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Tang Y, Gao Z, Yang J, Li C, Wang W, Wu C, Wu M, Li M, Wu H, Sun Y, Zhang H, Chai Y, Xie F, Qian J, Shen H, Wang D. Breaking the synergism of iron overload and miR-122 to rescue lipid accumulation and peroxidation in MASLD. Pharmacol Res 2025; 215:107728. [PMID: 40188979 DOI: 10.1016/j.phrs.2025.107728] [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: 01/22/2025] [Revised: 03/01/2025] [Accepted: 04/01/2025] [Indexed: 04/10/2025]
Abstract
MASLD is a multifactorial disease with specific subtypes being featured by hepatic iron overload and loss of miR-122, a liver-specific microRNA regulating hepatic lipid homeostasis. Previously we reported the mechanism of iron overload decreasing miR-122. Interestingly, we found that mice lacking miR-122 were highly sensitive to iron overload-induced steatosis and fibrosis. The present study aimed to disclose the downstream mechanisms and the preventive measures targeting miR-122. We first validated the decreases in iron-related genes and miR-122 in MASLD. By using LC-MS/MS and gas-chromatography, we found that the combination of miR-122 knockout and iron overload significantly increased the production and peroxidation of polyunsaturated fatty acids (PUFAs). However, miR-122 knockout itself only incurred lipid accumulation, suggesting a synergistic effect of miR-122 knockout and iron overload in lipid peroxidation. We then located the key enzymes involved in PUFA production and peroxidation by the transcriptome and proteome analysis. Mechanistically, miR-122 and iron regulated fatty acid synthesis through Aacs, fatty acid desaturation through Fads2, and PUFAs oxidation through CYPs. Re-supplementation of miR-122 by recombinant adeno-associated virus or agomir effectively broke the synergism of miR-122 knockout and iron overload in vivo. We further designed a miR-122 expression reporter cell model for high-throughput screening on 2543 natural compounds, and eventually found and validated that the dihydroberberine could upregulate miR-122 expression and correct iron overload-induced lipid disorders. These results identified the synergistic role of miR-122 and iron in PUFAs production and peroxidation, and also proposed the potential application of dihydroberberine as a preventive and therapeutic candidate for MASLD.
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Affiliation(s)
- Yuxiao Tang
- Department of Nutrition, Second Military Medical University, Shanghai, China.
| | - Zelong Gao
- Department of Nutrition, Second Military Medical University, Shanghai, China
| | - Jianxin Yang
- Department of Nutrition, Second Military Medical University, Shanghai, China
| | - Chenqi Li
- Department of Nutrition, Second Military Medical University, Shanghai, China; Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Weili Wang
- Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China; Jiangxi University of Chinese Medicine, Jiangxi, China
| | - Chenghua Wu
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Mengpu Wu
- Department of Nutrition, Second Military Medical University, Shanghai, China
| | - Min Li
- Department of Nutrition, Second Military Medical University, Shanghai, China
| | - Huiwen Wu
- Department of Clinical Nutrition, Shanghai Chest Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yan Sun
- Department of Clinical Nutrition, Shanghai Chest Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Hongwei Zhang
- Department of Clinical Nutrition, Brain Disease Hospital, Zhengzhou University, Henan, China
| | - Yifeng Chai
- Department of Pharmaceutical Analysis, School of Pharmacy, Second Military Medical University, Shanghai, China
| | - Feng Xie
- Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China; Jiangxi University of Chinese Medicine, Jiangxi, China
| | - Jianxin Qian
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
| | - Hui Shen
- Department of Nutrition, Second Military Medical University, Shanghai, China.
| | - Dongyao Wang
- Department of Pharmaceutical Analysis, School of Pharmacy, Second Military Medical University, Shanghai, China.
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Corey DR. It is Time to Revisit miRNA Therapeutics. Nucleic Acid Ther 2025; 35:1-5. [PMID: 39570673 PMCID: PMC11971554 DOI: 10.1089/nat.2024.0069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Accepted: 10/30/2024] [Indexed: 01/18/2025] Open
Abstract
The recent Nobel Prizes awarded to Ambros and Ruvkun have refocused attention on microRNAs (miRNAs). The importance of miRNAs for basic science has always been clear, but the application to therapy has lagged behind. This delay has been made even more apparent by the accelerating pace of successful programs using duplex RNAs and antisense oligonucleotides to target mRNA. Why has progress been slow? A clear understanding of how miRNAs function in mammalian cells is obscured by the fact that miRNAs can exert their effects through multiple complex mechanisms. This gap in our knowledge has complicated progress in drug discovery. Better insights into the mechanism of miRNAs, more rigorous definitions of miRNAs, and more powerful tools for establishing the physical contacts necessary for miRNA action are now available. These advances lead to a central question for nucleic acid therapy-can miRNAs be productive targets for drug discovery and development?
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Affiliation(s)
- David R. Corey
- Departments of Pharmacology and Biochemistry, UT Southwestern Medical Center, Dallas, Texas, USA
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Mansour RM, Abdel Mageed SS, Abulsoud AI, Sayed GA, Lutfy RH, Awad FA, Sadek MM, Shaker AAS, Mohammed OA, Abdel-Reheim MA, Elimam H, Doghish AS. From fatty liver to fibrosis: the impact of miRNAs on NAFLD and NASH. Funct Integr Genomics 2025; 25:30. [PMID: 39888504 DOI: 10.1007/s10142-025-01544-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: 10/09/2024] [Revised: 12/30/2024] [Accepted: 01/27/2025] [Indexed: 02/01/2025]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a disease with various levels varying from fatty liver steatosis to acute steatosis which is non-alcoholic steatohepatitis (NASH), which can develop into hepatic failure, as well as in some conditions it can develop into hepatocellular carcinoma (HCC). In the NAFLD and NASH context, aberrant microRNA (miRNA) expression has a thorough contribution to the incidence and development of these liver disorders by influencing key biological actions, involving lipid metabolism, inflammation, and fibrosis. Dysregulated miRNAs can disrupt the balance between lipid accumulation and clearance, exacerbate inflammatory responses, and promote fibrogenesis, thus advancing the severeness of the disorder from simple steatosis to more complex NASH. In the current review, the latest development concerned with the activity of complex regulatory networks of miRNA in the incidence as well as the evolution of NAFLD is to be discussed, also conferring about the miRNAs' role in the onset, pathogenesis as well as diagnosis of NAFLD and NASH discussing miRNAs' role as diagnostic biomarkers and their therapeutic effects on NAFLD/NASH.
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Affiliation(s)
- Reda M Mansour
- Zoology and Entomology Department, Faculty of Science, Helwan University, Helwan, 11795, Egypt
- Biology Department, School of Biotechnology, Badr University in Cairo, Badr City, 11829, Cairo, Egypt
| | - Sherif S Abdel Mageed
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt
| | - Ahmed I Abulsoud
- Biochemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo, 11785, Egypt
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, 11231, Cairo, Egypt
| | - Ghadir A Sayed
- Department of Biochemistry, Faculty of Pharmacy, Egyptian Russian University, Cairo, Egypt
| | - Radwa H Lutfy
- School of Biotechnology, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt
| | - Farah A Awad
- School of Biotechnology, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt
| | - Mohamed M Sadek
- School of Biotechnology, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt
| | - Abanoub A S Shaker
- School of Biotechnology, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt
| | - Osama A Mohammed
- Department of Pharmacology, College of Medicine, University of Bisha, Bisha, 61922, Saudi Arabia
| | | | - Hanan Elimam
- Department of Biochemistry, Faculty of Pharmacy, University of Sadat City, Sadat City, 32897, Egypt
| | - Ahmed S Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt.
- Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, 11231, Cairo, Egypt.
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Liu F, Liu B, Xu S, Ni Y, Liu X. MicroRNA-122 protects against interferon-α-induced hepatic inflammatory response via the Janus kinase-signal transducer and activator of transcription pathway. Endocr J 2025; 72:53-67. [PMID: 39358210 PMCID: PMC11778391 DOI: 10.1507/endocrj.ej24-0317] [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: 06/04/2024] [Accepted: 08/26/2024] [Indexed: 10/04/2024] Open
Abstract
Significant overlap in the epidemiology and coinfection of chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) has been identified, which accelerates the development of severe liver cirrhosis and hepatocellular carcinoma worldwide. Interferon-α (IFN-α), a cytokine with antiviral properties, exerts profound physiological effects on innate immunity by regulating interferon-stimulated genes (ISGs) within cells. However, the underlying mechanism of IFN-α in hepatic inflammation remains to be fully elucidated. Here, we utilized LO2 cells treated with the recombinant IFN-α protein and conducted microRNA (miR) sequencing. MiR-122-3p and miR-122-5p_R+1 were the most enriched miRNAs involved in the pathogenesis of IFN-α-induced inflammatory responses and were significantly downregulated by IFN-α treatment. Furthermore, we identified interferon induced protein with tetratricopeptide repeats 1 (IFIT1) as a potential target gene of miR-122. IFN-α markedly increased the expression of proinflammatory cytokines and fibrogenic genes but decreased the mRNA expression of ISGs. Additionally, IFN-α significantly activated the NF-κB p-p65, MAPK p-p38, and Jak/STAT pathways to trigger inflammation. Importantly, supplementation with a miR-122 mimic significantly alleviated IFN-α-induced inflammation and induced IFIT1 expression in LO2 cells. Conversely, the suppression of miR-122 markedly exacerbated the inflammatory response triggered by IFN-α. Furthermore, silencing IFIT1 via an siRNA elicited an inflammatory response, whereas IFIT1 overexpression ameliorated hepatic inflammation and fibrosis in a manner comparable to that induced by IFN-α treatment. Taken together, our findings suggest that miR-122 and its target, IFIT1, reciprocally regulate the inflammatory response associated with IFN through the Jak/STAT pathway.
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Affiliation(s)
- Fanwei Liu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Department of Infectious Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, China
| | - Bowen Liu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Department of Infectious Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, China
| | - Shanshan Xu
- Department of Anesthesia, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, China
| | - Yinhua Ni
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, Zhejiang 310014, China
| | - Xiaoli Liu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Department of Infectious Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, China
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Luo S, Jiang H, Li Q, Yang S, Yu X, Xu X, Xie Q, Ke X, Zheng Q. The Intra-Articular Delivery of a Low-Dose Adeno-Associated Virus-IL-1 Receptor Antagonist Vector Alleviates the Progress of Arthritis in an Osteoarthritis Rat Model. Pharmaceutics 2024; 16:1518. [PMID: 39771498 PMCID: PMC11728506 DOI: 10.3390/pharmaceutics16121518] [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: 10/08/2024] [Revised: 11/11/2024] [Accepted: 11/21/2024] [Indexed: 01/16/2025] Open
Abstract
Background/Objectives: Interleukin-1 (IL-1) is a pivotal mediator in the pathological progression of osteoarthritis (OA), playing a central role in disease progression. However, the rapid clearance of IL-1 receptor antagonist (IL-1Ra) from the joints may hinder the efficacy of intra-articular IL-1Ra injections in reducing OA-associated pain or cartilage degradation. Methods: Sustaining sufficient levels of IL-1Ra within the joints via adeno-associated virus (AAV)-mediated gene therapy presents a promising therapeutic strategy for OA. In this study, we constructed an IL-1Ra expression cassette employing intron insertion in the coding sequence (CDS) region to enhance protein expression levels. Furthermore, we incorporated precisely targeted liver-specific microRNA (miRNA) sequences to specifically downregulate transgene expression within hepatic tissues, thereby ensuring more targeted and controlled regulation of gene expression. Results: A rat model of OA was employed to compare the efficacy of AAV5 and AAV9 for IL-1Ra delivery at both high and low doses. It was observed that low-dose, but not high-dose, AAV9-IL-1Ra resulted in a significant reduction in joint swelling, accompanied by a decrease in the diameter of the affected area and the preservation of biomarkers associated with trabecular bone integrity. Conclusions: These results highlight the great potential of AAV9-IL-1Ra in osteoarthritis therapy, with the promise of achieving long-term improvement through a single intra-articular injection.
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Affiliation(s)
- Shuang Luo
- Chengdu Origen Biotechnology Co., Ltd., Chengdu 610036, China; (S.L.); (H.J.); (Q.L.); (S.Y.); (X.Y.); (X.X.); (Q.X.)
- Therapeutic Proteins Key Laboratory of Sichuan Province, Chengdu 610037, China
| | - Hao Jiang
- Chengdu Origen Biotechnology Co., Ltd., Chengdu 610036, China; (S.L.); (H.J.); (Q.L.); (S.Y.); (X.Y.); (X.X.); (Q.X.)
- Therapeutic Proteins Key Laboratory of Sichuan Province, Chengdu 610037, China
| | - Qingwei Li
- Chengdu Origen Biotechnology Co., Ltd., Chengdu 610036, China; (S.L.); (H.J.); (Q.L.); (S.Y.); (X.Y.); (X.X.); (Q.X.)
- Therapeutic Proteins Key Laboratory of Sichuan Province, Chengdu 610037, China
| | - Shiping Yang
- Chengdu Origen Biotechnology Co., Ltd., Chengdu 610036, China; (S.L.); (H.J.); (Q.L.); (S.Y.); (X.Y.); (X.X.); (Q.X.)
| | - Xuemei Yu
- Chengdu Origen Biotechnology Co., Ltd., Chengdu 610036, China; (S.L.); (H.J.); (Q.L.); (S.Y.); (X.Y.); (X.X.); (Q.X.)
| | - Xiongliang Xu
- Chengdu Origen Biotechnology Co., Ltd., Chengdu 610036, China; (S.L.); (H.J.); (Q.L.); (S.Y.); (X.Y.); (X.X.); (Q.X.)
| | - Qing Xie
- Chengdu Origen Biotechnology Co., Ltd., Chengdu 610036, China; (S.L.); (H.J.); (Q.L.); (S.Y.); (X.Y.); (X.X.); (Q.X.)
- Therapeutic Proteins Key Laboratory of Sichuan Province, Chengdu 610037, China
| | - Xiao Ke
- Chengdu Origen Biotechnology Co., Ltd., Chengdu 610036, China; (S.L.); (H.J.); (Q.L.); (S.Y.); (X.Y.); (X.X.); (Q.X.)
- Therapeutic Proteins Key Laboratory of Sichuan Province, Chengdu 610037, China
- Chengdu Kanghong Pharmaceuticals Group Co., Ltd., Chengdu 610037, China
| | - Qiang Zheng
- Chengdu Origen Biotechnology Co., Ltd., Chengdu 610036, China; (S.L.); (H.J.); (Q.L.); (S.Y.); (X.Y.); (X.X.); (Q.X.)
- Therapeutic Proteins Key Laboratory of Sichuan Province, Chengdu 610037, China
- Chengdu Kanghong Pharmaceuticals Group Co., Ltd., Chengdu 610037, China
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Lee EJ, Jeong M, Lee H, Je MA, Park K, Lee DG, Xuan X, Kim S, Park S, Kim J. MiR-122, miR-133a, and miR-206 as potential biomarkers for post-mortem interval estimation. Genes Genomics 2024; 46:1175-1182. [PMID: 39207675 DOI: 10.1007/s13258-024-01559-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Accepted: 08/12/2024] [Indexed: 09/04/2024]
Abstract
BACKGROUD Accurate estimation of post-mortem interval (PMI) is crucial in forensic investigations. MicroRNAs (miRNAs or miRs) are small non-coding RNAs that remain relatively stable within the cell nucleus despite post-mortem changes. OBJECTIVE We assessed three target genes (miR-122, miR-133a, and miR-206) for PMI estimation using 72 healthy adult male BALB/c mice exposed to two different temperatures (4 and 21℃) at nine different time points over 10 days. METHODS Initially, the stability of the two reference genes (RNU6B and 5 srRNA) was evaluated using gene stability analysis tools (Delta Ct, Best Keeper, and Genorm) to select the optimal reference gene. RNU6B was found to be the most stable endogenous control. Subsequently, the expression patterns of miR-122, miR-133a, and miR-206 were analyzed within a 10-day PMI period using the heart, skeletal muscle, liver, and brain tissues. RESULTS At 4℃, miR-122 levels significantly decreased on days 8 and 10 in all tissues, with only the liver showing significant changes at 21℃. MiR-133a decreased over time in the heart, muscles, and brain, showing a dramatic decrease on days 8 and 10 in the heart and muscles at both temperatures. Although miR-206 levels decreased over time in muscles and liver at 4 ℃, these increased in the brain at 21 ℃, with no expression changes in other organs. CONCLUSION In summary, miR-122, miR-133a, and miR-206 are potential PMI markers in heart and skeletal muscle tissues.
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Affiliation(s)
- Eun Ju Lee
- Department of Clinical Laboratory Science, College of Health Sciences, Catholic University of Pusan, Busan, 46252, Republic of Korea
- Department of Research and Development, Korea Mycobacterium Resource Center (KMRC), The Korean Institute of Tuberculosis, Osong, 28158, Republic of Korea
| | - Mingyoung Jeong
- Department of Forensic Science, Graduate School, Catholic University of Pusan, Busan, 46252, Republic of Korea
| | - Haneul Lee
- Department of Forensic Science, Graduate School, Catholic University of Pusan, Busan, 46252, Republic of Korea
- Next-Generation Industrial Field-Based Specialist Program for Molecular Diagnostics, Brain Busan 21 Plus Project, Graduate School, Catholic University of Pusan, Busan, 46252, Republic of Korea
| | - Min-A Je
- Department of Clinical Laboratory Science, College of Health Sciences, Catholic University of Pusan, Busan, 46252, Republic of Korea
| | - Kwangmin Park
- Department of Clinical Laboratory Science, College of Health Sciences, Catholic University of Pusan, Busan, 46252, Republic of Korea
- Next-Generation Industrial Field-Based Specialist Program for Molecular Diagnostics, Brain Busan 21 Plus Project, Graduate School, Catholic University of Pusan, Busan, 46252, Republic of Korea
| | - Dong Geon Lee
- Department of Clinical Laboratory Science, College of Health Sciences, Catholic University of Pusan, Busan, 46252, Republic of Korea
- Next-Generation Industrial Field-Based Specialist Program for Molecular Diagnostics, Brain Busan 21 Plus Project, Graduate School, Catholic University of Pusan, Busan, 46252, Republic of Korea
| | - Xianglan Xuan
- Department of Clinical Laboratory Science, College of Health Sciences, Catholic University of Pusan, Busan, 46252, Republic of Korea
- Next-Generation Industrial Field-Based Specialist Program for Molecular Diagnostics, Brain Busan 21 Plus Project, Graduate School, Catholic University of Pusan, Busan, 46252, Republic of Korea
| | - Sunghyun Kim
- Department of Clinical Laboratory Science, College of Health Sciences, Catholic University of Pusan, Busan, 46252, Republic of Korea
- Department of Forensic Science, Graduate School, Catholic University of Pusan, Busan, 46252, Republic of Korea
- Next-Generation Industrial Field-Based Specialist Program for Molecular Diagnostics, Brain Busan 21 Plus Project, Graduate School, Catholic University of Pusan, Busan, 46252, Republic of Korea
| | - Sunyoung Park
- School of Mechanical Engineering, Yonsei University, Seoul, 03772, Republic of Korea.
| | - Jungho Kim
- Department of Clinical Laboratory Science, College of Health Sciences, Catholic University of Pusan, Busan, 46252, Republic of Korea.
- Department of Forensic Science, Graduate School, Catholic University of Pusan, Busan, 46252, Republic of Korea.
- Next-Generation Industrial Field-Based Specialist Program for Molecular Diagnostics, Brain Busan 21 Plus Project, Graduate School, Catholic University of Pusan, Busan, 46252, Republic of Korea.
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Zhang X, Wang T, Fan X, Wang M, Duan Z, He F, Wang HH, Li Z. Development of a Modular miRNA-Responsive Biosensor for Organ-Specific Evaluation of Liver Injury. BIOSENSORS 2024; 14:450. [PMID: 39329825 PMCID: PMC11430419 DOI: 10.3390/bios14090450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 09/01/2024] [Accepted: 09/19/2024] [Indexed: 09/28/2024]
Abstract
MicroRNAs (miRNAs) are increasingly being considered essential diagnostic biomarkers and therapeutic targets for multiple diseases. In recent years, researchers have emphasized the need to develop probes that can harness extracellular miRNAs as input signals for disease diagnostics. In this study, we introduce a novel miRNA-responsive biosensor (miR-RBS) designed to achieve highly sensitive and specific detection of miRNAs, with a particular focus on targeted organ-specific visualization. The miR-RBS employs a Y-structured triple-stranded DNA probe (Y-TSDP) that exhibits a fluorescence-quenched state under normal physiological conditions. The probe switches to an activated state with fluorescence signals in the presence of high miRNA concentrations, enabling rapid and accurate disease reporting. Moreover, the miR-RBS probe had a modular design, with a fluorescence-labeled strand equipped with a functional module that facilitates specific binding to organs that express high levels of the target receptors. This allowed the customization of miRNA detection and cell targeting using aptameric anchors. In a drug-induced liver injury model, the results demonstrate that the miR-RBS probe effectively visualized miR-122 levels, suggesting it has good potential for disease diagnosis and organ-specific imaging. Together, this innovative biosensor provides a versatile tool for the early detection and monitoring of diseases through miRNA-based biomarkers.
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Affiliation(s)
- Xinxin Zhang
- College of Biology, Hunan University, No. 27 Tianma Road, Yuelu District, Changsha 410082, China
| | - Tingting Wang
- College of Biology, Hunan University, No. 27 Tianma Road, Yuelu District, Changsha 410082, China
| | - Xiangqing Fan
- College of Biology, Hunan University, No. 27 Tianma Road, Yuelu District, Changsha 410082, China
| | - Meixia Wang
- College of Biology, Hunan University, No. 27 Tianma Road, Yuelu District, Changsha 410082, China
| | - Zhixi Duan
- Department of Emergency Medicine, The Second Xiangya Hospital of Central South University, Changsha 410011, China
- Department of Trauma Center, The Second Xiangya Hospital of Central South University, Changsha 410011, China
- FuRong Laboratory, Changsha 410078, China
| | - Fang He
- College of Biology, Hunan University, No. 27 Tianma Road, Yuelu District, Changsha 410082, China
| | - Hong-Hui Wang
- College of Biology, Hunan University, No. 27 Tianma Road, Yuelu District, Changsha 410082, China
| | - Zhihong Li
- Department of Trauma Center, The Second Xiangya Hospital of Central South University, Changsha 410011, China
- FuRong Laboratory, Changsha 410078, China
- Department of Orthopaedics, The Second Xiangya Hospital of Central South University, Changsha 410011, China
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Li P, Ma X, Huang D, Gu X. Exploring the roles of non-coding RNAs in liver regeneration. Noncoding RNA Res 2024; 9:945-953. [PMID: 38680418 PMCID: PMC11046251 DOI: 10.1016/j.ncrna.2024.04.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Revised: 03/26/2024] [Accepted: 04/16/2024] [Indexed: 05/01/2024] Open
Abstract
Liver regeneration (LR) is a complex process encompassing three distinct phases: priming, proliferation phase and restoration, all influenced by various regulatory factors. After liver damage or partial resection, the liver tissue demonstrates remarkable restorative capacity, driven by cellular proliferation and repair mechanisms. The essential roles of non-coding RNAs (ncRNAs), predominantly microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNA (circRNA), in regulating LR have been vastly studied. Additionally, the impact of ncRNAs on LR and their abnormal expression profiles during this process have been extensively documented. Mechanistic investigations have revealed that ncRNAs interact with genes involved in proliferation to regulate hepatocyte proliferation, apoptosis and differentiation, along with liver progenitor cell proliferation and migration. Given the significant role of ncRNAs in LR, an in-depth exploration of their involvement in the liver's self-repair capacity can reveal promising therapeutic strategies for LR and liver-related diseases. Moreover, understanding the unique regenerative potential of the adult liver and the mechanisms and regulatory factors of ncRNAs in LR are crucial for improving current treatment strategies and exploring new therapeutic approaches for various liver-related diseases. This review provides a brief overview of the LR process and the ncRNA expression profiles during this process. Furthermore, we also elaborate on the specific molecular mechanisms through which multiple key ncRNAs regulate the LR process. Finally, based on the expression characteristics of ncRNAs and their interactions with proliferation-associated genes, we explore their potential clinical application, such as developing predictive indicators reflecting liver regenerative activity and manipulating LR processes for therapeutic purposes.
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Affiliation(s)
- Penghui Li
- Department of Oncology, The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang, 471000, Henan, China
| | - Xiao Ma
- Zhejiang University School of Medicine, Hangzhou, 310000, Zhejiang, China
| | - Di Huang
- Department of Child Health Care, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, Henan, China
| | - Xinyu Gu
- Department of Oncology, The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang, 471000, Henan, China
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9
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Toropko M, Chuvpilo S, Karabelsky A. miRNA-Mediated Mechanisms in the Generation of Effective and Safe Oncolytic Viruses. Pharmaceutics 2024; 16:986. [PMID: 39204331 PMCID: PMC11360794 DOI: 10.3390/pharmaceutics16080986] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Revised: 07/19/2024] [Accepted: 07/22/2024] [Indexed: 09/04/2024] Open
Abstract
MicroRNAs (miRNAs) are short non-coding RNAs that regulate gene expression by inhibiting the translation of target transcripts. The expression profiles of miRNAs vary in different tissues and change with the development of diseases, including cancer. This feature has begun to be used for the modification of oncolytic viruses (OVs) in order to increase their selectivity and efficacy. OVs represent a relatively new class of anticancer drugs; they are designed to replicate in cancer tumors and destroy them. These can be natural viruses that can replicate within cancer tumor cells, or recombinant viruses created in laboratories. There are some concerns regarding OVs' toxicity, due to their ability to partially replicate in healthy tissues. In addition, lytic and immunological responses upon OV therapy are not always sufficient, so various OV editing methods are used. This review discusses the latest results of preclinical and clinical studies of OVs, modifications of which are associated with the miRNA-mediated mechanism of gene silencing.
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Affiliation(s)
- Mariia Toropko
- Gene Therapy Department, Sirius University of Science and Technology, Olympic Avenue, 1, 354340 Sochi, Russia; (S.C.); (A.K.)
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Wang QL, Meng LC, Zhao Z, Du JF, Li P, Jiang Y, Li HJ. Ultrasensitive upconverting nanoprobes for in situ imaging of drug-induced liver injury using miR-122 as the biomarker. Talanta 2024; 274:126108. [PMID: 38640602 DOI: 10.1016/j.talanta.2024.126108] [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: 10/01/2023] [Revised: 01/09/2024] [Accepted: 04/12/2024] [Indexed: 04/21/2024]
Abstract
Drug-induced liver injury (DILI) is a frequent adverse drug reaction. The current clinical diagnostic methods are inadequate for accurate and early detection of DILI due to the lack of effective diagnostic biomarkers. Hepatocyte-specific miR-122 is released from injured hepatocytes promptly and its efflux is significantly correlated with the progression of DILI. Therefore, achieving precise in situ detection of miR-122 with high sensitivity is vital for early visualization of DILI. Herein, a new nanoprobe, consisting of miR-122 aptamer, upconversion nanoparticles (UCNPs) and Prussian blue nanoparticles (PBNPs) was introduced for the early and sensitive detection of DILI in situ. As the nanoprobes reached in the liver, miR-122 aptamer-based entropy-driven strand displacement (ESDR) signal amplification reaction was triggered and luminescence resonance energy transfer (LRET) between UCNPs and PBNPs was responded to achieve the high-fidelity detection of DILI. A negative correlation was observed between the intensity of upconversion luminescence (UCL) and the concentration of miR-122. UCL imaging conducted both in vivo and ex vivo indicated that a reduction in miR-122 concentration led to an increase in UCL intensity, revealing a precise state of DILI. The detection technique demonstrated a positive correlation between signal intensity and severity, offering a more straightforward and intuitive method of visualizing DILI.
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Affiliation(s)
- Qiao-Lei Wang
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China
| | - Ling-Chang Meng
- Institute of Chinese Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University, Nanjing, China
| | - Zhen Zhao
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China
| | - Jin-Fa Du
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China
| | - Ping Li
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China
| | - Yan Jiang
- College of Chemical Engineering, Nanjing Forestry University, Nanjing, 210037, China.
| | - Hui-Jun Li
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China.
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11
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Harlow J, Dallner M, Nasheri N. Optimization of the replication of hepatitis E virus genotype 3 in vitro. J Appl Microbiol 2024; 135:lxae137. [PMID: 38849307 DOI: 10.1093/jambio/lxae137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2024] [Revised: 05/31/2024] [Accepted: 06/06/2024] [Indexed: 06/09/2024]
Abstract
AIMS Hepatitis E virus (HEV) is responsible for ∼20 million human infections worldwide every year. The genotypes HEV-3 and HEV-4 are zoonotic and are responsible for most of the autochthonous HEV cases in high-income countries. There are several cell culture systems that allow for propagation of different HEV genotypes in vitro. One of these systems uses human lung carcinoma cells (A549), and was further optimized for propagation of HEV-3 47832c strain. In this study, we investigated the effect of different media supplements as well as microRNA-122 (miR-122) on improving the replication of HEV-3 47832c in A549 cells. METHODS AND RESULTS We observed that supplementation of maintenance media with 5% fetal bovine serum was sufficient for efficient replication of HEV-3, and verified the positive effect of media supplementation with Amphotericin B, MgCl2, and dimethyl sulfoxide on replication of HEV-3. We have also demonstrated that adding miR-122 mimics to the culture media does not have any significant effect on the replication of HEV-3 47832c. CONCLUSIONS Herein, we detected over a 6-fold increase in HEV-3 replication in A549/D3 cells by adding all three supplements: Amphotericin B, MgCl2, and dimethyl sulfoxide to the culture media, while demonstrating that miR-122 might not play a key role in replication of HEV-3 47832c.
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Affiliation(s)
- Jennifer Harlow
- National Food Virology Reference Centre, Bureau of Microbial Hazards, Food Directorate, Health Canada, 251 Sir Frederick Banting Driveway, Ottawa, ON K1A 0K9, Canada
| | - Matthew Dallner
- National Food Virology Reference Centre, Bureau of Microbial Hazards, Food Directorate, Health Canada, 251 Sir Frederick Banting Driveway, Ottawa, ON K1A 0K9, Canada
| | - Neda Nasheri
- National Food Virology Reference Centre, Bureau of Microbial Hazards, Food Directorate, Health Canada, 251 Sir Frederick Banting Driveway, Ottawa, ON K1A 0K9, Canada
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada
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12
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Di Carlo D, Falasca F, Mazzuti L, Guerrizio G, Migliara G, Santori M, Lazzaro A, Mezzaroma I, D'Ettorre G, Fimiani C, Iaiani G, Antonelli G, Turriziani O. MicroRNA Expression Levels in Peripheral Blood Mononuclear Cells from Human Immunodeficiency Virus Type 1 Positive Individuals and Relationship with Different Levels of Viral Suppression. AIDS Res Hum Retroviruses 2024; 40:321-329. [PMID: 37523231 DOI: 10.1089/aid.2022.0165] [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] [Indexed: 08/01/2023] Open
Abstract
The persistence of low human immunodeficiency virus type 1 (HIV-1) replication in individuals undergoing antiretroviral therapy (ART) still threatens their health. Previous findings have shown that microRNAs (miRNAs) could interfere with several steps of the viral life cycle. Herein, we set out to investigate the expression of miR-150, miR-223, miR-382, miR-324-5p, miR-33a-5p, miR-34a, and miR-132 in the whole peripheral blood mononuclear cell (PBMC) population from people living with HIV-1 showing different levels of viral suppression. Levels of PBMC-associated miRNAs were analyzed in 30 individuals with undetectable viremia (target not detected) and 30 individuals with detectable low-level viremia (1-200 copies/mL). In addition, 30 samples from treatment-naive (NAIVE) individuals were investigated. Results were compared to a control group of 28 HIV-negative donors. All miRNAs analyzed were strongly downregulated in the NAIVE population, either compared to the treated group or to controls. Stratification of ART-treated donors according to the therapeutic regimen showed the downregulation of miR-33a-5p in subjects treated with non-nucleoside reverse transcriptase inhibitors compared with those treated with protease inhibitors. Collectively, the present study shows that uncontrolled viral replication leads to profound miRNA deregulation while treated individuals, irrespective of the degree of viral suppression, and even the types of antiviral drugs seem to be specifically associated with miRNA expression profiles. These evidences suggest that virological suppression could be favored by miRNA modulation.
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Affiliation(s)
- Daniele Di Carlo
- Department of Molecular Medicine, Sapienza University of Rome, Policlinico Umberto I, Rome, Italy
- Pasteur Laboratories, Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Rome, Italy
| | - Francesca Falasca
- Department of Molecular Medicine, Sapienza University of Rome, Policlinico Umberto I, Rome, Italy
- Transfusion Medicine Unit, "F. Veneziale" Hospital, Isernia, Italy
| | - Laura Mazzuti
- Department of Molecular Medicine, Sapienza University of Rome, Policlinico Umberto I, Rome, Italy
- Department of Clinical and Molecular Medicine, Sapienza University, Sant'Andrea Hospital, Rome, Italy
| | - Giuliana Guerrizio
- Department of Molecular Medicine, Sapienza University of Rome, Policlinico Umberto I, Rome, Italy
| | - Giuseppe Migliara
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Policlinico Umberto I, Rome, Italy
| | - Marta Santori
- Department Internal Medicine, Endocrine-Metabolic Sciences and Infectious Diseases, Policlinico Umberto I, Rome, Italy
| | - Alessandro Lazzaro
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Policlinico Umberto I, Rome, Italy
| | - Ivano Mezzaroma
- Department of Translational and Precision Medicine, Sapienza University of Rome, Policlinico Umberto I, Rome, Italy
| | - Gabriella D'Ettorre
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Policlinico Umberto I, Rome, Italy
| | - Caterina Fimiani
- Department Internal Medicine, Endocrine-Metabolic Sciences and Infectious Diseases, Policlinico Umberto I, Rome, Italy
| | - Giancarlo Iaiani
- Department Internal Medicine, Endocrine-Metabolic Sciences and Infectious Diseases, Policlinico Umberto I, Rome, Italy
| | - Guido Antonelli
- Department of Molecular Medicine, Sapienza University of Rome, Policlinico Umberto I, Rome, Italy
| | - Ombretta Turriziani
- Department of Molecular Medicine, Sapienza University of Rome, Policlinico Umberto I, Rome, Italy
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13
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Seyhan AA. Trials and Tribulations of MicroRNA Therapeutics. Int J Mol Sci 2024; 25:1469. [PMID: 38338746 PMCID: PMC10855871 DOI: 10.3390/ijms25031469] [Citation(s) in RCA: 85] [Impact Index Per Article: 85.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Revised: 01/15/2024] [Accepted: 01/17/2024] [Indexed: 02/12/2024] Open
Abstract
The discovery of the link between microRNAs (miRNAs) and a myriad of human diseases, particularly various cancer types, has generated significant interest in exploring their potential as a novel class of drugs. This has led to substantial investments in interdisciplinary research fields such as biology, chemistry, and medical science for the development of miRNA-based therapies. Furthermore, the recent global success of SARS-CoV-2 mRNA vaccines against the COVID-19 pandemic has further revitalized interest in RNA-based immunotherapies, including miRNA-based approaches to cancer treatment. Consequently, RNA therapeutics have emerged as highly adaptable and modular options for cancer therapy. Moreover, advancements in RNA chemistry and delivery methods have been pivotal in shaping the landscape of RNA-based immunotherapy, including miRNA-based approaches. Consequently, the biotechnology and pharmaceutical industry has witnessed a resurgence of interest in incorporating RNA-based immunotherapies and miRNA therapeutics into their development programs. Despite substantial progress in preclinical research, the field of miRNA-based therapeutics remains in its early stages, with only a few progressing to clinical development, none reaching phase III clinical trials or being approved by the US Food and Drug Administration (FDA), and several facing termination due to toxicity issues. These setbacks highlight existing challenges that must be addressed for the broad clinical application of miRNA-based therapeutics. Key challenges include establishing miRNA sensitivity, specificity, and selectivity towards their intended targets, mitigating immunogenic reactions and off-target effects, developing enhanced methods for targeted delivery, and determining optimal dosing for therapeutic efficacy while minimizing side effects. Additionally, the limited understanding of the precise functions of miRNAs limits their clinical utilization. Moreover, for miRNAs to be viable for cancer treatment, they must be technically and economically feasible for the widespread adoption of RNA therapies. As a result, a thorough risk evaluation of miRNA therapeutics is crucial to minimize off-target effects, prevent overdosing, and address various other issues. Nevertheless, the therapeutic potential of miRNAs for various diseases is evident, and future investigations are essential to determine their applicability in clinical settings.
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Affiliation(s)
- Attila A. Seyhan
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI 02912, USA;
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, RI 02912, USA
- Joint Program in Cancer Biology, Lifespan Health System and Brown University, Providence, RI 02912, USA
- Legorreta Cancer Center, Brown University, Providence, RI 02912, USA
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14
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Beňačka R, Szabóová D, Guľašová Z, Hertelyová Z, Radoňak J. Non-Coding RNAs in Human Cancer and Other Diseases: Overview of the Diagnostic Potential. Int J Mol Sci 2023; 24:16213. [PMID: 38003403 PMCID: PMC10671391 DOI: 10.3390/ijms242216213] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Revised: 11/07/2023] [Accepted: 11/08/2023] [Indexed: 11/26/2023] Open
Abstract
Non-coding RNAs (ncRNAs) are abundant single-stranded RNA molecules in human cells, involved in various cellular processes ranging from DNA replication and mRNA translation regulation to genome stability defense. MicroRNAs are multifunctional ncRNA molecules of 18-24 nt in length, involved in gene silencing through base-pair complementary binding to target mRNA transcripts. piwi-interacting RNAs are an animal-specific class of small ncRNAs sized 26-31 nt, responsible for the defense of genome stability via the epigenetic and post-transcriptional silencing of transposable elements. Long non-coding RNAs are ncRNA molecules defined as transcripts of more than 200 nucleotides, their function depending on localization, and varying from the regulation of cell differentiation and development to the regulation of telomere-specific heterochromatin modifications. The current review provides recent data on the several forms of small and long non-coding RNA's potential to act as diagnostic, prognostic or therapeutic target for various human diseases.
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Affiliation(s)
- Roman Beňačka
- Department of Pathophysiology, Medical Faculty, Pavol Jozef Šafarik University, 04011 Košice, Slovakia; (R.B.); (D.S.)
| | - Daniela Szabóová
- Department of Pathophysiology, Medical Faculty, Pavol Jozef Šafarik University, 04011 Košice, Slovakia; (R.B.); (D.S.)
| | - Zuzana Guľašová
- Center of Clinical and Preclinical Research MEDIPARK, Pavol Jozef Šafarik University, 04011 Košice, Slovakia; (Z.G.); (Z.H.)
| | - Zdenka Hertelyová
- Center of Clinical and Preclinical Research MEDIPARK, Pavol Jozef Šafarik University, 04011 Košice, Slovakia; (Z.G.); (Z.H.)
| | - Jozef Radoňak
- 1st Department of Surgery, Faculty of Medicine, Louis Pasteur University Hospital (UNLP) and Pavol Jozef Šafarik University, 04011 Košice, Slovakia
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15
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Wang HC, Yin WX, Jiang M, Han JY, Kuai XW, Sun R, Sun YF, Ji JL. Function and biomedical implications of exosomal microRNAs delivered by parenchymal and nonparenchymal cells in hepatocellular carcinoma. World J Gastroenterol 2023; 29:5435-5451. [PMID: 37900996 PMCID: PMC10600808 DOI: 10.3748/wjg.v29.i39.5435] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 08/13/2023] [Accepted: 10/16/2023] [Indexed: 10/19/2023] Open
Abstract
Small extracellular vesicles (exosomes) are important components of the tumor microenvironment. They are small membrane-bound vesicles derived from almost all cell types and play an important role in intercellular communication. Exosomes transmit biological molecules obtained from parent cells, such as proteins, lipids, and nucleic acids, and are involved in cancer development. MicroRNAs (miRNAs), the most abundant contents in exosomes, are selectively packaged into exosomes to carry out their biological functions. Recent studies have revealed that exosome-delivered miRNAs play crucial roles in the tumorigenesis, progression, and drug resistance of hepatocellular carcinoma (HCC). In addition, exosomes have great industrial prospects in the diagnosis, treatment, and prognosis of patients with HCC. This review summarized the composition and function of exosomal miRNAs of different cell origins in HCC and highlighted the association between exosomal miRNAs from stromal cells and immune cells in the tumor microenvironment and the progression of HCC. Finally, we described the potential applicability of exosomal miRNAs derived from mesenchymal stem cells in the treatment of HCC.
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Affiliation(s)
- Hai-Chen Wang
- Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Wen-Xuan Yin
- Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Meng Jiang
- Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
- Key Laboratory of Microenvironment and Translational Cancer Research, Science and Technology Bureau of Nantong City, Nantong 226001, Jiangsu Province, China
| | - Jia-Yi Han
- Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
- Key Laboratory of Microenvironment and Translational Cancer Research, Science and Technology Bureau of Nantong City, Nantong 226001, Jiangsu Province, China
| | - Xing-Wang Kuai
- Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
- Key Laboratory of Microenvironment and Translational Cancer Research, Science and Technology Bureau of Nantong City, Nantong 226001, Jiangsu Province, China
| | - Rui Sun
- Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
- Key Laboratory of Microenvironment and Translational Cancer Research, Science and Technology Bureau of Nantong City, Nantong 226001, Jiangsu Province, China
| | - Yu-Feng Sun
- Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
- Key Laboratory of Microenvironment and Translational Cancer Research, Science and Technology Bureau of Nantong City, Nantong 226001, Jiangsu Province, China
| | - Ju-Ling Ji
- Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
- Key Laboratory of Microenvironment and Translational Cancer Research, Science and Technology Bureau of Nantong City, Nantong 226001, Jiangsu Province, China
- Department of Pathology, The Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
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16
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Mirzaei R, Karampoor S, Korotkova NL. The emerging role of miRNA-122 in infectious diseases: Mechanisms and potential biomarkers. Pathol Res Pract 2023; 249:154725. [PMID: 37544130 DOI: 10.1016/j.prp.2023.154725] [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: 07/06/2023] [Revised: 07/25/2023] [Accepted: 07/26/2023] [Indexed: 08/08/2023]
Abstract
microRNAs (miRNAs) are small, non-coding RNA molecules that play crucial regulatory roles in numerous cellular processes. Recent investigations have highlighted the significant involvement of miRNA-122 (miR-122) in the pathogenesis of infectious diseases caused by diverse pathogens, encompassing viral, bacterial, and parasitic infections. In the context of viral infections, miR-122 exerts regulatory control over viral replication by binding to the viral genome and modulating the host's antiviral response. For instance, in hepatitis B virus (HBV) infection, miR-122 restricts viral replication, while HBV, in turn, suppresses miR-122 expression. Conversely, miR-122 interacts with the hepatitis C virus (HCV) genome, facilitating viral replication. Regarding bacterial infections, miR-122 has been found to regulate host immune responses by influencing inflammatory cytokine production and phagocytosis. In Vibrio anguillarum infections, there is a significant reduction in miR-122 expression, contributing to the pathophysiology of bacterial infections. Toll-like receptor 14 (TLR14) has been identified as a novel target gene of miR-122, affecting inflammatory and immune responses. In the context of parasitic infections, miR-122 plays a crucial role in regulating host lipid metabolism and immune responses. For example, during Leishmania infection, miR-122-containing extracellular vesicles from liver cells are unable to enter infected macrophages, leading to a suppression of the inflammatory response. Furthermore, miR-122 exhibits promise as a potential biomarker for various infectious diseases. Its expression level in body fluids, particularly in serum and plasma, correlates with disease severity and treatment response in patients affected by HCV, HBV, and tuberculosis. This paper also discusses the potential of miR-122 as a biomarker in infectious diseases. In summary, this review provides a comprehensive and insightful overview of the emerging role of miR-122 in infectious diseases, detailing its mechanism of action and potential implications for the development of novel therapeutic strategies.
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Affiliation(s)
- Rasoul Mirzaei
- Venom and Biotherapeutics Molecules Lab, Medical Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
| | - Sajad Karampoor
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran.
| | - Nadezhda Lenoktovna Korotkova
- I.M. Sechenov First Moscow State Medical University (Sechenov University), Russia; Federal State Budgetary Educational Institution of Higher Education "Privolzhsky Research Medical University" of the Ministry of Health of the Russian Federation (FSBEI HE PRMU MOH Russia), Russia
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17
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Dai J, Hao Y, Chen X, Yu Q, Wang B. miR‑122/SENP1 axis confers stemness and chemoresistance to liver cancer through Wnt/β‑catenin signaling. Oncol Lett 2023; 26:390. [PMID: 37559577 PMCID: PMC10407855 DOI: 10.3892/ol.2023.13976] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Accepted: 06/22/2023] [Indexed: 08/11/2023] Open
Abstract
The property of inherent stemness of tumor cells coupled with the development of chemoresistance results in a poor prognosis for patients with liver cancer. Therefore, the present study focused on microRNA (miR)-122, a potential tumor suppressor, the expression of which has been previously shown to be significantly decreased and negatively associated with cancer cell stemness in liver cancer. The present study aimed to identify the molecular targets of miR-122 whilst uncovering the mechanism underlying chemoresistance and stemness of HepG2 cells in liver cancer. Bioinformatics online tools, such as ENCORI, coupled with dual-luciferase reporter assays in HepG2 cells, were used to identify and validate small ubiquitin-like modifier (SUMO) specific peptidase 1 (SENP1) as a potential target of miR-122 in liver cancer. The liver cancer stem cell population was determined using sphere formation assays and flow cytometry, whilst stem cell markers (Oct3/4, Nanog, B lymphoma Mo-MLV insertion region 1 homolog and Notch1) were detected by reverse transcription-quantitative PCR. Chemoresistance, cell proliferation and migratory ability of HepG2 cells were monitored using Cell Counting Kit-8, colony formation and Transwell assays, respectively. The overexpression of miR-122 by mimic transfection led to a significant decrease in the number spheres, downregulation of stem cell marker expression, the number of CD24+ cells, drug-resistance protein levels (P-glycoprotein and multidrug resistance protein), impaired chemoresistance, proliferation and migration of HepG2 cells. The transfection of SENP1 overexpression vector resulted in contrasting functions to miR-122 mimics, by partially reversing the effects induced by miR-122 mimic transfection in HepG2 cells. Wnt/β-catenin signaling has been proven to be involved in cancer stemness and malignant behavior. Western blotting analysis in HepG2 cells showed that the expression levels of both Wnt1 and β-catenin were significantly reduced after overexpressing miR-122, but increased after overexpressing SENP1. Co-transfection with the SENP1 overexpression vector reversed the suppression induced by the miR-122 mimics on Wnt1 and β-catenin expression. Co-immunoprecipitation, SUMOylation and half-life assays showed SENP1 interacted with β-catenin and decreased the SUMOylation of β-catenin, thereby enhancing its stability. Finally, tumor xenograft analyses revealed that HepG2 cells transfected with Agomir-122 exerted significantly lower tumor initiation frequency and growth rate, and a superior response to DOX in vivo, compared with those transfected with Agomir NC. Taken together, data from the present study miR-122/SENP1 axis can regulate β-catenin stability through de-SUMOylation, thereby promoting stemness and chemoresistance in liver cancer.
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Affiliation(s)
- Jianbo Dai
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400060, P.R. China
- Department of General Surgery, Nan'an District People's Hospital of Chongqing, Chongqing 400060, P.R. China
| | - Yaqin Hao
- Department of Gastroenterology, The Fifth People's Hospital of Chongqing, Chongqing 400060, P.R. China
| | - Xun Chen
- Department of Anesthesiology, Nan'an District People's Hospital of Chongqing, Chongqing 400060, P.R. China
| | - Qingsan Yu
- Department of General Surgery, Nan'an District People's Hospital of Chongqing, Chongqing 400060, P.R. China
| | - Bin Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400060, P.R. China
- Department of General Surgery, Chongqing Hospital of Integrated Traditional Chinese and Western Medicine, Chongqing 400060, P.R. China
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18
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Öksüz Z, Gragnani L, Lorini S, Temel GÖ, Serin MS, Zignego AL. Evaluation of Plasma miR-17-5p, miR-24-3p and miRNA-223-3p Profile of Hepatitis C Virus-Infected Patients after Treatment with Direct-Acting Antivirals. J Pers Med 2023; 13:1188. [PMID: 37623439 PMCID: PMC10455277 DOI: 10.3390/jpm13081188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 07/21/2023] [Accepted: 07/24/2023] [Indexed: 08/26/2023] Open
Abstract
The expression of miR-223-3p, miR-17-5p, and miR-24-3p was evaluated in hepatitis C virus (HCV) patient serum samples, collected before DAA treatment and after a sustained virological response (SVR). Fifty HCV patients were stratified based on their liver damage stages into three different subgroups (21 with chronic hepatitis-CH, 15 with cirrhosis, and 14 with hepatocellular carcinoma-HCC). Considering the entire HCV population, the miRNA expression levels were significantly downregulated after the SVR compared to pre-treatment ones (p < 0.05). Stratifying the patients based on liver damage, the post-SVR values of the three miRNAs were significantly downregulated compared to the pre-treatment levels for both cirrhosis and HCC patients. No significant differences emerged from the analysis of the CH group. To our knowledge, this is the first study to detail the behavior of miR-223-3p, miR-17-5p, and miR-24-3p levels in patients with HCV-related CH, cirrhosis, and HCC after DAA therapy. Our findings show that HCV-infected patients have different miRNA profiles before and after treatment with DAAs, strongly suggesting that miRNAs may be involved in the pathogenesis of HCV-related damage. In this respect, the correlation observed among the three studied miRNAs could imply that they share common pathways by which they contribute the progression of HCV-induced chronic liver damage.
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Affiliation(s)
- Zehra Öksüz
- Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Mersin University, 33160 Mersin, Turkey;
| | - Laura Gragnani
- MASVE Interdepartmental Hepatology Center, Department of Experimental and Clinical Medicine, University of Florence, Center for Research and Innovation CRIA-MASVE, AOU Careggi, 50134 Firenze, Italy; (L.G.); (S.L.)
- Department of Translational Research & New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy
| | - Serena Lorini
- MASVE Interdepartmental Hepatology Center, Department of Experimental and Clinical Medicine, University of Florence, Center for Research and Innovation CRIA-MASVE, AOU Careggi, 50134 Firenze, Italy; (L.G.); (S.L.)
| | - Gülhan Örekici Temel
- Department of Biostatistics, Faculty of Medicine, Mersin University, 33343 Mersin, Turkey;
| | - Mehmet Sami Serin
- Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Mersin University, 33160 Mersin, Turkey;
| | - Anna Linda Zignego
- MASVE Interdepartmental Hepatology Center, Department of Experimental and Clinical Medicine, University of Florence, Center for Research and Innovation CRIA-MASVE, AOU Careggi, 50134 Firenze, Italy; (L.G.); (S.L.)
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19
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Park SH, Lee EK, Yim J, Lee MH, Lee E, Lee YS, Seo W. Exosomes: Nomenclature, Isolation, and Biological Roles in Liver Diseases. Biomol Ther (Seoul) 2023; 31:253-263. [PMID: 37095734 PMCID: PMC10129856 DOI: 10.4062/biomolther.2022.161] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 03/09/2023] [Accepted: 03/10/2023] [Indexed: 04/26/2023] Open
Abstract
The biogenesis and biological roles of extracellular vesicles (EVs) in the progression of liver diseases have attracted considerable attention in recent years. EVs are membrane-bound nanosized vesicles found in different types of body fluids and contain various bioactive materials, including proteins, lipids, nucleic acids, and mitochondrial DNA. Based on their origin and biogenesis, EVs can be classified as apoptotic bodies, microvesicles, and exosomes. Among these, exosomes are the smallest EVs (30-150 nm in diameter), which play a significant role in cell-to-cell communication and epigenetic regulation. Moreover, exosomal content analysis can reveal the functional state of the parental cell. Therefore, exosomes can be applied to various purposes, including disease diagnosis and treatment, drug delivery, cell-free vaccines, and regenerative medicine. However, exosome-related research faces two major limitations: isolation of exosomes with high yield and purity and distinction of exosomes from other EVs (especially microvesicles). No standardized exosome isolation method has been established to date; however, various exosome isolation strategies have been proposed to investigate their biological roles. Exosome-mediated intercellular communications are known to be involved in alcoholic liver disease and nonalcoholic fatty liver disease development. Damaged hepatocytes or nonparenchymal cells release large numbers of exosomes that promote the progression of inflammation and fibrogenesis through interactions with neighboring cells. Exosomes are expected to provide insight on the progression of liver disease. Here, we review the biogenesis of exosomes, exosome isolation techniques, and biological roles of exosomes in alcoholic liver disease and nonalcoholic fatty liver disease.
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Affiliation(s)
- Seol Hee Park
- College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul 08826, Republic of Korea
| | - Eun Kyeong Lee
- College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea
| | - Joowon Yim
- College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea
| | - Min Hoo Lee
- College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea
| | - Eojin Lee
- College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea
| | - Young-Sun Lee
- Department of Internal Medicine, Korea University Medical Center, Seoul 08308, Republic of Korea
| | - Wonhyo Seo
- College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea
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20
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Günay N, Taheri S, Memiş M, Yilmaz Şükranli Z, Şahin T, Demiryürek Ş, Ekici Günay N, Aslan YE, Demiryürek AT. Male- and female-specific microRNA expression patterns in a mouse model of methanol poisoning. Food Chem Toxicol 2023; 174:113666. [PMID: 36780935 DOI: 10.1016/j.fct.2023.113666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 01/29/2023] [Accepted: 02/09/2023] [Indexed: 02/13/2023]
Abstract
The aims of this study were to determine the miRNAs involved in the methanol poisoning, and identify the male- and female-specific miRNA expression patterns in mice. Methanol was applied orally at the doses of 4 g/kg and 8 g/kg to induce mild and severe methanol poisoning in Balb/c mice. miRNA expression levels were detected at 3 different time periods (30, 60, and 180 min) following methanol exposure. miRNA expression profiles were determined using the high-throughput Fluidigm BioMark real-time PCR. We observed that serum miR-206 expression in male mice and miR-6357 expression in female mice could be an indicator of methanol poisoning. miR-9-3p downregulation and miR-1187 upregulation could be important for liver tissue. miR-3106-5p and miR-133a-5p upregulations and miR-122-3p downregulation could be poison biomarkers for ocular tissue in male mice. However, miR-194-5p downregulation could be a biomarker for ocular tissue in female mice. miR-122-5p and miR-124-3p downregulations and miR-499a-5p upregulation appeared to be important for kidney tissue in male mice. miR-543 and miR-6342 upregulations could be potential candidate biomarkers for kidney tissue in female mice. Our study is the first to report that differential miRNA expressions are involved in blood and tissues in male and female mice after methanol treatment.
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Affiliation(s)
- Nurullah Günay
- Department of Emergency Medicine, Faculty of Medicine, Erciyes University, Kayseri, 38039, Turkey.
| | - Serpil Taheri
- Department of Medical Biology, Faculty of Medicine, Erciyes University, Kayseri, 38280, Turkey; Erciyes University, Betül-Ziya Eren Genome and Stem Cell Center (GENKOK), Kayseri, 38280, Turkey
| | - Mehmet Memiş
- Erciyes University, Betül-Ziya Eren Genome and Stem Cell Center (GENKOK), Kayseri, 38280, Turkey; Erciyes University, Gevher Nesibe Genome and Stem Cell Institute, Department of Medical Biology and Genetics, Kayseri, 38280, Turkey
| | - Zeynep Yilmaz Şükranli
- Erciyes University, Betül-Ziya Eren Genome and Stem Cell Center (GENKOK), Kayseri, 38280, Turkey
| | - Taner Şahin
- Kayseri City Hospital, Clinics of Emergency Medicine, Kayseri, 38080, Turkey
| | - Şeniz Demiryürek
- Department of Physiology, Faculty of Medicine, Gaziantep University, Gaziantep, 27310, Turkey
| | - Nahide Ekici Günay
- Kayseri City Hospital, Clinics of Medical Biochemistry, Kayseri, 38080, Turkey
| | - Yusuf Ertugrul Aslan
- Department of Emergency Medicine, Faculty of Medicine, Erciyes University, Kayseri, 38039, Turkey
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21
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Atic AI, Thiele M, Munk A, Dalgaard LT. Circulating miRNAs associated with nonalcoholic fatty liver disease. Am J Physiol Cell Physiol 2023; 324:C588-C602. [PMID: 36645666 DOI: 10.1152/ajpcell.00253.2022] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
MicroRNAs (miRNAs) are secreted from cells as either protein-bound or enclosed in extracellular vesicles. Circulating liver-derived miRNAs are modifiable by weight-loss or insulin-sensitizing treatments, indicating that they could be important biomarker candidates for diagnosis, monitoring, and prognosis in nonalcoholic liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Unfortunately, the noninvasive diagnosis of NASH and fibrosis remains a key challenge, which limits case finding. Current diagnostic guidelines, therefore, recommend liver biopsies, with risks of pain and bleeding for the patient and substantial healthcare costs. Here, we summarize mechanisms of RNA secretion and review circulating RNAs associated with NAFLD and NASH for their biomarker potential. Few circulating miRNAs are consistently associated with NAFLD/NASH: miR-122, miR-21, miR-34a, miR-192, miR-193, and the miR-17-92 miRNA-cluster. The hepatocyte-enriched miRNA-122 is consistently increased in NAFLD and NASH but decreased in liver cirrhosis. Circulating miR-34a, part of an existing diagnostic algorithm for NAFLD, and miR-21 are consistently increased in NAFLD and NASH. MiR-192 appears to be prominently upregulated in NASH compared with NAFDL, whereas miR-193 was reported to distinguish NASH from fibrosis. Various members of miRNA cluster miR-17-92 are reported to be associated with NAFLD and NASH, although with less consistency. Several other circulating miRNAs have been reported to be associated with fatty liver in a few studies, indicating the existence of more circulating miRNAs with relevant as diagnostic markers for NAFLD or NASH. Thus, circulating miRNAs show potential as biomarkers of fatty liver disease, but more information about phenotype specificity and longitudinal regulation is needed.
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Affiliation(s)
- Amila Iriskic Atic
- Department of Science and Environment, Roskilde University, Roskilde, Denmark.,Novo Nordisk A/S, Obesity Research, Måløv, Denmark
| | - Maja Thiele
- Department of Gastroenterology and Hepatology, Center for Liver Research, Odense University Hospital, Odense, Denmark.,Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
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Ali FE, Abd El-Aziz MK, Sharab EI, Bakr AG. Therapeutic interventions of acute and chronic liver disorders: A comprehensive review. World J Hepatol 2023; 15:19-40. [PMID: 36744165 PMCID: PMC9896501 DOI: 10.4254/wjh.v15.i1.19] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 11/17/2022] [Accepted: 12/21/2022] [Indexed: 01/16/2023] Open
Abstract
Liver disorders are one of the most common pathological problems worldwide. It affects more than 1.5 billion worldwide. Many types of hepatic cells have been reported to be involved in the initiation and propagation of both acute and chronic liver diseases, including hepatocytes, Kupffer cells, sinusoidal endothelial cells, and hepatic stellate cells (HSCs). In addition, oxidative stress, cytokines, fibrogenic factors, microRNAs, and autophagy are also involved. Understanding the molecular mechanisms of liver diseases leads to discovering new therapeutic interventions that can be used in clinics. Recently, antioxidant, anti-inflammatory, anti-HSCs therapy, gene therapy, cell therapy, gut microbiota, and nanoparticles have great potential for preventing and treating liver diseases. Here, we explored the recent possible molecular mechanisms involved in the pathogenesis of acute and chronic liver diseases. Besides, we overviewed the recent therapeutic interventions that targeted liver diseases and summarized the recent studies concerning liver disorders therapy.
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Affiliation(s)
- Fares Em Ali
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut 71524, Egypt.
| | | | - Elham I Sharab
- Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut 71524, Egypt
| | - Adel G Bakr
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut 71524, Egypt
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23
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Das O, Kundu J, Ghosh A, Gautam A, Ghosh S, Chakraborty M, Masid A, Gauri SS, Mitra D, Dutta M, Mukherjee B, Sinha S, Bhaumik M. AUF-1 knockdown in mice undermines gut microbial butyrate-driven hypocholesterolemia through AUF-1-Dicer-1-mir-122 hierarchy. Front Cell Infect Microbiol 2022; 12:1011386. [PMID: 36601302 PMCID: PMC9806232 DOI: 10.3389/fcimb.2022.1011386] [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: 08/04/2022] [Accepted: 11/28/2022] [Indexed: 12/23/2022] Open
Abstract
Introduction and objective Cholesterol homeostasis is a culmination of cellular synthesis, efflux, and catabolism to important physiological entities where short chain fatty acid, butyrate embodied as a key player. This discourse probes the mechanistic molecular details of butyrate action in maintaining host-cholesterol balance. Methods Hepatic mir-122 being the most indispensable regulator of cholesterol metabolic enzymes, we studied upstream players of mir-122 biogenesis in the presence and absence of butyrate in Huh7 cells and mice model. We synthesized unique self-transfecting GMO (guanidinium-morpholino-oligo) linked PMO (Phosphorodiamidate-Morpholino Oligo)-based antisense cell-penetrating reagent to selectively knock down the key player in butyrate mediated cholesterol regulation. Results We showed that butyrate treatment caused upregulation of RNA-binding protein, AUF1 resulting in RNase-III nuclease, Dicer1 instability, and significant diminution of mir-122. We proved the importance of AUF1 and sequential downstream players in AUF1-knock-down mice. Injection of GMO-PMO of AUF1 in mouse caused near absence of AUF1 coupled with increased Dicer1 and mir-122, and reduced serum cholesterol regardless of butyrate treatment indicating that butyrate acts through AUF1. Conclusion The roster of intracellular players was as follows: AUF1-Dicer1-mir-122 for triggering butyrate driven hypocholesterolemia. To our knowledge this is the first report linking AUF-1 with cholesterol biogenesis.
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Affiliation(s)
- Oishika Das
- Department of Immunology, Indian Council of Medical Research-National Institute of Cholera and Enteric Diseases, Kolkata, India
| | - Jayanta Kundu
- School of Applied and Interdisciplinary Sciences, Indian Associations for Cultivation of Science, Kolkata, India
| | - Atanu Ghosh
- School of Applied and Interdisciplinary Sciences, Indian Associations for Cultivation of Science, Kolkata, India
| | - Anupam Gautam
- Department of Algorithms in Bioinformatics, Institute for Bioinformatics and Medical Informatics, University of Tübingen, Tübingen, Germany,International Max Planck Research School “From Molecules to Organisms”, Max Planck Institute for Biology Tübingen, Tübingen, Germany,Cluster of Excellence: EXC 2124: Controlling Microbes to Fight Infection, University of Tübingen, Tübingen, Germany
| | - Souradeepa Ghosh
- School of Medical Science and Technology, Indian Institute of Technology, Kharagpur, India
| | - Mainak Chakraborty
- Department of Immunology, Indian Council of Medical Research-National Institute of Cholera and Enteric Diseases, Kolkata, India
| | - Aaheli Masid
- Department of Immunology, Indian Council of Medical Research-National Institute of Cholera and Enteric Diseases, Kolkata, India
| | - Samiran Sona Gauri
- School of Medical Science and Technology, Indian Institute of Technology, Kharagpur, India
| | - Debmalya Mitra
- Department of Immunology, Indian Council of Medical Research-National Institute of Cholera and Enteric Diseases, Kolkata, India
| | - Moumita Dutta
- Department of Immunology, Indian Council of Medical Research-National Institute of Cholera and Enteric Diseases, Kolkata, India
| | - Budhaditya Mukherjee
- School of Medical Science and Technology, Indian Institute of Technology, Kharagpur, India
| | - Surajit Sinha
- School of Applied and Interdisciplinary Sciences, Indian Associations for Cultivation of Science, Kolkata, India
| | - Moumita Bhaumik
- Department of Immunology, Indian Council of Medical Research-National Institute of Cholera and Enteric Diseases, Kolkata, India,*Correspondence: Moumita Bhaumik,
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24
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Matsuzaki J, Kato K, Oono K, Tsuchiya N, Sudo K, Shimomura A, Tamura K, Shiino S, Kinoshita T, Daiko H, Wada T, Katai H, Ochiai H, Kanemitsu Y, Takamaru H, Abe S, Saito Y, Boku N, Kondo S, Ueno H, Okusaka T, Shimada K, Ohe Y, Asakura K, Yoshida Y, Watanabe SI, Asano N, Kawai A, Ohno M, Narita Y, Ishikawa M, Kato T, Fujimoto H, Niida S, Sakamoto H, Takizawa S, Akiba T, Okanohara D, Shiraishi K, Kohno T, Takeshita F, Nakagama H, Ota N, Ochiya T, Project Team for Development and Diagnostic Technology for Detection of miRNA in Body Fluids
HottaTomomitsuNakagamaHitoshiOchiyaTakahiroFurutaKohKatoKenOchiaiAtsushiMitsunagaShuichiNiidaShumpeiMimoriKoshiHatadaIzuhoKurodaMasahikoYokotaTakanoriMoriMasakiIshiiHideshiMurakamiYoshikiTaharaHidetoshiBabaYoshinobuAkioKoboriTakizawaSatokoHashimotoKojiHiraiMitsuharuKobayashiMasahikoFujimiyaHitoshiOkanoharaDaisukeNakaeHirokiTakashimaHideaki. Prediction of tissue-of-origin of early stage cancers using serum miRNomes. JNCI Cancer Spectr 2022; 7:6847090. [PMID: 36426871 PMCID: PMC9825310 DOI: 10.1093/jncics/pkac080] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Revised: 10/02/2022] [Accepted: 10/17/2022] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND Noninvasive detection of early stage cancers with accurate prediction of tumor tissue-of-origin could improve patient prognosis. Because miRNA profiles differ between organs, circulating miRNomics represent a promising method for early detection of cancers, but this has not been shown conclusively. METHODS A serum miRNA profile (miRNomes)-based classifier was evaluated for its ability to discriminate cancer types using advanced machine learning. The training set comprised 7931 serum samples from patients with 13 types of solid cancers and 5013 noncancer samples. The validation set consisted of 1990 cancer and 1256 noncancer samples. The contribution of each miRNA to the cancer-type classification was evaluated, and those with a high contribution were identified. RESULTS Cancer type was predicted with an accuracy of 0.88 (95% confidence interval [CI] = 0.87 to 0.90) in all stages and an accuracy of 0.90 (95% CI = 0.88 to 0.91) in resectable stages (stages 0-II). The F1 score for the discrimination of the 13 cancer types was 0.93. Optimal classification performance was achieved with at least 100 miRNAs that contributed the strongest to accurate prediction of cancer type. Assessment of tissue expression patterns of these miRNAs suggested that miRNAs secreted from the tumor environment could be used to establish cancer type-specific serum miRNomes. CONCLUSIONS This study demonstrates that large-scale serum miRNomics in combination with machine learning could lead to the development of a blood-based cancer classification system. Further investigations of the regulating mechanisms of the miRNAs that contributed strongly to accurate prediction of cancer type could pave the way for the clinical use of circulating miRNA diagnostics.
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Affiliation(s)
- Juntaro Matsuzaki
- Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan,Division of Pharmacotherapeutics, Keio University Faculty of Pharmacy, Minato-ku, Tokyo, Japan
| | - Ken Kato
- Department of Head and Neck, Esophageal Medical Oncology and Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
| | - Kenta Oono
- Preferred Networks, Inc, Chiyoda-ku, Tokyo, Japan
| | - Naoto Tsuchiya
- Laboratory of Molecular Carcinogenesis, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan
| | - Kazuki Sudo
- Department of Breast and Medical Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
| | - Akihiko Shimomura
- Department of Breast and Medical Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
| | - Kenji Tamura
- Department of Breast and Medical Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
| | - Sho Shiino
- Department of Breast Surgery, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
| | - Takayuki Kinoshita
- Department of Breast Surgery, National Hospital Organization Tokyo Medical Center, Meguro-ku, Tokyo, Japan
| | - Hiroyuki Daiko
- Department of Esophageal Surgery, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
| | - Takeyuki Wada
- Department of Gastric Surgery, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
| | - Hitoshi Katai
- Department of Gastric Surgery, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
| | - Hiroki Ochiai
- Department of Colorectal Surgery, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
| | - Yukihide Kanemitsu
- Department of Colorectal Surgery, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
| | - Hiroyuki Takamaru
- Endoscopy Division, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
| | - Seiichiro Abe
- Endoscopy Division, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
| | - Yutaka Saito
- Endoscopy Division, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
| | - Narikazu Boku
- Department of Head and Neck, Esophageal Medical Oncology and Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
| | - Shunsuke Kondo
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
| | - Hideki Ueno
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
| | - Takuji Okusaka
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
| | - Kazuaki Shimada
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
| | - Yuichiro Ohe
- Department of Thoracic Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
| | - Keisuke Asakura
- Department of Thoracic Surgery, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
| | - Yukihiro Yoshida
- Department of Thoracic Surgery, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
| | - Shun-Ichi Watanabe
- Department of Thoracic Surgery, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
| | - Naofumi Asano
- Department of Musculoskeletal Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
| | - Akira Kawai
- Department of Musculoskeletal Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
| | - Makoto Ohno
- Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
| | - Yoshitaka Narita
- Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
| | - Mitsuya Ishikawa
- Department of Gynecology, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
| | - Tomoyasu Kato
- Department of Gynecology, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
| | - Hiroyuki Fujimoto
- Department of Urology, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
| | - Shumpei Niida
- Research Institute, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan
| | - Hiromi Sakamoto
- Department of Biobank and Tissue Resources, Fundamental Innovative Oncology Core, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan
| | - Satoko Takizawa
- Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan,Toray Industries, Inc, Kamakura, Kanagawa, Japan
| | - Takuya Akiba
- Preferred Networks, Inc, Chiyoda-ku, Tokyo, Japan
| | | | - Kouya Shiraishi
- Division of Genome Biology, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan
| | - Takashi Kohno
- Division of Genome Biology, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan
| | - Fumitaka Takeshita
- Department of Translational Oncology, Fundamental Innovative Oncology Core, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan
| | | | | | - Takahiro Ochiya
- Correspondence to: Takahiro Ochiya, PhD, Department of Molecular and Cellular Medicine, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan (e-mail: )
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Micro-Players of Great Significance-Host microRNA Signature in Viral Infections in Humans and Animals. Int J Mol Sci 2022; 23:ijms231810536. [PMID: 36142450 PMCID: PMC9504570 DOI: 10.3390/ijms231810536] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 09/04/2022] [Accepted: 09/08/2022] [Indexed: 11/22/2022] Open
Abstract
Over time, more and more is becoming known about micro-players of great significance. This is particularly the case for microRNAs (miRNAs; miR), which have been found to participate in the regulation of many physiological and pathological processes in both humans and animals. One such process is viral infection in humans and animals, in which the host miRNAs—alone or in conjunction with the virus—interact on two levels: viruses may regulate the host’s miRNAs to evade its immune system, while the host miRNAs can play anti- or pro-viral roles. The purpose of this comprehensive review is to present the key miRNAs involved in viral infections in humans and animals. We summarize the data in the available literature, indicating that the signature miRNAs in human viral infections mainly include 12 miRNAs (i.e., miR-155, miR-223, miR-146a, miR-122, miR-125b, miR-132, miR-34a, miR -21, miR-16, miR-181 family, let-7 family, and miR-10a), while 10 miRNAs are commonly found in animals (i.e., miR-155, miR-223, miR-146a, miR-145, miR-21, miR-15a/miR-16 cluster, miR-181 family, let-7 family, and miR-122) in this context. Knowledge of which miRNAs are involved in different viral infections and the biological functions that they play can help in understanding the pathogenesis of viral diseases, facilitating the future development of therapeutic agents for both humans and animals.
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Liu TY, Feng H, Yousuf S, Xie LL, Miao XY. Genome-Wide Analysis of microRNAs Identifies the Lipid Metabolism Pathway to Be a Defining Factor in Adipose Tissue From Different Sheep. Front Vet Sci 2022; 9:938311. [PMID: 35880040 PMCID: PMC9308008 DOI: 10.3389/fvets.2022.938311] [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: 05/07/2022] [Accepted: 06/06/2022] [Indexed: 11/13/2022] Open
Abstract
microRNAs are a class of important non-coding RNAs, which can participate in the regulation of biological processes. In recent years, miRNA has been widely studied not only in humans and mice, but also in animal husbandry. However, compared with other livestock and poultry breeds, the study of miRNA in subcutaneous adipose tissue of sheep is not comprehensive. Transcriptome analysis of miRNAs in subcutaneous adipose tissue of Duolang sheep, and Small Tail Han sheep was performed using RNA-Seq technology. Differentially expressed miRNAs were screened between different breeds. Target genes were predicted, and then the joint analysis of candidate genes were conducted based on Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment. Finally, the RNA-Seq data were verified by real-time quantitative polymerase chain reaction (qRT-PCR). Herein, we identified 38 differentially expressed miRNAs (9 novel miRNAs and 29 known miRNAs). In addition, a total of 854 target genes were predicted by miRanda software. GO and KEGG pathway analysis demonstrated that regulation of lipolysis in adipocytes plays a key role in the deposition of subcutaneous adipose tissue in Duolang sheep and Small Tail Han sheep. The miRNAs might regulate fat deposits by regulating genes involved in regulation of lipolysis in adipocytes. Specifically, NC_ 040278.1_ 37602, oar-mir-493-3p, NC_ 040278.1_ 37521 and NC_ 040255.1_ 11627 might target PTGS2, AKT2, AKT3, and PIK3CA, respectively, and then play critical regulatory role. In conclusion, all the results provide a good idea for further revealing the mechanism of subcutaneous adipose tissue deposition and improving the meat production performance of sheep, and lay a foundation for promoting the development of animal husbandry.
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27
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Yu X, Zhang S, Wang W. Determination of microRNA-122 in hepatocytes by two-step amplification of duplex-specific nuclease with laser-induced fluorescence detection. ANALYTICAL METHODS : ADVANCING METHODS AND APPLICATIONS 2022; 14:1715-1720. [PMID: 35438691 DOI: 10.1039/d2ay00360k] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
MicroRNAs (miRNAs) play important roles in physiological and pathological processes of cells. To develop a fast, simple and sensitive method to determine miRNAs is significant for miRNA studies. In this work, determination of microRNA-122 (miR-122) was achieved by laser-induced fluorescence (LIF) detection. A vial-LIF interface was first applied for sample analysis. A two-step amplification of the fluorescence signal for miR-122 was designed and realized by applying duplex-specific nuclease in the cleaving of two sensing probes. Under optimized conditions, the analysis of a miR-122 sample could be completed in less than 50 min. Only 10 μL sample was required for each test and the detection limit for the method was 0.60 pM equal to 1.2 amol of miR-122 in 10 μL solution. Lastly, the developed method was successfully applied to determine miR-122 in chicken and duck liver. The developed method was fast, selective, sensitive and sample-saving for the determination of miRNAs.
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Affiliation(s)
- Xiufeng Yu
- Ministry of Education Key Laboratory for Analytical Science of Food Safety and Biology, Fujian Provincial Key Laboratory of Analysis and Detection Technology for Food Safety, School of Chemistry, Fuzhou University, Fuzhou, 350116, P. R. China.
| | - Shaoyan Zhang
- Ministry of Education Key Laboratory for Analytical Science of Food Safety and Biology, Fujian Provincial Key Laboratory of Analysis and Detection Technology for Food Safety, School of Chemistry, Fuzhou University, Fuzhou, 350116, P. R. China.
| | - Wei Wang
- Ministry of Education Key Laboratory for Analytical Science of Food Safety and Biology, Fujian Provincial Key Laboratory of Analysis and Detection Technology for Food Safety, School of Chemistry, Fuzhou University, Fuzhou, 350116, P. R. China.
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Shwe A, Krasnov A, Visnovska T, Ramberg S, Østbye TKK, Andreassen R. Expression Analysis in Atlantic Salmon Liver Reveals miRNAs Associated with Smoltification and Seawater Adaptation. BIOLOGY 2022; 11:biology11050688. [PMID: 35625416 PMCID: PMC9138835 DOI: 10.3390/biology11050688] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Accepted: 04/24/2022] [Indexed: 01/23/2023]
Abstract
Simple Summary Smoltification is a developmental process that preadapts Atlantic salmon for a life in seawater. Suboptimal smoltification and poor timing of transfer to seawater is associated with increased mortality. MicroRNAs (miRNAs) are small non-coding genes. They regulate gene expression post-transcriptionally as part of the miRNA induce silencing complex (miRISC) where they guide miRISC to particular mRNAs (target genes). The aim of this study was to identify Atlantic salmon miRNAs expressed in liver that are associated with smoltification and adaptation to seawater as well as to predict their target genes. In total, 62 guide miRNAs were identified, and by their expression patterns they were clustered into three groups. Target gene predictions followed by gene enrichment analysis of the predicted targets indicated that the guide miRNAs were involved in post-transcriptional regulation of important smoltification associated biological processes. Some of these were energy metabolism, protein metabolism and transport, circadian rhythm, stress and immune response. Together, the results indicate that certain miRNAs are involved in the regulation of many of the important changes occurring in the liver during this developmental transition. Abstract Optimal smoltification is crucial for normal development, growth, and health of farmed Atlantic salmon in seawater. Here, we characterize miRNA expression in liver to reveal whether miRNAs regulate gene expression during this developmental transition. Expression changes of miRNAs and mRNAs was studied by small-RNA sequencing and microarray analysis, respectively. This revealed 62 differentially expressed guide miRNAs (gDE-miRNAs) that could be divided into three groups with characteristic dynamic expression patterns. Three of miRNA families are known as highly expressed in liver. A rare arm shift was observed during smoltification in the Atlantic salmon-specific novel-ssa-miR-16. The gDE-miRNAs were predicted to target 2804 of the genes revealing expression changes in the microarray analysis. Enrichment analysis revealed that targets were significantly enriched in smoltification-associated biological process groups. These included lipid and cholesterol synthesis, carbohydrate metabolism, protein metabolism and protein transport, immune system genes, circadian rhythm and stress response. The results indicate that gDE-miRNAs may regulate many of the changes associated with this developmental transition in liver. The results pave the way for validation of the predicted target genes and further study of gDE-miRNA and their targets by functional assays.
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Affiliation(s)
- Alice Shwe
- Department of Life Science and Health, Faculty of Health Sciences, OsloMet-Oslo Metropolitan University, 0167 Oslo, Norway; (A.S.); (S.R.)
| | - Aleksei Krasnov
- Nofima (Norwegian Institute of Food, Fisheries and Aquaculture Research), 1430 Ås, Norway; (A.K.); (T.-K.K.Ø.)
| | - Tina Visnovska
- Bioinformatics Core Facility, Oslo University Hospital, 0372 Oslo, Norway;
| | - Sigmund Ramberg
- Department of Life Science and Health, Faculty of Health Sciences, OsloMet-Oslo Metropolitan University, 0167 Oslo, Norway; (A.S.); (S.R.)
| | - Tone-Kari K. Østbye
- Nofima (Norwegian Institute of Food, Fisheries and Aquaculture Research), 1430 Ås, Norway; (A.K.); (T.-K.K.Ø.)
| | - Rune Andreassen
- Department of Life Science and Health, Faculty of Health Sciences, OsloMet-Oslo Metropolitan University, 0167 Oslo, Norway; (A.S.); (S.R.)
- Correspondence:
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29
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Huang X, Jie S, Li W, Li H, Ni J, Liu C. miR-122-5p targets GREM2 to protect against glucocorticoid-induced endothelial damage through the BMP signaling pathway. Mol Cell Endocrinol 2022; 544:111541. [PMID: 34973370 DOI: 10.1016/j.mce.2021.111541] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Revised: 12/22/2021] [Accepted: 12/27/2021] [Indexed: 01/05/2023]
Abstract
Glucocorticoid (GC)-induced osteonecrosis of the femoral head (ONFH) accounts for a big portion of non-traumatic ONFH; nevertheless, the pathogenesis has not yet been fully understood. GC-induced endothelial dysfunction might be a major contributor to ONFH progression. The Gene Expression Omnibus (GEO) dataset was analyzed to identify deregulated miRNAs in ONFH; among deregulated miRNAs, the physiological functions of miR-122-5p on ONFH and endothelial dysfunction remain unclear. In the present study, miR-122-5p showed to be under-expressed within GC-induced ONFH femoral head tissues and GC-stimulated bone microvascular endothelial cells (BMECs). In human umbilical vein endothelial cells (HUVECs) and BMECs, GC stimulation significantly repressed cell viability, promoted cell apoptosis and increased the mRNA expression of proinflammatory cytokines, such as TNF-α, IL-1β, and IFN-γ. After overexpressing miR-122-5p, GC-induced endothelial injuries were attenuated, as manifested by rescued cell viability, cell migration, and tube formation capacity. Regarding the BMP signaling, GC decreased the protein levels of BMP-2/6/7 and SMAD-1/5/8, whereas miR-122-5p overexpression significantly attenuated the inhibitory effects of GC on these proteins. Online tool and experimental analyses revealed the direct binding between miR-122-5p and GREM2, a specific antagonist of BMP-2. In contrast to miR-122-5p overexpression, GREM2 overexpression aggravated GC-induced endothelial injury; GREM2 silencing partially eliminated the effects of miR-122-5p inhibition on GC-stimulated HUVECs and BMECs. Finally, GREM2 silencing reversed the suppressive effects of GC on BMP-2/6/7 and SMAD-1/5/8, and attenuated the effects of miR-122-5p inhibition on these proteins upon GC stimulation. Conclusively, the present study demonstrates a miR-122-5p/GREM2 axis modulating the GC-induced endothelial damage via the BMP/SMAD signaling. Considering the critical role of endothelial function in ONFH pathogenesis, the in vivo role and clinical application of the miR-122-5p/GREM2 axis is worthy of further investigation.
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Affiliation(s)
- Xianzhe Huang
- Department of Orthopedics, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
| | - Shuo Jie
- Department of Orthopedics, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
| | - Wenzhao Li
- Department of Orthopedics, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
| | - Hui Li
- Department of Orthopedics, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
| | - Jiangdong Ni
- Department of Orthopedics, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
| | - Chan Liu
- Department of International Medical, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China.
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30
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Panigrahi M, Thibault PA, Wilson JA. MicroRNA 122 Affects both the Initiation and the Maintenance of Hepatitis C Virus Infections. J Virol 2022; 96:e0190321. [PMID: 34908444 PMCID: PMC8865533 DOI: 10.1128/jvi.01903-21] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Accepted: 12/08/2021] [Indexed: 11/20/2022] Open
Abstract
A liver-specific microRNA, miR-122, anneals to the hepatitis C virus (HCV) genomic 5' terminus and is essential for virus replication in cell culture. However, bicistronic HCV replicons and full-length RNAs with specific mutations in the 5' untranslated region (UTR) can replicate, albeit to low levels, without miR-122. In this study, we have identified that HCV RNAs lacking the structural gene region or having encephalomyocarditis virus internal ribosomal entry site (EMCV IRES)-regulated translation had reduced requirements for miR-122. In addition, we found that a smaller proportion of cells supported miR-122-independent replication compared a population of cells supporting miR-122-dependent replication, while viral protein levels per positive cell were similar. Further, the proportion of cells supporting miR-122-independent replication increased with the amount of viral RNA delivered, suggesting that establishment of miR-122-independent replication in a cell is affected by the amount of viral RNA delivered. HCV RNAs replicating independently of miR-122 were not affected by supplementation with miR-122, suggesting that miR-122 is not essential for maintenance of an miR-122-independent HCV infection. However, miR-122 supplementation had a small positive impact on miR-122-dependent replication, suggesting a minor role in enhancing ongoing virus RNA accumulation. We suggest that miR-122 functions primarily to initiate an HCV infection but has a minor influence on its maintenance, and we present a model in which miR-122 is required for replication complex formation at the beginning of an infection and also supports new replication complex formation during ongoing infection and after infected cell division. IMPORTANCE The mechanism by which miR-122 promotes the HCV life cycle is not well understood, and a role in directly promoting genome amplification is still debated. In this study, we have shown that miR-122 increases the rate of viral RNA accumulation and promotes the establishment of an HCV infection in a greater number of cells than in the absence of miR-122. However, we also confirm a minor role in promoting ongoing virus replication and propose a role in the initiation of new replication complexes throughout a virus infection. This study has implications for the use of anti-miR-122 as a potential HCV therapy.
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Affiliation(s)
- Mamata Panigrahi
- Department of Biochemistry, Microbiology, and Immunology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - Patricia A. Thibault
- Division of Neurology, Department of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
- Office of the Saskatchewan Multiple Sclerosis Clinical Research Chair, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - Joyce A. Wilson
- Department of Biochemistry, Microbiology, and Immunology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
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31
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Zhao X, Ji Z, Xuan R, Wang A, Li Q, Zhao Y, Chao T, Wang J. Characterization of the microRNA Expression Profiles in the Goat Kid Liver. Front Genet 2022; 12:794157. [PMID: 35082837 PMCID: PMC8784682 DOI: 10.3389/fgene.2021.794157] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Accepted: 12/21/2021] [Indexed: 12/12/2022] Open
Abstract
The liver is the largest digestive gland in goats with an important role in early metabolic function development. MicroRNAs (miRNA) are crucial for regulating the development and metabolism in the goat liver. In the study, we sequenced the miRNAs in the liver tissues of the goat kid to further research their regulation roles in early liver development. The liver tissues were procured at 5-time points from the Laiwu black goats of 1 day (D1), 2 weeks (W2), 4 weeks (W4), 8 weeks (W8), and 12 weeks (W12) after birth, respectively with five goats per time point, for a total of 25 goats. Our study identified 214 differential expression miRNAs, and the expression patterns of 15 randomly selected miRNAs were examined among all five age groups. The Gene ontology annotation results showed that differential expression miRNA (DE miRNA) target genes were significantly enriched in the fatty acid synthase activity, toxin metabolic process, cell surface, and antibiotic metabolic process. The KEGG analysis result was significantly enriched in steroid hormone synthesis and retinol metabolism pathways. Further miRNA-mRNA regulation network analysis reveals 9 differently expressed miRNA with important regulation roles. Overall, the DE miRNAs were mainly involved in liver development, lipid metabolism, toxin related metabolism-related biological process, and pathways. Our results provide new information about the molecular mechanisms and pathways in the goat kid liver development.
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Affiliation(s)
- Xiaodong Zhao
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Taian, China
| | - Zhibin Ji
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Taian, China
| | - Rong Xuan
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Taian, China
| | - Aili Wang
- Shandong Peninsula Engineering Research Center of Comprehensive Brine Utilization, Weifang University of Science and Technology, Shouguang, China
| | - Qing Li
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Taian, China
| | - Yilin Zhao
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Taian, China
| | - Tianle Chao
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Taian, China
| | - Jianmin Wang
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Taian, China
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32
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Kilikevicius A, Meister G, Corey DR. Reexamining assumptions about miRNA-guided gene silencing. Nucleic Acids Res 2022; 50:617-634. [PMID: 34967419 PMCID: PMC8789053 DOI: 10.1093/nar/gkab1256] [Citation(s) in RCA: 115] [Impact Index Per Article: 38.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 12/01/2021] [Accepted: 12/06/2021] [Indexed: 12/16/2022] Open
Abstract
MicroRNAs (miRNAs) are short endogenously expressed RNAs that have the potential to regulate the expression of any RNA. This potential has led to the publication of several thousand papers each year connecting miRNAs to many different genes and human diseases. By contrast, relatively few papers appear that investigate the molecular mechanism used by miRNAs. There is a disconnect between rigorous understanding of mechanism and the extraordinary diversity of reported roles for miRNAs. Consequences of this disconnect include confusion about the assumptions underlying the basic science of human miRNAs and slow development of therapeutics that target miRNAs. Here, we present an overview of investigations into miRNAs and their impact on gene expression. Progress in our understanding of miRNAs would be aided by a greater focus on the mechanism of miRNAs and a higher burden of evidence on researchers who seek to link expression of a particular miRNA to a biological phenotype.
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Affiliation(s)
- Audrius Kilikevicius
- Department of Pharmacology and Biochemistry, UT Southwestern Medical Center, 6001 Forest Park Road, Dallas, TX, USA
| | - Gunter Meister
- Regensburg Center for Biochemistry (RCB), Laboratory for RNA Biology, University of Regensburg, Regensburg, Germany
| | - David R Corey
- Department of Pharmacology and Biochemistry, UT Southwestern Medical Center, 6001 Forest Park Road, Dallas, TX, USA
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33
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Xie Y, Yao J, Jin W, Ren L, Li X. Induction and Maturation of Hepatocyte-Like Cells In Vitro: Focus on Technological Advances and Challenges. Front Cell Dev Biol 2021; 9:765980. [PMID: 34901010 PMCID: PMC8662991 DOI: 10.3389/fcell.2021.765980] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2021] [Accepted: 11/08/2021] [Indexed: 12/17/2022] Open
Abstract
Limited by the poor proliferation and restricted sources of adult hepatocytes, there is an urgent need to find substitutes for proliferation and cultivation of mature hepatocytes in vitro for use in disease treatment, drug approval, and toxicity testing. Hepatocyte-like cells (HLCs), which originate from undifferentiated stem cells or modified adult cells, are considered good candidates because of their advantages in terms of cell source and in vitro expansion ability. However, the majority of induced HLCs are in an immature state, and their degree of differentiation is heterogeneous, diminishing their usability in basic research and limiting their clinical application. Therefore, various methods have been developed to promote the maturation of HLCs, including chemical approaches, alteration of cell culture systems, and genetic manipulation, to meet the needs of in vivo transplantation and in vitro model establishment. This review proposes different cell types for the induction of HLCs, and provide a comprehensive overview of various techniques to promote the generation and maturation of HLCs in vitro.
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Affiliation(s)
- Ye Xie
- The First Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Jia Yao
- The First Clinical Medical College, Lanzhou University, Lanzhou, China.,Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou, China
| | - Weilin Jin
- The First Clinical Medical College, Lanzhou University, Lanzhou, China.,Institute of Cancer Neuroscience, The First Hospital of Lanzhou University, Lanzhou, China.,The Medical Frontier Innovation Research Center, The First Hospital of Lanzhou University, Lanzhou, China
| | - Longfei Ren
- The First Clinical Medical College, Lanzhou University, Lanzhou, China.,The Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China
| | - Xun Li
- The First Clinical Medical College, Lanzhou University, Lanzhou, China.,Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou, China.,The Medical Frontier Innovation Research Center, The First Hospital of Lanzhou University, Lanzhou, China.,The Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China.,Hepatopancreatobiliary Surgery Institute of Gansu Province, Lanzhou, China
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34
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Zhang Y, Tan YY, Chen PP, Xu H, Xie SJ, Xu SJ, Li B, Li JH, Liu S, Yang JH, Zhou H, Qu LH. Genome-wide identification of microRNA targets reveals positive regulation of the Hippo pathway by miR-122 during liver development. Cell Death Dis 2021; 12:1161. [PMID: 34907157 PMCID: PMC8671590 DOI: 10.1038/s41419-021-04436-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 11/16/2021] [Accepted: 11/24/2021] [Indexed: 12/19/2022]
Abstract
Liver development is a highly complex process that is regulated by the orchestrated interplay of epigenetic regulators, transcription factors, and microRNAs (miRNAs). Owing to the lack of global in vivo targets of all miRNAs during liver development, the mechanisms underlying the dynamic control of hepatocyte differentiation by miRNAs remain elusive. Here, using Argonaute (Ago) high-throughput sequencing of RNA isolated by crosslinking immunoprecipitation (HITS-CLIP) in the mouse liver at different developmental stages, we characterized massive Ago-binding RNAs and obtained a genome-wide map of liver miRNA-mRNA interactions. The dynamic changes of five clusters of miRNAs and their potential targets were identified to be differentially involved at specific stages, a dozen of high abundant miRNAs and their epigenetic regulation by super-enhancer were found during liver development. Remarkably, miR-122, a liver-specific and most abundant miRNA in newborn and adult livers, was found by its targetome and pathway reporter analyses to regulate the Hippo pathway, which is crucial for liver size control and homeostasis. Mechanistically, we further demonstrated that miR-122 negatively regulates the outcomes of the Hippo pathway transcription factor TEAD by directly targeting a number of hippo pathway regulators, including the coactivator TAZ and a key factor of the phosphatase complex PPP1CC, which contributes to the dephosphorylation of YAP, another coactivator downstream of the Hippo pathway. This study identifies for the first time the genome-wide miRNA targetomes during mouse liver development and demonstrates a novel mechanism of terminal differentiation of hepatocytes regulated by the miR-122/Hippo pathway in a coordinated manner. As the Hippo pathway plays important roles in cell proliferation and liver pathological processes like inflammation, fibrosis, and hepatocellular carcinoma (HCC), our study could also provide a new insight into the function of miR-122 in liver pathology.
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Affiliation(s)
- Yin Zhang
- grid.12981.330000 0001 2360 039XMOE Key Laboratory of Gene function and regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, 510275 China ,grid.12981.330000 0001 2360 039XGuangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Research Center of Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120 China
| | - Ye-Ya Tan
- grid.12981.330000 0001 2360 039XMOE Key Laboratory of Gene function and regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, 510275 China
| | - Pei-Pei Chen
- grid.12981.330000 0001 2360 039XMOE Key Laboratory of Gene function and regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, 510275 China ,grid.413402.00000 0004 6068 0570Guangdong Province Hospital of Chinese Medicine, AMI Key Laboratory of Chinese Medicine in Guangzhou, , The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Science, Guangzhou, 510006 China
| | - Hui Xu
- grid.12981.330000 0001 2360 039XMOE Key Laboratory of Gene function and regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, 510275 China
| | - Shu-Juan Xie
- grid.12981.330000 0001 2360 039XMOE Key Laboratory of Gene function and regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, 510275 China
| | - Shi-Jun Xu
- grid.12981.330000 0001 2360 039XMOE Key Laboratory of Gene function and regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, 510275 China
| | - Bin Li
- grid.12981.330000 0001 2360 039XMOE Key Laboratory of Gene function and regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, 510275 China
| | - Jun-Hao Li
- grid.12981.330000 0001 2360 039XMOE Key Laboratory of Gene function and regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, 510275 China
| | - Shun Liu
- grid.12981.330000 0001 2360 039XMOE Key Laboratory of Gene function and regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, 510275 China
| | - Jian-Hua Yang
- grid.12981.330000 0001 2360 039XMOE Key Laboratory of Gene function and regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, 510275 China
| | - Hui Zhou
- grid.12981.330000 0001 2360 039XMOE Key Laboratory of Gene function and regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, 510275 China
| | - Liang-Hu Qu
- MOE Key Laboratory of Gene function and regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, 510275, China.
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35
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Lee HM, Wong WKK, Fan B, Lau ES, Hou Y, O CK, Luk AOY, Chow EYK, Ma RCW, Chan JCN, Kong APS. Detection of increased serum miR-122-5p and miR-455-3p levels before the clinical diagnosis of liver cancer in people with type 2 diabetes. Sci Rep 2021; 11:23756. [PMID: 34887498 PMCID: PMC8660865 DOI: 10.1038/s41598-021-03222-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 11/30/2021] [Indexed: 12/14/2022] Open
Abstract
People with type 2 diabetes (T2D) have increased cancer risk. Liver cancer (LC) has a high prevalence in East Asia and is one of the leading causes of cancer death globally. Diagnosis of LC at early stage carries good prognosis. We used stored serum from patients of Hong Kong Diabetes Register before cancer diagnosis to extract RNA to screen for microRNA markers for early detection of LC in T2D. After screening with Affymetrix GeneChip microarray with serum RNA from 19 incident T2D LC (T2D-LC), 20 T2D cancer free (T2D-CF) and 20 non-T2D non-cancer patients, top signals were validated in a 3-group comparison including 1888 T2D-CF, 127 T2D-LC, and 487 T2D patients with non-liver cancer patients using qPCR. We detected 2.55-fold increase in miR-122-5p and 9.21-fold increase in miR-455-3p in the T2D-LC group. Using ROC analysis, miR-122-5p and miR-455-3p jointly predicted LC with an area under the curve of 0.770. After adjustment for confounders, each unit increase of miR-455-3p increased the odds ratio for liver cancer by 1.022. Increased serum levels of miR-122-5p and miR-455-3p were independently associated with increased risk of incident LC in T2D and may serve as potential biomarkers for early detection of LC in T2D.
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Affiliation(s)
- Heung Man Lee
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong SAR, China
| | - Willy Kwun Kiu Wong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong SAR, China
| | - Baoqi Fan
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong SAR, China
| | - Eric Siu Lau
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong SAR, China
| | - Yong Hou
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong SAR, China
| | - Chun Kwan O
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong SAR, China
| | - Andrea On Yan Luk
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong SAR, China.,Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
| | - Elaine Yee Kwan Chow
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong SAR, China.,Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
| | - Ronald Ching Wan Ma
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong SAR, China.,Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China.,Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
| | - Juliana Chung Ngor Chan
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong SAR, China.,Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China.,Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
| | - Alice Pik Shan Kong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong SAR, China. .,Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China. .,Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China.
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36
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Rashidi S, Mansouri R, Ali-Hassanzadeh M, Ghani E, Barazesh A, Karimazar M, Nguewa P, Carrera Silva EA. Highlighting the interplay of microRNAs from Leishmania parasites and infected-host cells. Parasitology 2021; 148:1434-1446. [PMID: 34218829 PMCID: PMC11010138 DOI: 10.1017/s0031182021001177] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2021] [Revised: 06/10/2021] [Accepted: 06/27/2021] [Indexed: 02/05/2023]
Abstract
Leishmania parasites, the causative agents of leishmaniasis, are protozoan parasites with the ability to modify the signalling pathway and cell responses of their infected host cells. These parasite strategies alter the host cell environment and conditions favouring their replication, survival and pathogenesis. Since microRNAs (miRNAs) are able to post-transcriptionally regulate gene expression processes, these biomolecules can exert critical roles in controlling Leishmania-host cell interplay. Therefore, the identification of relevant miRNAs differentially expressed in Leishmania parasites as well as in infected cells, which affect the host fitness, could be critical to understand the infection biology, pathogenicity and immune response against these parasites. Accordingly, the current review aims to address the differentially expressed miRNAs in both, the parasite and infected host cells and how these biomolecules change cell signalling and host immune responses during infection. A deep understanding of these processes could provide novel guidelines and therapeutic strategies for managing and treating leishmaniasis.
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Affiliation(s)
- Sajad Rashidi
- Department of Parasitology and Mycology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Reza Mansouri
- Department of Immunology, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences and Health Services, Yazd, Iran
| | - Mohammad Ali-Hassanzadeh
- Department of Immunology, School of Medicine, Jiroft University of Medical Sciences, Jiroft, Iran
| | - Esmaeel Ghani
- Endocrinology and Metabolism Research Center, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Afshin Barazesh
- Department of Microbiology and Parasitology, Faculty of Medicine, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Mohammadreza Karimazar
- Department of Parasitology and Mycology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Paul Nguewa
- University of Navarra, ISTUN Instituto de Salud Tropical, Department of Microbiology and Parasitology, IdiSNA (Navarra Institute for Health Research), c/Irunlarrea 1, 31008Pamplona, Spain
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Chang Y, Han JA, Kang SM, Jeong SW, Ryu T, Park HS, Yoo JJ, Lee SH, Kim SG, Kim YS, Kim HS, Jin SY, Ryu S, Jang JY. Clinical impact of serum exosomal microRNA in liver fibrosis. PLoS One 2021; 16:e0255672. [PMID: 34506494 PMCID: PMC8432846 DOI: 10.1371/journal.pone.0255672] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Accepted: 07/22/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND/AIM We investigated alterations in the expression of serum exosomal miRNAs with the progression of liver fibrosis and evaluated their clinical applicability as biomarkers. METHODS This study prospectively enrolled 71 patients who underwent liver biopsy at an academic hospital in Korea. Exosomes were extracted from serum samples, followed by next-generation sequencing (NGS) of miRNAs and targeted real-time quantitative polymerase chain reaction. A model was derived to discriminate advanced fibrosis based on miRNA levels and the performance of this model was evaluated. Validation of the effect of miRNA on liver fibrosis in vitro was followed. RESULTS NGS data revealed that exosomal miR-660-5p, miR-125a-5p, and miR-122 expression were changed significantly with the progression of liver fibrosis, of which miR-122 exhibited high read counts enough to be used as a biomarker. The level of exosomal miR-122 decreased as the pathologic fibrosis grade progressed and patients with biopsy-proven advanced fibrosis had significantly lower levels of exosomal miR-122 (P < 0.001) than those without advanced fibrosis. Exosomal miR-122 exhibited a fair performance in discriminating advanced fibrosis especially in combination with fibrosis-4 score and transient elastography. In a subgroup of patients with a non-viral etiology of liver disease, the performance of exosomal miR-122 as a biomarker was greatly improved. Inhibition of miR-122 expression increased the proliferation of the human hepatic stellate cell line, LX-2, and upregulated the expression of various fibrosis related proteins. CONCLUSION Exosomal miR-122 may serve as a useful non-invasive biomarker for liver fibrosis, especially in patients with non-viral etiologies of chronic liver disease.
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Affiliation(s)
- Young Chang
- Department of Internal Medicine, Institute for Digestive Research, Digestive Disease Center, Soonchunhyang University College of Medicine, Seoul, Korea
| | - Jae-A. Han
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Cheonan, Korea
| | - Suk Min Kang
- Department of Internal Medicine, Institute for Digestive Research, Digestive Disease Center, Soonchunhyang University College of Medicine, Seoul, Korea
| | - Soung Won Jeong
- Department of Internal Medicine, Institute for Digestive Research, Digestive Disease Center, Soonchunhyang University College of Medicine, Seoul, Korea
| | - Tom Ryu
- Department of Internal Medicine, Institute for Digestive Research, Digestive Disease Center, Soonchunhyang University College of Medicine, Seoul, Korea
| | - Han Seul Park
- Department of Internal Medicine, Institute for Digestive Research, Digestive Disease Center, Soonchunhyang University College of Medicine, Seoul, Korea
| | - Jeong-Ju Yoo
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Bucheon, Korea
| | - Sae Hwan Lee
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Cheonan, Korea
| | - Sang Gyune Kim
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Bucheon, Korea
| | - Young Seok Kim
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Bucheon, Korea
| | - Hong Soo Kim
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Cheonan, Korea
| | - So Young Jin
- Department of Pathology, Soonchunhyang University College of Medicine, Seoul, Korea
| | - Seongho Ryu
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Cheonan, Korea
| | - Jae Young Jang
- Department of Internal Medicine, Institute for Digestive Research, Digestive Disease Center, Soonchunhyang University College of Medicine, Seoul, Korea
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Fu Z, Wang L, Li S, Chen F, Au-Yeung KKW, Shi C. MicroRNA as an Important Target for Anticancer Drug Development. Front Pharmacol 2021; 12:736323. [PMID: 34512363 PMCID: PMC8425594 DOI: 10.3389/fphar.2021.736323] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Accepted: 08/10/2021] [Indexed: 12/15/2022] Open
Abstract
Cancer has become the second greatest cause of death worldwide. Although there are several different classes of anticancer drugs that are available in clinic, some tough issues like side-effects and low efficacy still need to dissolve. Therefore, there remains an urgent need to discover and develop more effective anticancer drugs. MicroRNAs (miRNAs) are a class of small endogenous non-coding RNAs that regulate gene expression by inhibiting mRNA translation or reducing the stability of mRNA. An abnormal miRNA expression profile was found to exist widely in cancer cell, which induces limitless replicative potential and evading apoptosis. MiRNAs function as oncogenes (oncomiRs) or tumor suppressors during tumor development and progression. It was shown that regulation of specific miRNA alterations using miRNA mimics or antagomirs can normalize the gene regulatory network and signaling pathways, and reverse the phenotypes in cancer cells. The miRNA hence provides an attractive target for anticancer drug development. In this review, we will summarize the latest publications on the role of miRNA in anticancer therapeutics and briefly describe the relationship between abnormal miRNAs and tumorigenesis. The potential of miRNA-based therapeutics for anticancer treatment has been critically discussed. And the current strategies in designing miRNA targeting therapeutics are described in detail. Finally, the current challenges and future perspectives of miRNA-based therapy are conferred.
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Affiliation(s)
- Zhiwen Fu
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, China
| | - Liu Wang
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, China
| | - Shijun Li
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, China
| | - Fen Chen
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, China
| | | | - Chen Shi
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, China
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Boštjančič E, Večerić-Haler Ž, Kojc N. The Role of Immune-Related miRNAs in the Pathology of Kidney Transplantation. Biomolecules 2021; 11:biom11081198. [PMID: 34439863 PMCID: PMC8393721 DOI: 10.3390/biom11081198] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2021] [Revised: 08/07/2021] [Accepted: 08/10/2021] [Indexed: 01/04/2023] Open
Abstract
MicroRNAs (miRNAs) are members of the non-coding regulatory RNA family that play pivotal roles in physiological and pathological conditions, including immune response. They are particularly interesting as promising therapeutic targets, prognostic and diagnostic markers due to their easy detection in body fluids and stability. There is accumulating evidence that different miRNAs provide disease-specific signatures in liquid samples of distinct kidney injuries. Using experimental models and human samples, there have been numerous suggestions that immune-related miRNAs are also important contributors to the development of different kidney diseases as well as important markers for monitoring response after kidney transplantation. However, there are limited data for understanding their function in the molecular pathways of allograft pathologies. In our review, we focused on microRNAs that are related to different aspects of immune response after kidney transplantation.
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Affiliation(s)
- Emanuela Boštjančič
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia;
| | - Željka Večerić-Haler
- Department of Nephrology, University Medical Centre, 1000 Ljubljana, Slovenia;
- Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
| | - Nika Kojc
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia;
- Correspondence: ; Tel.: +386-154-371-25
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Pelizzaro F, Cardin R, Sartori A, Imondi A, Penzo B, Aliberti C, Ponzoni A, Vitale A, Cillo U, Farinati F. Circulating MicroRNA-21 and MicroRNA-122 as Prognostic Biomarkers in Hepatocellular Carcinoma Patients Treated with Transarterial Chemoembolization. Biomedicines 2021; 9:890. [PMID: 34440094 PMCID: PMC8389644 DOI: 10.3390/biomedicines9080890] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 07/22/2021] [Accepted: 07/23/2021] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND MicroRNAs (miRNAs) have been proposed as biomarkers in hepatocellular carcinoma (HCC). We aim at evaluating miR-21 and miR-122 in HCC patients treated with drug-eluting beads transarterial chemoembolization (DEB-TACE) as prognostic biomarkers and investigating their correlation with hypoxia inducible factor-1α (HIF-1α) serum levels. METHODS In this retrospective study, 12 healthy subjects, 28 cirrhotics, and 54 HCC patients (tested before and four weeks after DEB-TACE) were included. Whole blood miR-21 and miR-122 levels were measured by quantitative real time (qRT)-PCR, while serum HIF-1α was assessed by an enzyme-linked immunosorbent assay (ELISA) test. RESULTS The highest level of miR-21 was found in cirrhotics, while HCC patients had the highest level of miR-122 (which was even higher in "viral" HCC, p = 0.006). miR-21 ratio (after/before DEB-TACE) and miR-122 below their respective cut-offs identified patients with longer progression-free survival (p = 0.0002 and p = 0.02, respectively). The combined assessment of alpha-fetoprotein and miR-21 ratio, both independent prognostic predictors, identified early progressors among patients with complete or partial radiological response. miR-21 levels positively correlated with HIF-1α before (p = 0.045) and after DEB-TACE (p = 0.035). CONCLUSIONS miR-21 ratio and miR-122 are useful prognostic markers after DEB-TACE. miR-21 correlates with HIF-1α and probably has a role in modulating angiogenesis in HCC.
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Affiliation(s)
- Filippo Pelizzaro
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy; (F.P.); (R.C.); (A.S.); (A.I.); (B.P.)
| | - Romilda Cardin
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy; (F.P.); (R.C.); (A.S.); (A.I.); (B.P.)
| | - Anna Sartori
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy; (F.P.); (R.C.); (A.S.); (A.I.); (B.P.)
| | - Angela Imondi
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy; (F.P.); (R.C.); (A.S.); (A.I.); (B.P.)
| | - Barbara Penzo
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy; (F.P.); (R.C.); (A.S.); (A.I.); (B.P.)
| | - Camillo Aliberti
- Radiology Unit, Azienda Ospedale-Università di Padova, 35128 Padova, Italy; (C.A.); (A.P.)
- Diagnostic Imaging Department, Pederzoli Hospital, Peschiera del Garda, 37019 Verona, Italy
| | - Alberto Ponzoni
- Radiology Unit, Azienda Ospedale-Università di Padova, 35128 Padova, Italy; (C.A.); (A.P.)
| | - Alessandro Vitale
- Hepatobiliary Surgery and Liver Transplantation Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy; (A.V.); (U.C.)
| | - Umberto Cillo
- Hepatobiliary Surgery and Liver Transplantation Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy; (A.V.); (U.C.)
| | - Fabio Farinati
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy; (F.P.); (R.C.); (A.S.); (A.I.); (B.P.)
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Abstract
Genomic and transcriptomic analyses have well established that the major fraction of the mammalian genome is transcribed into different classes of RNAs ranging in size from a few nucleotides to hundreds of thousands of nucleotides, which do not encode any protein. Some of these noncoding RNAs (ncRNAs) are directly or indirectly linked to the regulation of expression or functions of 25,000 proteins coded by <2% of the human genome. Among these regulatory RNAs, microRNAs are small (2125 nucleotides) RNAs that are processed from precursor RNAs that have stemloop structure, whereas noncoding RNAs >200 nucleotides are termed long noncoding RNAs (lncRNAs). Circular RNAs (circRNAs) are newly identified lncRNA members that are generated by back-splicing of primary transcripts. The functions of ncRNAs in modulating liver toxicity of xenobiotics are emerging only recently. Acetaminophen (N-acetyl-para-aminophenol, paracetamol or APAP) is a safe analgesic and antipyretic drug at the therapeutic dose. However, it can cause severe liver toxicity that may lead to liver failure if overdosed or combined with alcohol, herbs, or other xenobiotics. This review discusses the role of ncRNAs in acetaminophen metabolism, toxicity, and liver regeneration after APAP-induced liver injury (AILI).
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Affiliation(s)
- Vivek Chowdhary
- *Department of Pathology, College of Medicine, The Ohio State University, Columbus, OH, USA
- †Comprehensive Cancer Center, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Pipasha Biswas
- †Comprehensive Cancer Center, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Kalpana Ghoshal
- *Department of Pathology, College of Medicine, The Ohio State University, Columbus, OH, USA
- †Comprehensive Cancer Center, College of Medicine, The Ohio State University, Columbus, OH, USA
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Histone Methyltransferase G9a-Promoted Progression of Hepatocellular Carcinoma Is Targeted by Liver-Specific Hsa-miR-122. Cancers (Basel) 2021; 13:cancers13102376. [PMID: 34069116 PMCID: PMC8157135 DOI: 10.3390/cancers13102376] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 05/11/2021] [Accepted: 05/11/2021] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Targeting epigenetic alterations in hepatocellular carcinoma (HCC) provides therapeutic options in addition to traditional treatments. The aim of our study was to evaluate the potential of targeting histone methyltransferase G9a in the development of a therapeutic target. We confirmed the prognostic values of mRNA and protein levels of G9a expression in HCC respectively from public database and tissue microarray. We also confirmed the aggressive phenotypes supported by G9a in both HBV+ and HBV− HCC cells. The identification of a regulation axis between liver-specific tumor suppressor miR-122 and G9a further supported the important roles of G9a during the tumorigenesis and progression of HCC. Combination of lower miR-122 and higher G9a levels may provide prognostic potential for poor clinical outcomes and therapeutic potential for epigenetic targeting therapies. Abstract Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers, which is the second most lethal tumor worldwide. Epigenetic deregulation is a common trait observed in HCC. Recently, increasing evidence suggested that the G9a histone methyltransferase might be a novel regulator of HCC development. However, several HCC cell lines were recently noted to have HeLa cell contamination or to have been derived from non-hepatocellular origin, suggesting that functional validation of G9a in proper HCC models is still required. Herein, we first confirmed that higher G9a messenger RNA and protein expression levels were correlated with poor overall survival (OS) and disease-free survival (DFS) rates of HCC patients from The Cancer Genome Atlas (TCGA) dataset and our recruited HCC cohort. In an in vitro functional evaluation of HCC cells, HCC36 (hepatitis B virus-positive (HBV+) and Mahlavu (HBV−)) cells showed that G9a participated in promoting cell proliferation, colony formation, and migration/invasion abilities. Moreover, orthotopic inoculation of G9a-depleted Mahlavu cells in NOD-SCID mice also resulted in a significantly decreased tumor burden compared to the control group. Furthermore, after surveying microRNA (miRNA; miR) prediction databases, we identified the liver-specific miR-122 as a G9a-targeting miRNA. In various HCC cell lines, we observed that miR-122 expression levels tended to be inversely correlated to G9a expression levels. In clinical HCC specimens, a significant inverse correlation of miR-122 and G9a mRNA expression levels was also observed. Functionally, the colony formation and invasive ability were attenuated in miR-122-overexpressing HCC cells. HCC patients with low miR-122 and high G9a expression levels had the worst OS and DFS rates compared to others. Together, our results confirmed the importance of altered G9a expression during HCC progression and discovered that a novel liver-specific miR-122-G9a regulatory axis exists.
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Abstract
PURPOSE OF REVIEW Non-coding RNAs (ncRNAs) including microRNAs (miRNAs) and circular RNAs (circRNAs) are pivotal regulators of mRNA and protein expression that critically contribute to cardiovascular pathophysiology. Although little is known about the origin and function of such ncRNAs, they have been suggested as promising biomarkers with powerful therapeutic value in cardiovascular disease (CVD). In this review, we summarize the most recent findings on ncRNAs biology and their implication on cholesterol homeostasis and lipoprotein metabolism that highlight novel therapeutic avenues for treating dyslipidemia and atherosclerosis. RECENT FINDINGS Clinical and experimental studies have elucidated the underlying effects that specific miRNAs impose both directly and indirectly regulating circulating high-density lipoprotein (HDL), low-density lipoprotein (LDL), and very low-density lipoprotein (VLDL) metabolism and cardiovascular risk. Some of these relevant miRNAs include miR-148a, miR-128-1, miR-483, miR-520d, miR-224, miR-30c, miR-122, miR-33, miR-144, and miR-34. circRNAs are known to participate in a variety of physiological and pathological processes due to their abundance in tissues and their stage-specific expression activation. Recent studies have proven that circRNAs may be considered targets of CVD as well. Some of these cirRNAs are circ-0092317, circ_0003546, circ_0028198, and cirFASN that have been suggested to be strongly involved in lipoprotein metabolism; however, their relevance in CVD is still unknown. MicroRNA and cirRNAs have been proposed as powerful therapeutic targets for treating cardiometabolic disorders including atherosclerosis. Here, we discuss the recent findings in the field of lipid and lipoprotein metabolism underscoring the novel mechanisms by which some of these ncRNAs influence lipoprotein metabolism and CVD.
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Ghosh S, Börsch A, Ghosh S, Zavolan M. The transcriptional landscape of a hepatoma cell line grown on scaffolds of extracellular matrix proteins. BMC Genomics 2021; 22:238. [PMID: 33823809 PMCID: PMC8025518 DOI: 10.1186/s12864-021-07532-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Accepted: 03/14/2021] [Indexed: 11/10/2022] Open
Abstract
Background The behavior of cells in vivo is complex and highly dynamic, as it results from an interplay between intercellular matrix proteins with surface receptors and other microenvironmental cues. Although the effects of the cellular niche have been investigated for a number of cell types using different molecular approaches, comprehensive assessments of how the global transcriptome responds to 3D scaffolds composed of various extracellular matrix (ECM) constituents at different concentrations are still lacking. Results In this study, we explored the effects of two diverse extracellular matrix (ECM) components, Collagen I and Matrigel, on the transcriptional profile of cells in a cell culture system. Culturing Huh-7 cells on traditional cell culture plates (Control) or on the ECM components at different concentrations to modulate microenvironment properties, we have generated transcriptomics data that may be further explored to understand the differentiation and growth potential of this cell type for the development of 3D cultures. Our analysis infers transcription factors that are most responsible for the transcriptome response to the extracellular cues. Conclusion Our data indicates that the Collagen I substrate induces a robust transcriptional response in the Huh-7 cells, distinct from that induced by Matrigel. Enhanced hepatocyte markers (ALB and miR-122) reveal a potentially robust remodelling towards primary hepatocytes. Our results aid in defining the appropriate culture and transcription pathways while using hepatoma cell lines. As systems mimicking the in vivo structure and function of liver cells are still being developed, our study could potentially circumvent bottlenecks of limited availability of primary hepatocytes for preclinical studies of drug targets. Supplementary Information The online version contains supplementary material available at 10.1186/s12864-021-07532-2.
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Affiliation(s)
- Souvik Ghosh
- Biozentrum, University of Basel, Basel, Switzerland.
| | - Anastasiya Börsch
- Biozentrum, University of Basel, Basel, Switzerland.,Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | | | - Mihaela Zavolan
- Biozentrum, University of Basel, Basel, Switzerland. .,Swiss Institute of Bioinformatics, Lausanne, Switzerland.
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Wang X, He Y, Mackowiak B, Gao B. MicroRNAs as regulators, biomarkers and therapeutic targets in liver diseases. Gut 2021; 70:784-795. [PMID: 33127832 DOI: 10.1136/gutjnl-2020-322526] [Citation(s) in RCA: 286] [Impact Index Per Article: 71.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 10/01/2020] [Accepted: 10/09/2020] [Indexed: 12/11/2022]
Abstract
MicroRNAs (miRNAs) are small, non-coding RNAs that post-transcriptionally regulate gene expression by binding to specific mRNA targets and promoting their degradation and/or translational inhibition. miRNAs regulate both physiological and pathological liver functions. Altered expression of miRNAs is associated with liver metabolism dysregulation, liver injury, liver fibrosis and tumour development, making miRNAs attractive therapeutic strategies for the diagnosis and treatment of liver diseases. Here, we review recent advances regarding the regulation and function of miRNAs in liver diseases with a major focus on miRNAs that are specifically expressed or enriched in hepatocytes (miR-122, miR-194/192), neutrophils (miR-223), hepatic stellate cells (miR-29), immune cells (miR-155) and in circulation (miR-21). The functions and target genes of these miRNAs are emphasised in alcohol-associated liver disease, non-alcoholic fatty liver disease, drug-induced liver injury, viral hepatitis and hepatocellular carcinoma, as well liver fibrosis and liver failure. We touch on the roles of miRNAs in intercellular communication between hepatocytes and other types of cells via extracellular vesicles in the pathogenesis of liver diseases. We provide perspective on the application of miRNAs as biomarkers for early diagnosis, prognosis and assessment of liver diseases and discuss the challenges in miRNA-based therapy for liver diseases. Further investigation of miRNAs in the liver will help us better understand the pathogeneses of liver diseases and may identify biomarkers and therapeutic targets for liver diseases in the future.
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Affiliation(s)
- Xiaolin Wang
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
| | - Yong He
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
| | - Bryan Mackowiak
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
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Lin YC, Chen TH, Huang YM, Wei PL, Lin JC. Involvement of microRNA in Solid Cancer: Role and Regulatory Mechanisms. Biomedicines 2021; 9:biomedicines9040343. [PMID: 33805515 PMCID: PMC8065716 DOI: 10.3390/biomedicines9040343] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 03/21/2021] [Accepted: 03/24/2021] [Indexed: 12/24/2022] Open
Abstract
MicroRNAs (miRNAs) function as the post-transcriptional factor that finetunes the gene expression by targeting to the specific candidate. Mis-regulated expression of miRNAs consequently disturbs gene expression profile, which serves as the pivotal mechanism involved in initiation or progression of human malignancy. Cancer-relevant miRNA is potentially considered the therapeutic target or biomarker toward the precise treatment of cancer. Nevertheless, the regulatory mechanism underlying the altered expression of miRNA in cancer is largely uncovered. Detailed knowledge regarding the influence of miRNAs on solid cancer is critical for exploring its potential of clinical application. Herein, we elucidate the regulatory mechanism regarding how miRNA expression is manipulated and its impact on the pathogenesis of distinct solid cancer.
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Affiliation(s)
- Ying-Chin Lin
- Department of Family Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
- Department of Family Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan;
| | - Tso-Hsiao Chen
- Division of Nephrology, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan;
| | - Yu-Min Huang
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
- Division of Gastrointestinal Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei Medical University, Taipei 110, Taiwan;
| | - Po-Li Wei
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
- Division of Colorectal Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei Medical University, Taipei 110, Taiwan
- Cancer Research Center, Taipei Medical University Hospital, Taipei Medical University, Taipei 110, Taiwan
- Translational Laboratory, Department of Medical Research, Taipei Medical University Hospital, Taipei Medical University, Taipei 110, Taiwan
- Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei 110, Taiwan
- Correspondence: (P.-L.W.); (J.-C.L.); Tel.: +886-2-2736-1661 (ext. 3330) (J.-C.L.)
| | - Jung-Chun Lin
- School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan
- Program in Medical Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan
- Pulmonary Research Center, Wan Fang Hospital, Taipei Medical University, Taipei 110, Taiwan
- Correspondence: (P.-L.W.); (J.-C.L.); Tel.: +886-2-2736-1661 (ext. 3330) (J.-C.L.)
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Zhang S, Cheng Z, Wang Y, Han T. The Risks of miRNA Therapeutics: In a Drug Target Perspective. DRUG DESIGN DEVELOPMENT AND THERAPY 2021; 15:721-733. [PMID: 33654378 PMCID: PMC7910153 DOI: 10.2147/dddt.s288859] [Citation(s) in RCA: 138] [Impact Index Per Article: 34.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Accepted: 12/12/2020] [Indexed: 12/18/2022]
Abstract
RNAi therapeutics have been growing. Patisiran and givosiran, two siRNA-based drugs, were approved by the Food and Drug Administration in 2018 and 2019, respectively. However, there is rare news on the advance of miRNA drugs (another therapeutic similar to siRNA drug). Here we report the existing obstacles of miRNA therapeutics by analyses for resources available in a drug target perspective, despite being appreciated when it began. Only 10 obtainable miRNA drugs have been in clinical trials with none undergoing phase III, while over 60 siRNA drugs are in complete clinical trial progression including two approvals. We mechanically compared the two types of drug and found that their major distinction lay in the huge discrepancy of the target number of two RNA molecules, which was caused by different complementary ratios. One miRNA generally targets tens and even hundreds of genes. We named it “too many targets for miRNA effect” (TMTME). Further, two adverse events from the discontinuation of two miRNA therapeutics were exactly answered by TMTME. In summary, TMTME is inevitable because of the special complementary approach between miRNA and its target. It means that miRNA therapeutics would trigger a series of unknown and unpreventable consequences, which makes it a considerable alternative for application.
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Affiliation(s)
- Song Zhang
- Jiangxi Institute of Respiratory Disease, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, People's Republic of China.,College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, People's Republic of China
| | - Zhujun Cheng
- Department of Burn, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, People's Republic of China
| | - Yanan Wang
- Jiangxi Institute of Respiratory Disease, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, People's Republic of China
| | - Tianyu Han
- Jiangxi Institute of Respiratory Disease, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, People's Republic of China
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Mohr R, Özdirik B, Lambrecht J, Demir M, Eschrich J, Geisler L, Hellberg T, Loosen SH, Luedde T, Tacke F, Hammerich L, Roderburg C. From Liver Cirrhosis to Cancer: The Role of Micro-RNAs in Hepatocarcinogenesis. Int J Mol Sci 2021; 22:1492. [PMID: 33540837 PMCID: PMC7867354 DOI: 10.3390/ijms22031492] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 01/23/2021] [Accepted: 01/28/2021] [Indexed: 12/19/2022] Open
Abstract
In almost all cases, hepatocellular carcinoma (HCC) develops as the endpoint of a sequence that starts with chronic liver injury, progresses to liver cirrhosis, and finally, over years and decades, results in liver cancer. Recently, the role of non-coding RNA such as microRNA (miRNA) has been demonstrated in the context of chronic liver diseases and HCC. Moreover, data from a phase II trial suggested a potential role of microRNAs as therapeutics in hepatitis-C-virus infection, representing a significant risk factor for development of liver cirrhosis and HCC. Despite progress in the clinical management of chronic liver diseases, pharmacological treatment options for patients with liver cirrhosis and/or advanced HCC are still limited. With their potential to regulate whole networks of genes, miRNA might be used as novel therapeutics in these patients but could also serve as biomarkers for improved patient stratification. In this review, we discuss available data on the role of miRNA in the transition from liver cirrhosis to HCC. We highlight opportunities for clinical translation and discuss open issues applicable to future developments.
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Affiliation(s)
- Raphael Mohr
- Department of Hepatology and Gastroenterology, Campus Virchow Klinikum (CVK) and Campus Charité Mitte (CCM), Charité University Medicine Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (B.Ö.); (J.L.); (M.D.); (J.E.); (L.G.); (T.H.); (F.T.); (L.H.); (C.R.)
| | - Burcin Özdirik
- Department of Hepatology and Gastroenterology, Campus Virchow Klinikum (CVK) and Campus Charité Mitte (CCM), Charité University Medicine Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (B.Ö.); (J.L.); (M.D.); (J.E.); (L.G.); (T.H.); (F.T.); (L.H.); (C.R.)
| | - Joeri Lambrecht
- Department of Hepatology and Gastroenterology, Campus Virchow Klinikum (CVK) and Campus Charité Mitte (CCM), Charité University Medicine Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (B.Ö.); (J.L.); (M.D.); (J.E.); (L.G.); (T.H.); (F.T.); (L.H.); (C.R.)
| | - Münevver Demir
- Department of Hepatology and Gastroenterology, Campus Virchow Klinikum (CVK) and Campus Charité Mitte (CCM), Charité University Medicine Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (B.Ö.); (J.L.); (M.D.); (J.E.); (L.G.); (T.H.); (F.T.); (L.H.); (C.R.)
| | - Johannes Eschrich
- Department of Hepatology and Gastroenterology, Campus Virchow Klinikum (CVK) and Campus Charité Mitte (CCM), Charité University Medicine Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (B.Ö.); (J.L.); (M.D.); (J.E.); (L.G.); (T.H.); (F.T.); (L.H.); (C.R.)
| | - Lukas Geisler
- Department of Hepatology and Gastroenterology, Campus Virchow Klinikum (CVK) and Campus Charité Mitte (CCM), Charité University Medicine Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (B.Ö.); (J.L.); (M.D.); (J.E.); (L.G.); (T.H.); (F.T.); (L.H.); (C.R.)
| | - Teresa Hellberg
- Department of Hepatology and Gastroenterology, Campus Virchow Klinikum (CVK) and Campus Charité Mitte (CCM), Charité University Medicine Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (B.Ö.); (J.L.); (M.D.); (J.E.); (L.G.); (T.H.); (F.T.); (L.H.); (C.R.)
| | - Sven H. Loosen
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty of Heinrich Heine University Düsseldorf, University Hospital Düsseldorf, Moorenstraße 5, 40225 Düsseldorf, Germany; (S.H.L.); (T.L.)
| | - Tom Luedde
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty of Heinrich Heine University Düsseldorf, University Hospital Düsseldorf, Moorenstraße 5, 40225 Düsseldorf, Germany; (S.H.L.); (T.L.)
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Campus Virchow Klinikum (CVK) and Campus Charité Mitte (CCM), Charité University Medicine Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (B.Ö.); (J.L.); (M.D.); (J.E.); (L.G.); (T.H.); (F.T.); (L.H.); (C.R.)
| | - Linda Hammerich
- Department of Hepatology and Gastroenterology, Campus Virchow Klinikum (CVK) and Campus Charité Mitte (CCM), Charité University Medicine Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (B.Ö.); (J.L.); (M.D.); (J.E.); (L.G.); (T.H.); (F.T.); (L.H.); (C.R.)
| | - Christoph Roderburg
- Department of Hepatology and Gastroenterology, Campus Virchow Klinikum (CVK) and Campus Charité Mitte (CCM), Charité University Medicine Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (B.Ö.); (J.L.); (M.D.); (J.E.); (L.G.); (T.H.); (F.T.); (L.H.); (C.R.)
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty of Heinrich Heine University Düsseldorf, University Hospital Düsseldorf, Moorenstraße 5, 40225 Düsseldorf, Germany; (S.H.L.); (T.L.)
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49
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Wang W, Zhu N, Yan T, Shi YN, Chen J, Zhang CJ, Xie XJ, Liao DF, Qin L. The crosstalk: exosomes and lipid metabolism. Cell Commun Signal 2020; 18:119. [PMID: 32746850 PMCID: PMC7398059 DOI: 10.1186/s12964-020-00581-2] [Citation(s) in RCA: 143] [Impact Index Per Article: 28.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2019] [Accepted: 04/13/2020] [Indexed: 02/08/2023] Open
Abstract
Exosomes have been considered as novel and potent vehicles of intercellular communication, instead of "cell dust". Exosomes are consistent with anucleate cells, and organelles with lipid bilayer consisting of the proteins and abundant lipid, enhancing their "rigidity" and "flexibility". Neighboring cells or distant cells are capable of exchanging genetic or metabolic information via exosomes binding to recipient cell and releasing bioactive molecules, such as lipids, proteins, and nucleic acids. Of note, exosomes exert the remarkable effects on lipid metabolism, including the synthesis, transportation and degradation of the lipid. The disorder of lipid metabolism mediated by exosomes leads to the occurrence and progression of diseases, such as atherosclerosis, cancer, non-alcoholic fatty liver disease (NAFLD), obesity and Alzheimer's diseases and so on. More importantly, lipid metabolism can also affect the production and secretion of exosomes, as well as interactions with the recipient cells. Therefore, exosomes may be applied as effective targets for diagnosis and treatment of diseases. Video abstract.
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Affiliation(s)
- Wei Wang
- School of Pharmacy, Hanpu Science and Education District, Hunan University of Chinese Medicine, 300 Xueshi Road, Changsha, 410208, Hunan, China.,Division of Stem Cell Regulation and Application, Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Neng Zhu
- The First Affiliated Hospital, Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Tao Yan
- School of Pharmacy, Hanpu Science and Education District, Hunan University of Chinese Medicine, 300 Xueshi Road, Changsha, 410208, Hunan, China.,Division of Stem Cell Regulation and Application, Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Ya-Ning Shi
- School of Pharmacy, Hanpu Science and Education District, Hunan University of Chinese Medicine, 300 Xueshi Road, Changsha, 410208, Hunan, China.,Division of Stem Cell Regulation and Application, Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Jing Chen
- Department of Neurosurgery in Changsha, 921 hospital, joint service support force of People's Liberation Army, Changsha, China
| | - Chan-Juan Zhang
- School of Pharmacy, Hanpu Science and Education District, Hunan University of Chinese Medicine, 300 Xueshi Road, Changsha, 410208, Hunan, China.,Division of Stem Cell Regulation and Application, Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Xue-Jiao Xie
- College of Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Duan-Fang Liao
- School of Pharmacy, Hanpu Science and Education District, Hunan University of Chinese Medicine, 300 Xueshi Road, Changsha, 410208, Hunan, China. .,Division of Stem Cell Regulation and Application, Hunan University of Chinese Medicine, Changsha, Hunan, China.
| | - Li Qin
- School of Pharmacy, Hanpu Science and Education District, Hunan University of Chinese Medicine, 300 Xueshi Road, Changsha, 410208, Hunan, China. .,Division of Stem Cell Regulation and Application, Hunan University of Chinese Medicine, Changsha, Hunan, China.
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50
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The Effect of Methylselenocysteine and Sodium Selenite Treatment on microRNA Expression in Liver Cancer Cell Lines. Pathol Oncol Res 2020; 26:2669-2681. [PMID: 32656599 PMCID: PMC7471166 DOI: 10.1007/s12253-020-00870-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Accepted: 06/30/2020] [Indexed: 12/14/2022]
Abstract
The unique character of selenium compounds, including sodium selenite and Se-methylselenocysteine (MSC), is that they exert cytotoxic effects on neoplastic cells, providing a great potential for treating cancer cells being highly resistant to cytostatic drugs. However, selenium treatment may affect microRNA (miRNA) expression as the pattern of circulating miRNAs changed in a placebo-controlled selenium supplement study. This necessitates exploring possible changes in the expression profiles of miRNAs. For this, miRNAs being critical for liver function were selected and their expression was measured in hepatocellular carcinoma (HLE and HLF) and cholangiocarcinoma cell lines (TFK-1 and HuH-28) using individual TaqMan MicroRNA Assays following selenite or MSC treatments. For establishing tolerable concentrations, IC50 values were determined by performing SRB proliferation assays. The results revealed much lower IC50 values for selenite (from 2.7 to 11.3 μM) compared to MSC (from 79.5 to 322.6 μM). The treatments resulted in cell line-dependent miRNA expression patterns, with all miRNAs found to show fold change differences; however, only a few of these changes were statistically different in treated cells compared to untreated cells below IC50. Namely, miR-199a in HLF, miR-143 in TFK-1 upon MSC treatment, miR-210 in HLF and TFK-1, miR-22, -24, -122, -143 in HLF upon selenite treatment. Fold change differences revealed that miR-122 with both selenium compounds, miR-199a with MSC and miR-22 with selenite were affected. The miRNAs showing minimal alterations included miR-125b and miR-194. In conclusion, our results revealed moderately altered miRNA expression in the cell lines (less alterations following MSC treatment), being miR-122, -199a the most affected and miR-125b, -194 the least altered miRNAs upon selenium treatment.
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