygen deficiency.
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Affiliation(s)
- Maria V Silina
- Avtsyn Research Institute of Human Morphology, Petrovsky National Research Centre of Surgery, Moscow, 117418, Russia.
| | - Dzhuliia Sh Dzhalilova
- Avtsyn Research Institute of Human Morphology, Petrovsky National Research Centre of Surgery, Moscow, 117418, Russia
| | - Olga V Makarova
- Avtsyn Research Institute of Human Morphology, Petrovsky National Research Centre of Surgery, Moscow, 117418, Russia
- Faculty of Biology, Lomonosov Moscow State University, Moscow, 119234, Russia
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25
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Schiano C, Balbi C, de Nigris F, Napoli C. Basic Pathogenic Mechanisms and Epigenetic Players Promoted by Extracellular Vesicles in Vascular Damage. Int J Mol Sci 2023; 24:ijms24087509. [PMID: 37108672 PMCID: PMC10138986 DOI: 10.3390/ijms24087509] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 04/14/2023] [Accepted: 04/16/2023] [Indexed: 04/29/2023] Open
Abstract
Both progression from the early pathogenic events to clinically manifest cardiovascular diseases (CVD) and cancer impact the integrity of the vascular system. Pathological vascular modifications are affected by interplay between endothelial cells and their microenvironment. Soluble factors, extracellular matrix molecules and extracellular vesicles (EVs) are emerging determinants of this network that trigger specific signals in target cells. EVs have gained attention as package of molecules with epigenetic reversible activity causing functional vascular changes, but their mechanisms are not well understood. Valuable insights have been provided by recent clinical studies, including the investigation of EVs as potential biomarkers of these diseases. In this paper, we review the role and the mechanism of exosomal epigenetic molecules during the vascular remodeling in coronary heart disease as well as in cancer-associated neoangiogenesis.
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Affiliation(s)
- Concetta Schiano
- Department of Advanced Medical and Surgical Sciences (DAMSS), University of Campania Luigi Vanvitelli, 80138 Naples, Italy
- Laboratory of Cellular and Molecular Cardiology, Cardiocentro Ticino Institute, 6807 Taverne-Torricella, Switzerland
| | - Carolina Balbi
- Laboratory of Cellular and Molecular Cardiology, Cardiocentro Ticino Institute, 6807 Taverne-Torricella, Switzerland
| | - Filomena de Nigris
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80138 Naples, Italy
| | - Claudio Napoli
- Department of Advanced Medical and Surgical Sciences (DAMSS), University of Campania Luigi Vanvitelli, 80138 Naples, Italy
- Clinical Department of Internal Medicine and Specialistic Units, Division of Clinical Immunology and Immunohematology, Transfusion Medicine and Transplant Immunology (SIMT), Azienda Universitaria Policlinico (AOU), 80138 Naples, Italy
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26
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Marwarha G, Slagsvold KH, Høydal MA. NF-κB Transcriptional Activity Indispensably Mediates Hypoxia–Reoxygenation Stress-Induced microRNA-210 Expression. Int J Mol Sci 2023; 24:ijms24076618. [PMID: 37047592 PMCID: PMC10095479 DOI: 10.3390/ijms24076618] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 03/27/2023] [Accepted: 03/30/2023] [Indexed: 04/05/2023] Open
Abstract
Ischemia–reperfusion (I-R) injury is a cardinal pathophysiological hallmark of ischemic heart disease (IHD). Despite significant advances in the understanding of what causes I-R injury and hypoxia–reoxygenation (H-R) stress, viable molecular strategies that could be targeted for the treatment of the deleterious biochemical pathways activated during I-R remain elusive. The master hypoxamiR, microRNA-210 (miR-210), is a major determinant of protective cellular adaptation to hypoxia stress but exacerbates apoptotic cell death during cellular reoxygenation. While the hypoxia-induced transcriptional up-regulation of miR-210 is well delineated, the cellular mechanisms and molecular entities that regulate the transcriptional induction of miR-210 during the cellular reoxygenation phase have not been elucidated yet. Herein, in immortalized AC-16 cardiomyocytes, we delineated the indispensable role of the ubiquitously expressed transcription factor, NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) in H-R-induced miR-210 expression during cellular reoxygenation. Using dominant negative and dominant active expression vectors encoding kinases to competitively inhibit NF-κB activation, we elucidated NF-κB activation as a significant mediator of H-R-induced miR-210 expression. Ensuing molecular assays revealed a direct NF-κB-mediated transcriptional up-regulation of miR-210 expression in response to the H-R challenge that is characterized by the NF-κB-mediated reorchestration of the entire repertoire of histone modification changes that are a signatory of a permissive actively transcribed miR-210 promoter. Our study confers a novel insight identifying NF-κB as a potential novel molecular target to combat H-R-elicited miR-210 expression that fosters augmented cardiomyocyte cell death.
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Affiliation(s)
- Gurdeep Marwarha
- Group of Molecular and Cellular Cardiology, Department of Circulation and Medical Imaging, Faculty of Medicine and Health, Norwegian University of Science and Technology (NTNU), 7034 Trondheim, Norway
| | - Katrine Hordnes Slagsvold
- Group of Molecular and Cellular Cardiology, Department of Circulation and Medical Imaging, Faculty of Medicine and Health, Norwegian University of Science and Technology (NTNU), 7034 Trondheim, Norway
- Department of Cardiothoracic Surgery, St. Olavs University Hospital, 7030 Trondheim, Norway
| | - Morten Andre Høydal
- Group of Molecular and Cellular Cardiology, Department of Circulation and Medical Imaging, Faculty of Medicine and Health, Norwegian University of Science and Technology (NTNU), 7034 Trondheim, Norway
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27
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Powell BH, Turchinovich A, Wang Y, Gololobova O, Buschmann D, Zeiger MA, Umbricht CB, Witwer KW. miR-210 Expression Is Strongly Hypoxia-Induced in Anaplastic Thyroid Cancer Cell Lines and Is Associated with Extracellular Vesicles and Argonaute-2. Int J Mol Sci 2023; 24:4507. [PMID: 36901936 PMCID: PMC10002857 DOI: 10.3390/ijms24054507] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 02/06/2023] [Accepted: 02/10/2023] [Indexed: 03/03/2023] Open
Abstract
Hypoxia, or low oxygen tension, is frequently found in highly proliferative solid tumors such as anaplastic thyroid carcinoma (ATC) and is believed to promote resistance to chemotherapy and radiation. Identifying hypoxic cells for targeted therapy may thus be an effective approach to treating aggressive cancers. Here, we explore the potential of the well-known hypoxia-responsive microRNA (miRNA) miR-210-3p as a cellular and extracellular biological marker of hypoxia. We compare miRNA expression across several ATC and papillary thyroid cancer (PTC) cell lines. In the ATC cell line SW1736, miR-210-3p expression levels indicate hypoxia during exposure to low oxygen conditions (2% O2). Furthermore, when released by SW1736 cells into the extracellular space, miR-210-3p is associated with RNA carriers such as extracellular vesicles (EVs) and Argonaute-2 (AGO2), making it a potential extracellular marker for hypoxia.
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Affiliation(s)
- Bonita H. Powell
- Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Andrey Turchinovich
- Division of Cancer Genome Research, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Heidelberg Biolabs GmbH, 69120 Heidelberg, Germany
| | - Yongchun Wang
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Olesia Gololobova
- Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Dominik Buschmann
- Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Martha A. Zeiger
- Center for Cancer Research, National Cancer Institute, National Institute of Health, Bethesda, MD 20892, USA
| | - Christopher B. Umbricht
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Kenneth W. Witwer
- Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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28
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Yang M, Zhang Y, Li M, Liu X, Darvishi M. The various role of microRNAs in breast cancer angiogenesis, with a special focus on novel miRNA-based delivery strategies. Cancer Cell Int 2023; 23:24. [PMID: 36765409 PMCID: PMC9912632 DOI: 10.1186/s12935-022-02837-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Accepted: 12/20/2022] [Indexed: 02/12/2023] Open
Abstract
After skin malignancy, breast cancer is the most widely recognized cancer detected in women in the United States. Breast cancer (BCa) can happen in all kinds of people, but it's much more common in women. One in four cases of cancer and one in six deaths due to cancer are related to breast cancer. Angiogenesis is an essential factor in the growth of tumors and metastases in various malignancies. An expanded level of angiogenesis is related to diminished endurance in BCa patients. This function assumes a fundamental part inside the human body, from the beginning phases of life to dangerous malignancy. Various factors, referred to as angiogenic factors, work to make a new capillary. Expanding proof demonstrates that angiogenesis is managed by microRNAs (miRNAs), which are small non-coding RNA with 19-25 nucleotides. MiRNA is a post-transcriptional regulator of gene expression that controls many critical biological processes. Endothelial miRNAs, referred to as angiomiRs, are probably concerned with tumor improvement and angiogenesis via regulation of pro-and anti-angiogenic factors. In this article, we reviewed therapeutic functions of miRNAs in BCa angiogenesis, several novel delivery carriers for miRNA-based therapeutics, as well as CRISPR/Cas9 as a targeted therapy in breast cancer.
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Affiliation(s)
- Min Yang
- College of Traditional Chinese Medicine, Jilin Agricultural Science and Technology University, Jilin, 132101 China
| | - Ying Zhang
- College of Traditional Chinese Medicine, Jilin Agricultural Science and Technology University, Jilin, 132101 China
| | - Min Li
- College of Traditional Chinese Medicine, Jilin Agricultural Science and Technology University, Jilin, 132101 China
| | - Xinglong Liu
- College of Traditional Chinese Medicine, Jilin Agricultural Science and Technology University, Jilin, 132101 China
| | - Mohammad Darvishi
- Infectious Diseases and Tropical Medicine Research Center (IDTMRC), Department of Aerospace and Subaquatic Medicine, AJA University of Medical Sciences, Tehran, Iran
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29
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Bahramy A, Zafari N, Rajabi F, Aghakhani A, Jayedi A, Khaboushan AS, Zolbin MM, Yekaninejad MS. Prognostic and diagnostic values of non-coding RNAs as biomarkers for breast cancer: An umbrella review and pan-cancer analysis. Front Mol Biosci 2023; 10:1096524. [PMID: 36726376 PMCID: PMC9885171 DOI: 10.3389/fmolb.2023.1096524] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Accepted: 01/06/2023] [Indexed: 01/19/2023] Open
Abstract
Background: Breast cancer (BC) is the most common cancer in women. The incidence and morbidity of BC are expected to rise rapidly. The stage at which BC is diagnosed has a significant impact on clinical outcomes. When detected early, an overall 5-year survival rate of up to 90% is possible. Although numerous studies have been conducted to assess the prognostic and diagnostic values of non-coding RNAs (ncRNAs) in breast cancer, their overall potential remains unclear. In this field of study, there are various systematic reviews and meta-analysis studies that report volumes of data. In this study, we tried to collect all these systematic reviews and meta-analysis studies in order to re-analyze their data without any restriction to breast cancer or non-coding RNA type, to make it as comprehensive as possible. Methods: Three databases, namely, PubMed, Scopus, and Web of Science (WoS), were searched to find any relevant meta-analysis studies. After thoroughly searching, the screening of titles, abstracts, and full-text and the quality of all included studies were assessed using the AMSTAR tool. All the required data including hazard ratios (HRs), sensitivity (SENS), and specificity (SPEC) were extracted for further analysis, and all analyses were carried out using Stata. Results: In the prognostic part, our initial search of three databases produced 10,548 articles, of which 58 studies were included in the current study. We assessed the correlation of non-coding RNA (ncRNA) expression with different survival outcomes in breast cancer patients: overall survival (OS) (HR = 1.521), disease-free survival (DFS) (HR = 1.33), recurrence-free survival (RFS) (HR = 1.66), progression-free survival (PFS) (HR = 1.71), metastasis-free survival (MFS) (HR = 0.90), and disease-specific survival (DSS) (HR = 0.37). After eliminating low-quality studies, the results did not change significantly. In the diagnostic part, 22 articles and 30 datasets were retrieved from 8,453 articles. The quality of all studies was determined. The bivariate and random-effects models were used to assess the diagnostic value of ncRNAs. The overall area under the curve (AUC) of ncRNAs in differentiated patients is 0.88 (SENS: 80% and SPEC: 82%). There was no difference in the potential of single and combined ncRNAs in differentiated BC patients. However, the overall potential of microRNAs (miRNAs) is higher than that of long non-coding RNAs (lncRNAs). No evidence of publication bias was found in the current study. Nine miRNAs, four lncRNAs, and five gene targets showed significant OS and RFS between normal and cancer patients based on pan-cancer data analysis, demonstrating their potential prognostic value. Conclusion: The present umbrella review showed that ncRNAs, including lncRNAs and miRNAs, can be used as prognostic and diagnostic biomarkers for breast cancer patients, regardless of the sample sources, ethnicity of patients, and subtype of breast cancer.
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Affiliation(s)
- Afshin Bahramy
- Pediatric Urology and Regenerative Medicine Research Center, Gene, Cell and Tissue Research Institute, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Narges Zafari
- Pediatric Urology and Regenerative Medicine Research Center, Gene, Cell and Tissue Research Institute, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Rajabi
- Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Amirhossein Aghakhani
- Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Ahmad Jayedi
- Social Determinants of Health Research Center, Semnan University of Medical Sciences, Semnan, Iran
| | - Alireza Soltani Khaboushan
- Pediatric Urology and Regenerative Medicine Research Center, Gene, Cell and Tissue Research Institute, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran,Students’ Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Masoumeh Majidi Zolbin
- Pediatric Urology and Regenerative Medicine Research Center, Gene, Cell and Tissue Research Institute, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran,*Correspondence: Mir Saeed Yekaninejad, , ; Masoumeh Majidi Zolbin, ,
| | - Mir Saeed Yekaninejad
- Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran,*Correspondence: Mir Saeed Yekaninejad, , ; Masoumeh Majidi Zolbin, ,
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30
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Nikulin S, Razumovskaya A, Poloznikov A, Zakharova G, Alekseev B, Tonevitsky A. ELOVL5 and IGFBP6 genes modulate sensitivity of breast cancer cells to ferroptosis. Front Mol Biosci 2023; 10:1075704. [PMID: 36714261 PMCID: PMC9880435 DOI: 10.3389/fmolb.2023.1075704] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Accepted: 01/03/2023] [Indexed: 01/14/2023] Open
Abstract
Introduction: Relapse of breast cancer is one of the key obstacles to successful treatment. Previously we have shown that low expression of ELOVL5 and IGFBP6 genes in breast cancer tissue corresponded to poor prognosis. ELOVL5 participates directly in the elongation of polyunsaturated fatty acids (PUFAs) that are considered to play an important role in cancer cell metabolism. Thus, in this work we studied the changes in lipid metabolism in breast cancer cells with reduced expression of either ELOVL5 or IGFBP6 gene. Methods: MDA-MB-231 cells with a stable knockdown of either ELOVL5 or IGFBP6 gene were used in this study. Transcriptomic and proteomic analysis as well as RT-PCR were utilized to assess gene expression. Content of individual fatty acids in the cells was measured with HPLC-MS. HPLC was used for analysis of the kinetics of PUFAs uptake. Cell viability was measured with MTS assay. Flow cytometry was used to measure activation of apoptosis. Fluorescent microscopy was utilized to assess accumulation of ROS and formation of lipid droplets. Glutathione peroxidase activity was measured with a colorimetric assay. Results: We found that the knockdown of IGFBP6 gene led to significant changes in the profile of fatty acids in the cells and in the expression of many genes associated with lipid metabolism. As some PUFAs are known to inhibit proliferation and cause death of cancer cells, we also tested the response of the cells to single PUFAs and to combinations of docosahexaenoic acid (DHA, a n-3 PUFA) with standard chemotherapeutic drugs. Our data suggest that external PUFAs cause cell death by activation of ferroptosis, an iron-dependent mechanism of cell death with excessive lipid peroxidation. Moreover, both knockdowns increased cells' sensitivity to ferroptosis, probably due to a significant decrease in the activity of the antioxidant enzyme GPX4. Addition of DHA to commonly used chemotherapeutic drugs enhanced their effect significantly, especially for the cells with low expression of IGFBP6 gene. Discussion: The results of this study suggest that addition of PUFAs to the treatment regimen for the patients with low expression of IGFBP6 and ELOVL5 genes can be potentially beneficial and is worth testing in a clinically relevant setting.
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Affiliation(s)
- Sergey Nikulin
- Faculty of Biology and Biotechnologies, Higher School of Economics, Moscow, Russia,*Correspondence: Sergey Nikulin,
| | | | - Andrey Poloznikov
- P. A. Hertsen Moscow Oncology Research Center, Branch of the National Medical Research Radiological Center, Ministry of Health of the Russian Federation, Moscow, Russia
| | - Galina Zakharova
- World-Class Research Center “Digital Biodesign and Personalized Healthcare”, Sechenov First Moscow State Medical University, Moscow, Russia
| | - Boris Alekseev
- P. A. Hertsen Moscow Oncology Research Center, Branch of the National Medical Research Radiological Center, Ministry of Health of the Russian Federation, Moscow, Russia
| | - Alexander Tonevitsky
- Faculty of Biology and Biotechnologies, Higher School of Economics, Moscow, Russia,Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia
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Gamal-Eldeen AM, Fahmy CA, Raafat BM, Althobaiti F, Bassyouni IH, Talaat RM. Association of Circulating Levels of Hypoxia-Inducible Factor-1α and miR-210 with Photosensitivity in Systemic Lupus Erythematosus Patients. Curr Mol Med 2023; 23:185-192. [PMID: 35034594 DOI: 10.2174/1566524022666220114145220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 11/11/2021] [Accepted: 11/25/2021] [Indexed: 12/16/2022]
Abstract
BACKGROUND miR-210, a key hypoxamiR, regulates hypoxia and inflammation-linked hypoxia. Systemic lupus erythematosus (SLE), a chronic autoimmune disease, is responsible for many pathological disorders, including photosensitivity. OBJECTIVE This study aimed to find the correlation between circulating miR-210/HIF-1α levels and photosensitivity in SLE patients and other SLE-associated pathological complications in a single-center case-control study. METHODS The study population comprised 104 SLE Egyptian patients with photosensitivity, 32 SLE patients without photosensitivity, and 32 healthy subjects. SLE activity was assessed for all patients using the SLE Disease Activity Index (SLEDAI). Clinical complications/manifestations and hematological/serological analyses were recorded. HIF-α concentration was investigated by ELISA, and miR-210 expression was analyzed by qRT-PCR. RESULTS The results revealed that circulating miR-210 was significantly increased in the SLE/photosensitivity group versus the SLE and control groups. The additional occurrence of malar rash, oral ulcers, renal disorders, or hypertension resulted in a higher expression of miR-210. SLEDAI activity status showed no effect on miR-210. Erythrocyte sedimentation rate, white blood cells, hemoglobin, platelets, patient age, and disease duration were positively correlated with circulatory miR-210. HIF-α concentration was significantly induced in the SLE/photosensitivity group versus the SLE and control groups. In SLE/photosensitivity, the presence of renal disorders and hypertension resulted in the highest HIF-α concentrations. A strong positive correlation was recorded between HIF-α concentration and circulatory miR-210 in SLE/photosensitivity patients (r = 0.886). CONCLUSION The dysregulation of circulating miR-210/HIF-1α levels in SLE/ photosensitivity patients is controlled by the presence of additional pathological complications, and results suggest that the hypoxia pathway might interact positively with the pathogenesis and disease progression of SLE.
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Affiliation(s)
- Amira M Gamal-Eldeen
- Clinical Laboratory Sciences Department, College of Applied Medical Sciences, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia
- High Altitude Research Center, Prince Sultan Medical Complex, Al- Hawiyah, Taif University, Taif, Saudi Arabia
| | - Cinderella A Fahmy
- Cancer Biology and Genetics Laboratory, Centre of Excellence for Advanced Sciences, National Research Centre, 33 El Buhouth St. Dokki, Cairo, 12622, Egypt
- Biochemistry Department, National Research Centre, 33 El Buhouth St. Dokki, Cairo, 12622, Egypt
| | - Bassem M Raafat
- Radiological Sciences Department, College of Applied Medical Sciences, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia
| | - Fayez Althobaiti
- High Altitude Research Center, Prince Sultan Medical Complex, Al- Hawiyah, Taif University, Taif, Saudi Arabia
- Biotechnology Department, Faculty of Science, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia
| | - Iman H Bassyouni
- Department of Rheumatology and Rehabilitation, Faculty of Medicine, Cairo University, El-Kasr El-Aini Hospital, Cairo 12613, Egypt
| | - Roba M Talaat
- Molecular Biology Department, Genetic Engineering and Biotechnology Research Institute (GEBRI), Sadat City University, Egypt
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Abstract
MicroRNA-210 (miR-210) is a miRNA with imperative effects in the pathophysiology of human disorders. miR-210 is encoded by MIR210 gene on chromosome 11p15.5. The stem-loop of this miRNA resides in an intron of the AK123483 noncoding RNA. This miRNA is a major hypoxamir whose expression is increased in hypoxic condition in several types of cells. miR-210 has been shown to be up-regulated in almost all types of examined cancer types, except for bladder cancer, angiosarcoma and glioblastoma. Dysregulation of miR-210 in colorectal carcinoma, gastric cancer, head and neck squamous cell carcinoma, pediatric acute lymphoblastic leukemia, glioblastoma and laryngeal carcinoma has been related with poor clinical outcomes. In the current review, we provide a comprehensive summary of participation of miR-210 in human disorders.
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Gamal-Eldeen AM, Fahmy CA, Raafat BM, Althobaiti F, Bassyouni IH, Talaat RM. Circulating Levels of Hypoxia-regulating MicroRNAs in Systemic Lupus Erythematosus Patients with Hemolytic Anemia. Curr Med Sci 2022; 42:1231-1239. [PMID: 36469203 DOI: 10.1007/s11596-022-2644-y] [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: 12/01/2021] [Accepted: 02/26/2022] [Indexed: 12/12/2022]
Abstract
OBJECTIVE MicroRNAs are fine regulators for gene expression during the post-transcriptional stage in many autoimmune diseases. HypoxamiRs (miR-210 and miR-21) play an important role in hypoxia and in inflammation-associated hypoxia. Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease that would potentiate many pathological complications, including hemolytic anemia. This study aimed to investigate the role of hypoxamiRs in SLE/hemolytic anemia patients. METHODS This work was designed to analyze the circulating levels of↱ the miR-210 and miR-21 expressions and hypoxia-inducible factor-1α (HIF-α) in SLE/hemolytic anemia patients. SLE activity was evaluated for all patients by SLE Disease Activity Index (SLEDAI). Clinical manifestations/complications and serological/hematological investigations were reported. HIF-α concentration was assayed by ELISA and expression of miR-21 and miR-210 was analyzed by qRT-PCR. RESULTS The results indicated that the fold change of the miR-210/miR-21 expressions in plasma was significantly elevated in SLE/hemolytic anemia patients. A strong positive correlation between the miR-210 and miR-21 expression levels was also recorded. Among the associated-disease complications, hypertension, arthritis, oral ulcers, and serositis were associated with a high circulating miR-210 expression, while the occurrence of renal disorders was associated with the increased miR-21 expression. Furthermore, the HIF-α level was remarkably elevated in SLE/hemolytic anemia patients. A high positive correlation was recorded between the HIF-α concentration and miR-210/miR-21 expression levels. The occurrence of oral ulcers, arthritis, and hypertension was associated with the increased HIF-α concentration. On the other hand, SLEDAI and white blood cell count were positively correlated with miR-21/ miR-210. The erythrocyte sedimentation rate was positively correlated with miR-21. CONCLUSION The dysregulation of the circulating miR-210/miR-210/HIF-1α levels in SLE/hemolytic anemia patients advocated that the hypoxia pathway might have an essential role in the pathogenesis and complications of these diseases.
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Affiliation(s)
- Amira M Gamal-Eldeen
- Clinical Laboratory Sciences Department, College of Applied Medical Sciences, Taif University, Taif, 21944, Saudi Arabia. .,High Altitude Research Center, Prince Sultan Medical Complex, Al-Hawiyah, Taif University, Taif, 21944, Saudi Arabia.
| | - Cinderella A Fahmy
- Cancer Biology and Genetics Laboratory, Centre of Excellence for Advanced Sciences, National Research Centre, Cairo, 12622, Egypt.,Biochemistry Department, National Research Centre, Cairo, 12622, Egypt
| | - Bassem M Raafat
- Radiological Sciences Department, College of Applied Medical Sciences, Taif University, Taif, 21944, Saudi Arabia
| | - Fayez Althobaiti
- High Altitude Research Center, Prince Sultan Medical Complex, Al-Hawiyah, Taif University, Taif, 21944, Saudi Arabia.,Biotechnology Department, Faculty of Science, Taif University, Taif, 21944, Saudi Arabia
| | - Iman H Bassyouni
- Department of Rheumatology and Rehabilitation, Faculty of Medicine, Cairo University, El-Kasr El-Aini Hospital, Cairo, 12613, Egypt
| | - Roba M Talaat
- Molecular Biology Department, Genetic Engineering and Biotechnology Research Institute (GEBRI), Sadat City University, Sadat City, 32897, Egypt
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Nakamura K, Hernández G, Sharma GG, Wada Y, Banwait JK, González N, Perea J, Balaguer F, Takamaru H, Saito Y, Toiyama Y, Kodera Y, Boland CR, Bujanda L, Quintero E, Goel A. A Liquid Biopsy Signature for the Detection of Patients With Early-Onset Colorectal Cancer. Gastroenterology 2022; 163:1242-1251.e2. [PMID: 35850198 PMCID: PMC9613521 DOI: 10.1053/j.gastro.2022.06.089] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 06/18/2022] [Accepted: 06/27/2022] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Early-onset colorectal cancer (EOCRC) is a distinct clinical and molecular entity with poor survival outcomes compared with late-onset CRC. Although the incidence of EOCRC is rising, current CRC screening strategies have several limitations in diagnostic performance for EOCRC. In view of this clinical challenge, novel and robust biomarkers for detection of EOCRC are necessary. The aim of this study was to develop a circulating micro RNA (miRNA) signature for the diagnosis of patients with EOCRC. METHODS A systematic discovery approach by analyzing a large, publicly available, noncoding RNA expression profiling dataset (GSE115513) was used. A panel of miRNAs was identified, which was subsequently validated in blood samples from patients with EOCRC in 2 independent cohorts (n = 149) compared with controls (n = 110) and pre/postoperative plasma specimens (n = 22) using quantitative reverse-transcription polymerase chain reaction assays. RESULTS In the discovery phase, 4 miRNAs were found to be expressed in blood samples. A combination signature of these 4 miRNAs (miR-193a-5p, miR-210, miR-513a-5p, and miR-628-3p) yielded an area under the curve of 0.92 (95% confidence interval, 0.85-0.96) for identification of EOCRC in the training cohort. The miRNA panel performance was then confirmed in an independent validation cohort (area under the curve, 0.88; 95% confidence interval, 0.82-0.93). Moreover, the miRNA panel robustly identified patients with early-stage EOCRC (P < .001). The decreased expression of miRNAs in postsurgery plasma specimens indicated their tumor specificity. CONCLUSIONS Our novel miRNA signature for the diagnosis of EOCRC has the potential to identify patients with EOCRC with high accuracy for clinical application in the noninvasive diagnosis of EOCRC.
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Affiliation(s)
- Kota Nakamura
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope, Monrovia, California; Department of Surgery, Nara Medical University, Nara, Japan
| | - Goretti Hernández
- Center for Gastrointestinal Research, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas; Gastroenterology Department, Hospital Universitario de Canarias, Instituto Universitario de Tecnologías Biomédicas (ITB) and Centro de Investigación Biomédica de Canarias (CIBICAN), Departamento de Medicina Interna, Universidad de La Laguna, Santa Cruz de Tenerife, Tenerife, Spain
| | - Geeta G Sharma
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope, Monrovia, California
| | - Yuma Wada
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope, Monrovia, California; Center for Gastrointestinal Research, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas
| | - Jasjit K Banwait
- Center for Gastrointestinal Research, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas
| | - Natalia González
- Gastroenterology Department, Hospital Universitario de Canarias, Instituto Universitario de Tecnologías Biomédicas (ITB) and Centro de Investigación Biomédica de Canarias (CIBICAN), Departamento de Medicina Interna, Universidad de La Laguna, Santa Cruz de Tenerife, Tenerife, Spain
| | - Jose Perea
- Department of Surgery, Fundación Jiménez Díaz University Hospital, Madrid, Spain; Fundación Jiménez Díaz University Hospital Health Research Institute, Madrid, Spain
| | - Francesc Balaguer
- Gastroenterology Department, Hospital Clinic de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | | | - Yutaka Saito
- Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan
| | - Yuji Toiyama
- Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Mie University Graduate School of Medicine, Mie, Japan
| | - Yasuhiro Kodera
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - C Richard Boland
- Division of Gastroenterology, School of Medicine, University of California San Diego, La Jolla, California
| | - Luis Bujanda
- Gastroenterology Department, Instituto Biodonostia, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Universidad del País Vasco (UPV/EHU), San Sebastián, Spain
| | - Enrique Quintero
- Gastroenterology Department, Hospital Universitario de Canarias, Instituto Universitario de Tecnologías Biomédicas (ITB) and Centro de Investigación Biomédica de Canarias (CIBICAN), Departamento de Medicina Interna, Universidad de La Laguna, Santa Cruz de Tenerife, Tenerife, Spain
| | - Ajay Goel
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope, Monrovia, California; Center for Gastrointestinal Research, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas; City of Hope Comprehensive Cancer Center, Duarte, California.
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Cheng W, Xiao X, Liao Y, Cao Q, Wang C, Li X, Jia Y. Conducive target range of breast cancer: Hypoxic tumor microenvironment. Front Oncol 2022; 12:978276. [PMID: 36226050 PMCID: PMC9550190 DOI: 10.3389/fonc.2022.978276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2022] [Accepted: 09/07/2022] [Indexed: 11/13/2022] Open
Abstract
Breast cancer is a kind of malignant tumor disease that poses a serious threat to human health. Its biological characteristics of rapid proliferation and delayed angiogenesis, lead to intratumoral hypoxia as a common finding in breast cancer. HIF as a transcription factor, mediate a series of reactions in the hypoxic microenvironment, including metabolic reprogramming, tumor angiogenesis, tumor cell proliferation and metastasis and other important physiological and pathological processes, as well as gene instability under hypoxia. In addition, in the immune microenvironment of hypoxia, both innate and acquired immunity of tumor cells undergo subtle changes to support tumor and inhibit immune activity. Thus, the elucidation of tumor microenvironment hypoxia provides a promising target for the resistance and limited efficacy of current breast cancer therapies. We also summarize the hypoxic mechanisms of breast cancer treatment related drug resistance, as well as the current status and prospects of latest related drugs targeted HIF inhibitors.
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Affiliation(s)
- Wen Cheng
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Xian Xiao
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Yang Liao
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Qingqing Cao
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Chaoran Wang
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Xiaojiang Li
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
- *Correspondence: Xiaojiang Li, ; Yingjie Jia,
| | - Yingjie Jia
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
- *Correspondence: Xiaojiang Li, ; Yingjie Jia,
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Matulić M, Gršković P, Petrović A, Begić V, Harabajsa S, Korać P. miRNA in Molecular Diagnostics. Bioengineering (Basel) 2022; 9:bioengineering9090459. [PMID: 36135005 PMCID: PMC9495386 DOI: 10.3390/bioengineering9090459] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2022] [Revised: 08/05/2022] [Accepted: 09/07/2022] [Indexed: 11/17/2022] Open
Abstract
MicroRNAs are a class of small non-coding RNA molecules that regulate gene expression on post-transcriptional level. Their biogenesis consists of a complex series of sequential processes, and they regulate expression of many genes involved in all cellular processes. Their function is essential for maintaining the homeostasis of a single cell; therefore, their aberrant expression contributes to development and progression of many diseases, especially malignant tumors and viral infections. Moreover, they can be associated with certain states of a specific disease, obtained in the least invasive manner for patients and analyzed with basic molecular methods used in clinical laboratories. Because of this, they have a promising potential to become very useful biomarkers and potential tools in personalized medicine approaches. In this review, miRNAs biogenesis, significance in cancer and infectious diseases, and current available test and methods for their detection are summarized.
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Affiliation(s)
- Maja Matulić
- Division of Molecular Biology, Department of Biology, Faculty of Science, University of Zagreb, 10000 Zagreb, Croatia
| | - Paula Gršković
- Division of Molecular Biology, Department of Biology, Faculty of Science, University of Zagreb, 10000 Zagreb, Croatia
| | - Andreja Petrović
- Division of Molecular Biology, Department of Biology, Faculty of Science, University of Zagreb, 10000 Zagreb, Croatia
- Institute of Clinical Pathology and Cytology, Merkur University Hospital, 10000 Zagreb, Croatia
| | - Valerija Begić
- Division of Molecular Biology, Department of Biology, Faculty of Science, University of Zagreb, 10000 Zagreb, Croatia
- Primary School “Sesvetski Kraljevec”, 10361 Sesvetski Kraljevec, Croatia
| | - Suzana Harabajsa
- Division of Molecular Biology, Department of Biology, Faculty of Science, University of Zagreb, 10000 Zagreb, Croatia
- Department of Pathology and Cytology, Division of Pulmonary Cytology Jordanovac, University Hospital Centre Zagreb, 10000 Zagreb, Croatia
| | - Petra Korać
- Division of Molecular Biology, Department of Biology, Faculty of Science, University of Zagreb, 10000 Zagreb, Croatia
- Correspondence: ; Tel.: +385-1-4606-278
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Liu X, Papukashvili D, Wang Z, Liu Y, Chen X, Li J, Li Z, Hu L, Li Z, Rcheulishvili N, Lu X, Ma J. Potential utility of miRNAs for liquid biopsy in breast cancer. Front Oncol 2022; 12:940314. [PMID: 35992785 PMCID: PMC9386533 DOI: 10.3389/fonc.2022.940314] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 07/04/2022] [Indexed: 12/18/2022] Open
Abstract
Breast cancer (BC) remains the most prevalent malignancy due to its incidence rate, recurrence, and metastasis in women. Conventional strategies of cancer detection– mammography and tissue biopsy lack the capacity to detect the complete cancer genomic landscape. Besides, they often give false- positive or negative results. The presence of this and other disadvantages such as invasiveness, high-cost, and side effects necessitates developing new strategies to overcome the BC burden. Liquid biopsy (LB) has been brought to the fore owing to its early detection, screening, prognosis, simplicity of the technique, and efficient monitoring. Remarkably, microRNAs (miRNAs)– gene expression regulators seem to play a major role as biomarkers detected in the samples of LB. Particularly, miR-21 and miR-155 among other possible candidates seem to serve as favorable biomarkers in the diagnosis and prognosis of BC. Hence, this review will assess the potential utility of miRNAs as biomarkers and will highlight certain promising candidates for the LB approach in the diagnosis and management of BC that may optimize the patient outcome.
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Affiliation(s)
- Xiangrong Liu
- Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, China
| | - Dimitri Papukashvili
- Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, China
| | - Zhixiang Wang
- Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, China
| | - Yan Liu
- Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, China
| | - Xiaoxia Chen
- Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, China
| | - Jianrong Li
- Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, China
| | - Zhiyuan Li
- Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, China
| | - Linjie Hu
- Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, China
| | - Zheng Li
- Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, China
| | - Nino Rcheulishvili
- Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, China
| | - Xiaoqing Lu
- Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, China
- *Correspondence: Xiaoqing Lu, ; Jinfeng Ma,
| | - Jinfeng Ma
- Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, China
- *Correspondence: Xiaoqing Lu, ; Jinfeng Ma,
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Coronel-Hernández J, Delgado-Waldo I, Cantú de León D, López-Camarillo C, Jacobo-Herrera N, Ramos-Payán R, Pérez-Plasencia C. HypoxaMIRs: Key Regulators of Hallmarks of Colorectal Cancer. Cells 2022; 11:1895. [PMID: 35741024 PMCID: PMC9221210 DOI: 10.3390/cells11121895] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 06/03/2022] [Accepted: 06/07/2022] [Indexed: 01/27/2023] Open
Abstract
Hypoxia in cancer is a thoroughly studied phenomenon, and the logical cause of the reduction in oxygen tension is tumor growth itself. While sustained hypoxia leads to death by necrosis in cells, there is an exquisitely regulated mechanism that rescues hypoxic cells from their fatal fate. The accumulation in the cytoplasm of the transcription factor HIF-1α, which, under normoxic conditions, is marked for degradation by a group of oxygen-sensing proteins known as prolyl hydroxylases (PHDs) in association with the von Hippel-Lindau anti-oncogene (VHL) is critical for the cell, as it regulates different mechanisms through the genes it induces. A group of microRNAs whose expression is regulated by HIF, collectively called hypoxaMIRs, have been recognized. In this review, we deal with the hypoxaMIRs that have been shown to be expressed in colorectal cancer. Subsequently, using data mining, we analyze a panel of hypoxaMIRs expressed in both normal and tumor tissues obtained from TCGA. Finally, we assess the impact of these hypoxaMIRs on cancer hallmarks through their target genes.
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Affiliation(s)
- Jossimar Coronel-Hernández
- Genomics Laboratory, The National Cancer Institute of México, Tlalpan, Mexico City 14080, Mexico; (I.D.-W.); (D.C.d.L.)
- Functional Genomics Laboratory, Biomedicine Unit, FES-IZTACALA, UNAM, Tlalnepantla 54090, Mexico
| | - Izamary Delgado-Waldo
- Genomics Laboratory, The National Cancer Institute of México, Tlalpan, Mexico City 14080, Mexico; (I.D.-W.); (D.C.d.L.)
| | - David Cantú de León
- Genomics Laboratory, The National Cancer Institute of México, Tlalpan, Mexico City 14080, Mexico; (I.D.-W.); (D.C.d.L.)
| | - César López-Camarillo
- Posgrado en Ciencias Genómicas, Universidad Autónoma de la Ciudad de México, Mexico City 03100, Mexico;
| | - Nadia Jacobo-Herrera
- Biochemistry Unit, Institute of Medical Sciences and Nutrition, Salvador Zubirán, Tlalpan, Mexico City 14080, Mexico;
| | - Rosalío Ramos-Payán
- Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Sinaloa, Culiacan City 80030, Mexico;
| | - Carlos Pérez-Plasencia
- Genomics Laboratory, The National Cancer Institute of México, Tlalpan, Mexico City 14080, Mexico; (I.D.-W.); (D.C.d.L.)
- Functional Genomics Laboratory, Biomedicine Unit, FES-IZTACALA, UNAM, Tlalnepantla 54090, Mexico
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Belpaire M, Taminiau A, Geerts D, Rezsohazy R. HOXA1, a breast cancer oncogene. Biochim Biophys Acta Rev Cancer 2022; 1877:188747. [PMID: 35675857 DOI: 10.1016/j.bbcan.2022.188747] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 04/27/2022] [Accepted: 06/01/2022] [Indexed: 12/24/2022]
Abstract
More than 25 years ago, the first literature records mentioned HOXA1 expression in human breast cancer. A few years later, HOXA1 was confirmed as a proper oncogene in mammary tissue. In the following two decades, molecular data about the mode of action of the HOXA1 protein, the factors contributing to activate and maintain HOXA1 gene expression and the identity of its target genes have accumulated and provide a wider view on the association of this transcription factor to breast oncogenesis. Large-scale transcriptomic data gathered from wide cohorts of patients further allowed refining the relationship between breast cancer type and HOXA1 expression. Several recent reports have reviewed the connection between cancer hallmarks and the biology of HOX genes in general. Here we take HOXA1 as a paradigm and propose an extensive overview of the molecular data centered on this oncoprotein, from what its expression modulators, to the interactors contributing to its oncogenic activities, and to the pathways and genes it controls. The data converge to an intricate picture that answers questions on the multi-modality of its oncogene activities, point towards better understanding of breast cancer aetiology and thereby provides an appraisal for treatment opportunities.
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Affiliation(s)
- Magali Belpaire
- Animal Molecular and Cellular Biology Group (AMCB), Louvain Institute of Biomolecular Science and Technology (LIBST), UCLouvain, Louvain-la-Neuve, Belgium
| | - Arnaud Taminiau
- Animal Molecular and Cellular Biology Group (AMCB), Louvain Institute of Biomolecular Science and Technology (LIBST), UCLouvain, Louvain-la-Neuve, Belgium
| | - Dirk Geerts
- Heart Failure Research Center, Amsterdam University Medical Center (AMC), Universiteit van Amsterdam, Amsterdam, the Netherlands.
| | - René Rezsohazy
- Animal Molecular and Cellular Biology Group (AMCB), Louvain Institute of Biomolecular Science and Technology (LIBST), UCLouvain, Louvain-la-Neuve, Belgium.
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Iwańczyk S, Lehmann T, Cieślewicz A, Radziemski A, Malesza K, Wrotyński M, Jagodziński P, Grygier M, Lesiak M, Araszkiewicz A. Circulating microRNAs in patients with aneurysmal dilatation of coronary arteries. Exp Ther Med 2022; 23:404. [PMID: 35619635 PMCID: PMC9115642 DOI: 10.3892/etm.2022.11331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Accepted: 03/22/2022] [Indexed: 12/03/2022] Open
Abstract
To understand the mechanism underlying coronary artery abnormal dilatation (CAAD), the present study identified and compared the expression of circulating microRNAs (miRNAs) in three groups of patients. Group 1 included 20 patients with CAAD, Group 2 included 20 patients with angiographically confirmed coronary artery disease (CAD), and Group 3 included 20 patients with normal coronary arteries (control). miRNAs were isolated from plasma samples and were profiled using PCR arrays and miRCURY LNA Serum/Plasma Focus PCR Panels. The present study demonstrated that the plasma miRNA levels were significantly different in Group 1 compared with in Group 2 and Group 3 (fold change >2 and P<0.05). The comparison of Group 1 with Group 3 identified 21 significantly upregulated and two downregulated miRNAs in patients with CAAD compared with in the control group. Moreover, six upregulated and two downregulated miRNAs were identified in patients with CAD compared with in the controls. The third comparison revealed four upregulated and three downregulated miRNAs in Group 1, when compared with patients with CAD. In conclusion, the present study identified a specific signature of plasma miRNAs, which were upregulated and downregulated in patients with CAAD compared with in patients with CAD and control individuals.
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Affiliation(s)
- Sylwia Iwańczyk
- 1st Department of Cardiology, Poznan University of Medical Sciences, 61‑848 Poznań, Poland
| | - Tomasz Lehmann
- Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, 60‑781 Poznań, Poland
| | - Artur Cieślewicz
- Department of Clinical Pharmacology, Angiology and Internal Medicine, Poznan University of Medical Sciences, 61‑848 Poznań, Poland
| | - Artur Radziemski
- Department of Hypertensiology, Angiology and Internal Medicine, Poznan University of Medical Sciences, 61‑848 Poznań, Poland
| | - Katarzyna Malesza
- Department of Clinical Pharmacology, Angiology and Internal Medicine, Poznan University of Medical Sciences, 61‑848 Poznań, Poland
| | - Michał Wrotyński
- 1st Department of Cardiology, Poznan University of Medical Sciences, 61‑848 Poznań, Poland
| | - Paweł Jagodziński
- Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, 60‑781 Poznań, Poland
| | - Marek Grygier
- 1st Department of Cardiology, Poznan University of Medical Sciences, 61‑848 Poznań, Poland
| | - Maciej Lesiak
- 1st Department of Cardiology, Poznan University of Medical Sciences, 61‑848 Poznań, Poland
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Zaccagnini G, Greco S, Voellenkle C, Gaetano C, Martelli F. miR-210 hypoxamiR in Angiogenesis and Diabetes. Antioxid Redox Signal 2022; 36:685-706. [PMID: 34521246 DOI: 10.1089/ars.2021.0200] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Significance: microRNA-210 (miR-210) is the master hypoxia-inducible miRNA (hypoxamiR) since it has been found to be significantly upregulated under hypoxia in a wide range of cell types. Recent advances: Gene ontology analysis of its targets indicates that miR-210 modulates several aspects of cellular response to hypoxia. Due to its high pleiotropy, miR-210 not only plays a protective role by fine-tuning mitochondrial metabolism and inhibiting red-ox imbalance and apoptosis, but it can also promote cell proliferation, differentiation, and migration, substantially contributing to angiogenesis. Critical issues: As most miRNAs, modulating different gene pathways, also miR-210 can potentially lead to different and even opposite effects, depending on the physio-pathological contexts in which it acts. Future direction: The use of miRNAs as therapeutics is a fast growing field. This review aimed at highlighting the role of miR-210 in angiogenesis in the context of ischemic cardiovascular diseases and diabetes in order to clarify the molecular mechanisms underpinning miR-210 action. Particular attention will be dedicated to experimentally validated miR-210 direct targets involved in cellular processes related to angiogenesis and diabetes mellitus, such as mitochondrial metabolism, redox balance, apoptosis, migration, and adhesion. Antioxid. Redox Signal. 36, 685-706.
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Affiliation(s)
- Germana Zaccagnini
- Molecular Cardiology Laboratory, IRCCS Policlinico San Donato, San Donato Milanese, Italy
| | - Simona Greco
- Molecular Cardiology Laboratory, IRCCS Policlinico San Donato, San Donato Milanese, Italy
| | - Christine Voellenkle
- Molecular Cardiology Laboratory, IRCCS Policlinico San Donato, San Donato Milanese, Italy
| | - Carlo Gaetano
- Laboratorio di Epigenetica, Istituti Clinici Scientifici Maugeri IRCCS, Pavia, Italy
| | - Fabio Martelli
- Molecular Cardiology Laboratory, IRCCS Policlinico San Donato, San Donato Milanese, Italy
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Shi W, Tang Y, Lu J, Zhuang Y, Wang J. MIR210HG promotes breast cancer progression by IGF2BP1 mediated m6A modification. Cell Biosci 2022; 12:38. [PMID: 35346372 PMCID: PMC8962467 DOI: 10.1186/s13578-022-00772-z] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2021] [Accepted: 03/07/2022] [Indexed: 02/03/2023] Open
Abstract
BACKGROUND Breast cancer is the most common cancer in women around the world, and the molecular mechanisms of breast cancer progression and metastasis are still unclear. This study aims to clarify the function and N6,2'-O-dimethyladenosine (m6A) regulation of lncRNA MIR210HG in breast cancer. RESULTS High expression of MIR210HG was confirmed in breast cancer. MIR210HG promoted breast cancer progression, which was mediated by its encoded miR-210. MIR210HG was regulated by IGF2BP1 mediated m6A modification. IGF2BP1 was confirmed highly expressed in breast cancer and induced both MIR210HG and miR-210 expression, which contributed to breast cancer progression. In addition, MIR210HG transcript was stabilized by IGF2BP1 and co-factor ELAVL1. IGF2BP1 was a direct target of MYCN via E-box binding motif. MYCN induced IGF2BP1 expression in breast cancer cells. MIR210HG and miR-210 expressions were also increased by MYCN. CONCLUSIONS In breast cancer, MIR210HG functions as an oncogenic lncRNA, which is also mediated by its encoded miR-210. In addition, both IGF2BP1 and ELAVL1 enhance the stability of MIR210HG, which contributes to the progression of breast cancer. Interestingly, IGF2BP1 is directly activated by MYCN, which explains the oncogenic role of MYCN. These findings clarify the m6A regulation related molecular mechanism of breast cancer progression. The MYCN/IGF2BP1/MIR210HG axis may serve as an alternative molecular mechanism of breast cancer progression.
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Affiliation(s)
- Wenjing Shi
- Department of Breast Diseases, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People's Republic of China.,Shanghai Key Laboratory of Embryo Original Diseases, Hengshan Rd. 910, Shanghai, 200030, China.,Experimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-University, Munich, Germany.,Shanghai Municipal Key Clinical Speciality, Shanghai, China
| | - Yongzhe Tang
- Department of Breast Diseases, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People's Republic of China.,Shanghai Key Laboratory of Embryo Original Diseases, Hengshan Rd. 910, Shanghai, 200030, China.,Shanghai Municipal Key Clinical Speciality, Shanghai, China
| | - Jing Lu
- Department of Breast Diseases, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People's Republic of China.,Shanghai Key Laboratory of Embryo Original Diseases, Hengshan Rd. 910, Shanghai, 200030, China.,Shanghai Municipal Key Clinical Speciality, Shanghai, China
| | - Yihui Zhuang
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Jie Wang
- Department of Breast Diseases, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People's Republic of China. .,Shanghai Key Laboratory of Embryo Original Diseases, Hengshan Rd. 910, Shanghai, 200030, China. .,Shanghai Municipal Key Clinical Speciality, Shanghai, China.
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Xu SY, Zeng CL, Ni SM, Peng YJ. The Angiogenesis Effects Of Electro-acupuncture Treatment Via Exosomal miR-210 In Cerebral Ischemia-Reperfusion Rats. Curr Neurovasc Res 2022; 19:61-72. [PMID: 35319370 DOI: 10.2174/1567202619666220321115412] [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: 01/12/2022] [Revised: 01/14/2022] [Accepted: 01/20/2022] [Indexed: 11/22/2022]
Abstract
BACKGROUND Acupuncture has been recommended as an alternative and complementary therapy for preventing and treating cerebral ischemia by the World Health Organization (WHO) for years. However, the mechanisms remain unclear. Accumulating evidence has shown that acupuncture can promote angiogenesis to attenuate brain damage after ischemic stroke. In recent years, exosome-carried microRNAs(miRNAs) activated by acupuncture has proven effective in regulating pathological changes. We, therefore, investigated whether electro-acupuncture(EA) enhanced angiogenesis in cerebral stroke via exosome-carried miR-210. METHODS We extracted and identified the exosomes from the serum of MCAO with EA treatment and injected them in MCAO rats for further observation. Simultaneously, miR-120 siRNA and HIF-1α inhibitor were transfected. Then, we evaluated the volume of infarction, pathological changes, and expression levels of angiogenic related factors of each group of rats by TTC and HE staining, transmission electron microscope(TEM), western blot, and quantitative PCR(qPCR). RESULTS Compared with the MCAO group, EA-Exosome(EA-EXO) treatment significantly decreased the infarct volume and the pathological damage, but miR-210 siRNA or HIF-1α inhibitor reversed the protective outcomes induced by EA-EXO. Moreover, EA-EXO treatment upregulated miR-210, and increases CD34、HIF-1α、VEGF、Notch1 protein and mRNA expressions compared with the MCAO group. MiR-210 siRNA or HIF-1α inhibitor treatments both down-regulated those angiogenic related proteins and mRNAs. CONCLUSION EA treatment could active the HIF-1α/VEGF/Notch 1 signal pathway to facilitate angiogenesis after ischemic stroke via exosomal miR-210.
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Affiliation(s)
- Shu-Ying Xu
- Department of Acupuncture and Rehabilitation, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, Jiangsu Province, China
| | - Chun-Li Zeng
- Department of Acupuncture and Rehabilitation, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, Jiangsu Province, China
| | - Si-Ming Ni
- Department of Acupuncture and Rehabilitation, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, Jiangsu Province, China
| | - Yong-Jun Peng
- Department of Acupuncture and Rehabilitation, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, Jiangsu Province, China
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Islam SU, Ahmed MB, Sonn JK, Jin EJ, Lee YS. PRP4 Induces Epithelial–Mesenchymal Transition and Drug Resistance in Colon Cancer Cells via Activation of p53. Int J Mol Sci 2022; 23:ijms23063092. [PMID: 35328513 PMCID: PMC8955441 DOI: 10.3390/ijms23063092] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 03/10/2022] [Accepted: 03/11/2022] [Indexed: 11/16/2022] Open
Abstract
Pre-mRNA processing factor 4B (PRP4) promotes pre-mRNA splicing and signal transduction. Recent studies have shown that PRP4 modulates the assembly of actin cytoskeleton in cancer cells and induces epithelial–mesenchymal transition (EMT) and drug resistance. PRP4 displays kinase domain-like cyclin-dependent kinases and mitogen-activated protein kinases, making it capable of phosphorylating p53 and other target proteins. In the current study, we report that PRP4 induces drug resistance and EMT via direct binding to the p53 protein, inducing its phosphorylation. Moreover, PRP4 overexpression activates the transcription of miR-210 in a hypoxia-inducible factor 1α (HIF-1α)-dependent manner, which activates p53. The involvement of miR-210 in the activation of p53 was confirmed by utilizing si-miR210. si-miR210 blocked the PRP4-activated cell survival pathways and reversed the PRP4-induced EMT phenotype. Moreover, we used deferoxamine as a hypoxia-mimetic agent, and si-HIF to silence HIF-1α. This procedure demonstrated that PRP4-induced EMT and drug resistance emerged in response to consecutive activation of HIF-1α, miR-210, and p53 by PRP4 overexpression. Collectively, our findings suggest that the PRP4 contributes to EMT and drug resistance induction via direct interactions with p53 and actions that promote upregulation of HIF-1α and miR-210. We conclude that PRP4 is an essential factor promoting cancer development and progression. Specific PRP4 inhibition could benefit patients with colon cancer.
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Affiliation(s)
- Salman Ul Islam
- Department of Pharmacy, Cecos University, Hayatabad, Peshawar 25000, Pakistan;
- School of Life Sciences, College of Natural Sciences, Kyungpook National University, Daegu 41566, Korea;
| | - Muhammad Bilal Ahmed
- School of Life Sciences, College of Natural Sciences, Kyungpook National University, Daegu 41566, Korea;
| | - Jong-Kyung Sonn
- Department of Biology, College of Natural Sciences, Kyungpook National University, Daegu 41566, Korea;
| | - Eun-Jung Jin
- Department of Biological Science, College of Natural Science, Wonkwang University, Iksan 54538, Korea
- Correspondence: (E.-J.J.); (Y.-S.L.); Tel.: +82-63-8500-6197(E.-J.J.); +82-53-950-6353 (Y.-S.L.); Fax: +82-53-943-2762 (E.-J.J.)
| | - Young-Sup Lee
- School of Life Sciences, College of Natural Sciences, Kyungpook National University, Daegu 41566, Korea;
- Correspondence: (E.-J.J.); (Y.-S.L.); Tel.: +82-63-8500-6197(E.-J.J.); +82-53-950-6353 (Y.-S.L.); Fax: +82-53-943-2762 (E.-J.J.)
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Spectrum of microRNAs and their target genes in cancer: intervention in diagnosis and therapy. Mol Biol Rep 2022; 49:6827-6846. [PMID: 35031927 DOI: 10.1007/s11033-021-07040-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Accepted: 11/30/2021] [Indexed: 12/11/2022]
Abstract
Till date, several groups have studied the mechanism of microRNA (miRNA) biogenesis, processing, stability, silencing, and their dysregulation in cancer. The miRNA coding genes recurrently go through abnormal amplification, deletion, transcription, and epigenetic regulation in cancer. Some miRNAs function as tumor promoters while few others are tumor suppressors based on the transcriptional regulation of target genes. A review of miRNAs and their target genes in a wide range of cancers is attempted in this article, which may help in the development of new diagnostic tools and intervention therapies. The contribution of miRNAs for drug sensitivity or resistance in cancer therapy and opportunities of miRNAs in cancer prognosis or diagnosis and therapy is also presented in detail.
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Dhawan A, Buffa FM. Machine Learning Using Gene-Sets to Infer miRNA Function. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1385:229-240. [DOI: 10.1007/978-3-031-08356-3_8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
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Mo Y, Zhang Y, Zhang Y, Yuan J, Mo L, Zhang Q. Nickel nanoparticle-induced cell transformation: involvement of DNA damage and DNA repair defect through HIF-1α/miR-210/Rad52 pathway. J Nanobiotechnology 2021; 19:370. [PMID: 34789290 PMCID: PMC8600818 DOI: 10.1186/s12951-021-01117-7] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Accepted: 11/02/2021] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Nickel nanoparticles (Nano-Ni) are increasingly used in industry and biomedicine with the development of nanotechnology. However, the genotoxic and carcinogenic effects of Nano-Ni and the underlying mechanisms are still unclear. METHODS At first, dose-response (0, 10, 20, and 30 μg/mL) and time-response (0, 3, 6, 12, and 24 h) studies were performed in immortalized normal human bronchial epithelial cells BEAS-2B to observe the effects of Nano-Ni on DNA damage response (DDR)-associated proteins and the HIF-1α/miR-210/Rad52 pathway by real-time PCR or Western blot. Then, a Hsp90 inhibitor (1 µM of 17-AAG, an indirect HIF-1α inhibitor), HIF-1α knock-out (KO) cells, and a miR-210 inhibitor (20 nM) were used to determine whether Nano-Ni-induced Rad52 down-regulation was through HIF-1α nuclear accumulation and miR-210 up-regulation. In the long-term experiments, cells were treated with 0.25 and 0.5 µg/mL of Nano-Ni for 21 cycles (~ 150 days), and the level of anchorage-independent growth was determined by plating the cells in soft agar. Transduction of lentiviral particles containing human Rad52 ORF into BEAS-2B cells was used to observe the role of Rad52 in Nano-Ni-induced cell transformation. Nano-Ni-induced DNA damage and dysregulation of HIF-1α/miR-210/Rad52 pathway were also investigated in vivo by intratracheal instillation of 50 µg per mouse of Nano-Ni. gpt delta transgenic mice were used to analyze mutant frequency and mutation spectrum in mouse lungs after Nano-Ni exposure. RESULTS Nano-Ni exposure caused DNA damage at both in vitro and in vivo settings, which was reflected by increased phosphorylation of DDR-associated proteins such as ATM at Ser1981, p53 at Ser15, and H2AX. Nano-Ni exposure also induced HIF-1α nuclear accumulation, miR-210 up-regulation, and down-regulation of homologous recombination repair (HRR) gene Rad52. Inhibition of or knocking-out HIF-1α or miR-210 ameliorated Nano-Ni-induced Rad52 down-regulation. Long-term low-dose Nano-Ni exposure led to cell malignant transformation, and augmentation of Rad52 expression significantly reduced Nano-Ni-induced cell transformation. In addition, increased immunostaining of cell proliferation markers, Ki-67 and PCNA, was observed in bronchiolar epithelial cells and hyperplastic pneumocytes in mouse lungs at day 7 and day 42 after Nano-Ni exposure. Finally, using gpt delta transgenic mice revealed that Nano-Ni exposure did not cause increased gpt mutant frequency and certain DNA mutations, such as base substitution and small base insertions/deletions, are not the main types of Nano-Ni-induced DNA damage. CONCLUSIONS This study unraveled the mechanisms underlying Nano-Ni-induced cell malignant transformation; the combined effects of Nano-Ni-induced DNA damage and DNA repair defects through HIF-1α/miR-210/Rad52 pathway likely contribute to Nano-Ni-induced genomic instability and ultimately cell transformation. Our findings will provide information to further elucidate the molecular mechanisms of Nano-Ni-induced genotoxicity and carcinogenicity.
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Affiliation(s)
- Yiqun Mo
- Department of Environmental and Occupational Health Sciences, School of Public Health and Information Sciences, University of Louisville, 485 E. Gray Street, Louisville, KY 40202 USA
| | - Yue Zhang
- Department of Environmental and Occupational Health Sciences, School of Public Health and Information Sciences, University of Louisville, 485 E. Gray Street, Louisville, KY 40202 USA
| | - Yuanbao Zhang
- Department of Environmental and Occupational Health Sciences, School of Public Health and Information Sciences, University of Louisville, 485 E. Gray Street, Louisville, KY 40202 USA
| | - Jiali Yuan
- Department of Environmental and Occupational Health Sciences, School of Public Health and Information Sciences, University of Louisville, 485 E. Gray Street, Louisville, KY 40202 USA
| | - Luke Mo
- Department of Environmental and Occupational Health Sciences, School of Public Health and Information Sciences, University of Louisville, 485 E. Gray Street, Louisville, KY 40202 USA
| | - Qunwei Zhang
- Department of Environmental and Occupational Health Sciences, School of Public Health and Information Sciences, University of Louisville, 485 E. Gray Street, Louisville, KY 40202 USA
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Sempere LF, Azmi AS, Moore A. microRNA-based diagnostic and therapeutic applications in cancer medicine. WILEY INTERDISCIPLINARY REVIEWS. RNA 2021; 12:e1662. [PMID: 33998154 PMCID: PMC8519065 DOI: 10.1002/wrna.1662] [Citation(s) in RCA: 80] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 04/10/2021] [Accepted: 04/12/2021] [Indexed: 01/18/2023]
Abstract
It has been almost two decades since the first link between microRNAs and cancer was established. In the ensuing years, this abundant class of short noncoding regulatory RNAs has been studied in virtually all cancer types. This tremendously large body of research has generated innovative technological advances for detection of microRNAs in tissue and bodily fluids, identified the diagnostic, prognostic, and/or predictive value of individual microRNAs or microRNA signatures as potential biomarkers for patient management, shed light on regulatory mechanisms of RNA-RNA interactions that modulate gene expression, uncovered cell-autonomous and cell-to-cell communication roles of specific microRNAs, and developed a battery of viral and nonviral delivery approaches for therapeutic intervention. Despite these intense and prolific research efforts in preclinical and clinical settings, there are a limited number of microRNA-based applications that have been incorporated into clinical practice. We review recent literature and ongoing clinical trials that highlight most promising approaches and standing challenges to translate these findings into viable microRNA-based clinical tools for cancer medicine. This article is categorized under: RNA in Disease and Development > RNA in Disease.
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Affiliation(s)
- Lorenzo F. Sempere
- Department of Radiology, Precision Health ProgramMichigan State UniversityEast LansingMichiganUSA
| | - Asfar S. Azmi
- Department of OncologyWayne State University School of MedicineDetroitMichiganUSA
- Karmanos Cancer InstituteDetroitMichiganUSA
| | - Anna Moore
- Departments of Radiology and Physiology, Precision Health ProgramMichigan State UniversityEast LansingMichiganUSA
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Abhange K, Makler A, Wen Y, Ramnauth N, Mao W, Asghar W, Wan Y. Small extracellular vesicles in cancer. Bioact Mater 2021; 6:3705-3743. [PMID: 33898874 PMCID: PMC8056276 DOI: 10.1016/j.bioactmat.2021.03.015] [Citation(s) in RCA: 80] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 03/03/2021] [Accepted: 03/04/2021] [Indexed: 02/07/2023] Open
Abstract
Extracellular vesicles (EV) are lipid-bilayer enclosed vesicles in submicron size that are released from cells. A variety of molecules, including proteins, DNA fragments, RNAs, lipids, and metabolites can be selectively encapsulated into EVs and delivered to nearby and distant recipient cells. In tumors, through such intercellular communication, EVs can regulate initiation, growth, metastasis and invasion of tumors. Recent studies have found that EVs exhibit specific expression patterns which mimic the parental cell, providing a fingerprint for early cancer diagnosis and prognosis as well as monitoring responses to treatment. Accordingly, various EV isolation and detection technologies have been developed for research and diagnostic purposes. Moreover, natural and engineered EVs have also been used as drug delivery nanocarriers, cancer vaccines, cell surface modulators, therapeutic agents and therapeutic targets. Overall, EVs are under intense investigation as they hold promise for pathophysiological and translational discoveries. This comprehensive review examines the latest EV research trends over the last five years, encompassing their roles in cancer pathophysiology, diagnostics and therapeutics. This review aims to examine the full spectrum of tumor-EV studies and provide a comprehensive foundation to enhance the field. The topics which are discussed and scrutinized in this review encompass isolation techniques and how these issues need to be overcome for EV-based diagnostics, EVs and their roles in cancer biology, biomarkers for diagnosis and monitoring, EVs as vaccines, therapeutic targets, and EVs as drug delivery systems. We will also examine the challenges involved in EV research and promote a framework for catalyzing scientific discovery and innovation for tumor-EV-focused research.
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Affiliation(s)
- Komal Abhange
- The Pq Laboratory of Micro/Nano BiomeDx, Department of Biomedical Engineering, Binghamton University-SUNY, Binghamton, NY 13902, USA
| | - Amy Makler
- Micro and Nanotechnology in Medicine, Department of Biological Sciences, Florida Atlantic University, Boca Raton, FL 33431, USA
| | - Yi Wen
- The Pq Laboratory of Micro/Nano BiomeDx, Department of Biomedical Engineering, Binghamton University-SUNY, Binghamton, NY 13902, USA
| | - Natasha Ramnauth
- Micro and Nanotechnology in Medicine, Department of Biological Sciences, Florida Atlantic University, Boca Raton, FL 33431, USA
| | - Wenjun Mao
- Department of Cardiothoracic Surgery, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, Jiangsu 214023, China
| | - Waseem Asghar
- Micro and Nanotechnology in Medicine, Department of Biological Sciences, Florida Atlantic University, Boca Raton, FL 33431, USA
| | - Yuan Wan
- The Pq Laboratory of Micro/Nano BiomeDx, Department of Biomedical Engineering, Binghamton University-SUNY, Binghamton, NY 13902, USA
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Das Gupta A, Krawczynska N, Nelson ER. Extracellular Vesicles-The Next Frontier in Endocrinology. Endocrinology 2021; 162:6310412. [PMID: 34180968 PMCID: PMC8294678 DOI: 10.1210/endocr/bqab133] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Indexed: 12/19/2022]
Abstract
Extracellular vesicles (EVs), including exosomes, are emerging as important carriers of signals in normal and pathological physiology. As EVs are a long-range communication or signaling modality-just like hormones are-the field of endocrinology is uniquely poised to offer insight into their functional biology and regulation. EVs are membrane-bound particles secreted by many different cell types and can have local or systemic effects, being transported in body fluids. They express transmembrane proteins, some of which are shared between EVs and some being specific to the tissue of origin, that can interact with target cells directly (much like hormones can). They also contain cargo within them that includes DNA, RNA, miRNA, and various metabolites. They can fuse with target cells to empty their cargo and alter their target cell physiology in this way also. Similar to the endocrine system, the EV system is likely to be under homeostatic control, making the regulation of their biogenesis and secretion important aspects to study. In this review, we briefly highlight select examples of how EVs are implicated in normal physiology and disease states. We also discuss what is known about their biogenesis and regulation of secretion. We hope that this paper inspires the endocrinology field to use our collective expertise to explore these new multimodal "hormones."
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Affiliation(s)
- Anasuya Das Gupta
- Department of Molecular and Integrative Physiology, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
| | - Natalia Krawczynska
- Department of Molecular and Integrative Physiology, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
| | - Erik R Nelson
- Department of Molecular and Integrative Physiology, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
- Cancer Center at Illinois, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
- Division of Nutritional Sciences, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
- University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, IL 61801, USA
- Carl R. Woese Institute for Genomic Biology, Anticancer Discovery from Pets to People Theme, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
- Correspondence: Erik R. Nelson, Ph.D., University of Illinois at Urbana-Champaign. 407 S Goodwin Ave (MC-114), Urbana, IL, 61801, USA.
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