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Tian M, Zhou Y, Guo Y, Xia Q, Wang Z, Zheng X, Shen J, Guo J, Duan S, Wang L. MicroRNAs in adipose tissue fibrosis: Mechanisms and therapeutic potential. Genes Dis 2025; 12:101287. [PMID: 40242037 PMCID: PMC12002615 DOI: 10.1016/j.gendis.2024.101287] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2023] [Accepted: 03/07/2024] [Indexed: 04/18/2025] Open
Abstract
Adipose tissue fibrosis, characterized by abnormal extracellular matrix deposition within adipose tissue, signifies a crucial indicator of adipose tissue malfunction, potentially leading to organ tissue dysfunction. Various factors, including a high-fat diet, non-alcoholic fatty liver disease, and insulin resistance, coincide with adipose tissue fibrosis. MicroRNAs (miRNAs) represent a class of small non-coding RNAs with significant influence on tissue fibrosis through diverse signaling pathways. For instance, in response to a high-fat diet, miRNAs can modulate signaling pathways such as TGF-β/Smad, PI3K/AKT, and PPAR-γ to impact adipose tissue fibrosis. Furthermore, miRNAs play roles in inhibiting fibrosis in different contexts: suppressing corneal fibrosis via the TGF-β/Smad pathway, mitigating cardiac fibrosis through the VEGF signaling pathway, reducing wound fibrosis via regulation of the MAPK signaling pathway, and diminishing fibrosis post-fat transplantation via involvement in the PDGFR-β signaling pathway. Notably, the secretome released by miRNA-transfected adipose-derived stem cells facilitates targeted delivery of miRNAs to evade host immune rejection, enhancing their anti-fibrotic efficacy. Hence, this study endeavors to elucidate the role and mechanism of miRNAs in adipose tissue fibrosis and explore the mechanisms and advantages of the secretome released by miRNA-transfected adipose-derived stem cells in combating fibrotic diseases.
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Affiliation(s)
- Mei Tian
- College of Pharmacy, Zhejiang University of Technology, Hangzhou, Zhejiang 310014, China
- Geriatric Medicine Center, Department of Endocrinology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang 310014, China
- Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou, Zhejiang 310015, China
| | - Yang Zhou
- Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou, Zhejiang 310015, China
| | - Yitong Guo
- Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou, Zhejiang 310015, China
| | - Qing Xia
- College of Pharmacy, Zhejiang University of Technology, Hangzhou, Zhejiang 310014, China
- Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou, Zhejiang 310015, China
| | - Zehua Wang
- Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou, Zhejiang 310015, China
| | - Xinying Zheng
- College of Pharmacy, Zhejiang University of Technology, Hangzhou, Zhejiang 310014, China
- Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou, Zhejiang 310015, China
| | - Jinze Shen
- Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou, Zhejiang 310015, China
| | - Junping Guo
- Rainbowfish Rehabilitation and Nursing School, Hangzhou Vocational & Technical College, Hangzhou, Zhejiang 310018, China
- Department of Clinical Medicine, School of Medicine, Hangzhou City University, Hangzhou, Zhejiang 310015, China
| | - Shiwei Duan
- Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou, Zhejiang 310015, China
| | - Lijun Wang
- Geriatric Medicine Center, Department of Endocrinology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang 310014, China
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Yang SM, Hu TH, Wu JC, Yi LN, Kuo HM, Kung ML, Chu TH, Huang ST, Huang CC, Kao YH, Lin YW, Tai MH. Hepatoma-Derived Growth Factor Promotes Liver Carcinogenesis by Inducing Phosphatase and Tensin Homolog Inactivation. J Transl Med 2025; 105:104127. [PMID: 40081662 DOI: 10.1016/j.labinv.2025.104127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 01/28/2025] [Accepted: 03/05/2025] [Indexed: 03/16/2025] Open
Abstract
Hepatoma-derived growth factor (HDGF) is located on chromosome 1q21-23, a locus frequently amplified in hepatocellular carcinoma (HCC), and has been proposed as an oncogenic factor by stimulating PI3K/Akt signaling. Phosphatase and tensin homolog (PTEN) acts as a tumor suppressor that antagonizes PI3K/Akt signaling, suggesting a possible regulatory effect of HDGF on PTEN. In this study, we aimed to investigate the regulatory role of HDGF on PTEN. The Cancer Genome Atlas cohort study was used to explore molecular significance and outcomes in liver cancer. Resected clinical specimens, consisting of paired tumor and adjacent nontumor tissue, were analyzed for expression of HDGF and PTEN in the liver cancer cohort. Liver tissue and primary hepatocytes derived from HDGF knockout mice were analyzed for PTEN status. The influence of HDGF on PTEN was investigated through in vitro and in vivo genetic manipulation studies. The Cancer Genome Atlas cohort study revealed an inverse correlation between HDGF and PTEN, with HDGF overexpression emerging as a dominant factor independent of PTEN levels and correlated with poor outcomes in patients with HCC. Paired clinical specimens revealed HDGF upregulation in tumor tissue is relevant to elevated alpha-fetoprotein, and poor survival and recurrent outcomes in the liver cancer cohort. HDGF knockout mice exhibited decreased liver C-tail--phosphorylated PTEN (p-PTEN) levels and increased PTEN expression. Furthermore, an in vitro study validated that overexpression of HDGF increased p-PTEN levels and tumor growth, whereas knockdown of HDGF yielded inverse results. Treatment with recombinant HDGF confirmed the stimulation of p-PTEN and accumulation of phosphatidylinositol 3,4,5-trisphosphate. Blockade of HDGF and casein kinase 2 signaling using anti-HDGF and a casein kinase 2 inhibitor validated the stimulation of p-PTEN. Our results reveal that HDGF is an oncogene frequently amplified and upregulated, leading to suppression of PTEN expression and activity, thereby contributing to malignant progression in liver cancer. HDGF upregulation in resected paired-HCC specimens may constitute a valuable prognostic biomarker for patients with HCC.
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Affiliation(s)
- Shih-Ming Yang
- Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Tsung-Hui Hu
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Jian-Ching Wu
- National Sun Yat-Sen University and Academia Sinica, Kaohsiung, Taiwan
| | - Li-Na Yi
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Hsiao-Mei Kuo
- Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Mei-Lang Kung
- Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Tian-Huei Chu
- Medical Laboratory, Medical Education and Research Center, Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan
| | - Shih-Tsung Huang
- National Sun Yat-Sen University and Academia Sinica, Kaohsiung, Taiwan
| | - Chao-Cheng Huang
- Department of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Ying-Hsien Kao
- Department of Medical Research, E-Da Hospital, Kaohsiung, Taiwan
| | - Yu-Wei Lin
- Department of Radiation Oncology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
| | - Ming-Hong Tai
- Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan.
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Chen H, Huang M, Zhang D, Wang H, Wang D, Li M, Wang X, Zhu R, Liu J, Ma L. Metformin's effect on metabolic dysfunction-associated steatotic liver disease through the miR-200a-5p and AMPK/SERCA2b pathway. Front Pharmacol 2024; 15:1477212. [PMID: 39741625 PMCID: PMC11685231 DOI: 10.3389/fphar.2024.1477212] [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: 08/07/2024] [Accepted: 12/02/2024] [Indexed: 01/03/2025] Open
Abstract
Introduction Metformin has shown benefits in treating metabolic dysfunction-associated steatotic liver disease (MASLD), but its mechanisms remain unclear. This study investigates miR-200a-5p's role in the AMPK/SERCA2b pathway to reduce liver fat accumulation and ER stress in MASLD. Methods A PA cell model induced by palmitic and oleic acids (2:1) was used to assess lipid accumulation via Oil Red O and Nile Red staining. mRNA levels of miR-200a-5p and lipid metabolism genes were measured with RT-PCR, and AMPK, p-AMPK, and SERCA2b protein levels were analyzed by Western blotting. The interaction between miR-200a-5p and AMPK was studied using a luciferase reporter assay. A high-fat diet-induced MASLD mouse model was used to evaluate metformin's effects on liver steatosis and lipid profiles. Serum miR-200a-5p levels were also analyzed in MASLD patients. Results In the PA cell model, elevated miR-200a-5p and lipid metabolism gene mRNA levels were observed, with decreased AMPK and SERCA2b protein levels. miR-200a-5p mimic reduced AMPK and SERCA2b expression. Metformin treatment reduced liver steatosis and lipid deposition in mice, normalizing miR-200a-5p, lipid metabolism gene mRNA, and AMPK/SERCA2b protein levels. Elevated serum miR-200a-5p was detected in MASLD patients. Discussion These findings suggest that metformin alleviates lipid deposition and ER stress in MASLD through the modulation of the AMPK/SERCA2b pathway via miR-200a-5p.
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Affiliation(s)
- Hang Chen
- The First Affiliated Hospital, Yunnan Institute of Digestive Disease, Kunming Medical University, Kunming, China
| | - Minshan Huang
- The First Affiliated Hospital, Yunnan Institute of Digestive Disease, Kunming Medical University, Kunming, China
| | - Dan Zhang
- The First Affiliated Hospital, Yunnan Institute of Digestive Disease, Kunming Medical University, Kunming, China
| | - Hui Wang
- The First Affiliated Hospital, Yunnan Institute of Digestive Disease, Kunming Medical University, Kunming, China
| | - Da Wang
- The First Affiliated Hospital, Yunnan Institute of Digestive Disease, Kunming Medical University, Kunming, China
| | - Mengwei Li
- The First Affiliated Hospital, Yunnan Institute of Digestive Disease, Kunming Medical University, Kunming, China
| | - Xianmei Wang
- The First Affiliated Hospital, Yunnan Institute of Digestive Disease, Kunming Medical University, Kunming, China
| | - Rui Zhu
- State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, School of Life Sciences, Yunnan University, Kunming, China
| | - Jianjun Liu
- Yunnan Key Laboratory of Breast Cancer Precision Medicine, Academy of Biomedical Engineering, Kunming Medical University, Kunming, China
| | - Lanqing Ma
- The First Affiliated Hospital, Yunnan Institute of Digestive Disease, Kunming Medical University, Kunming, China
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Bergez-Hernández F, Irigoyen-Arredondo M, Martínez-Camberos A. A systematic review of mechanisms of PTEN gene down-regulation mediated by miRNA in prostate cancer. Heliyon 2024; 10:e34950. [PMID: 39144981 PMCID: PMC11320309 DOI: 10.1016/j.heliyon.2024.e34950] [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: 07/15/2024] [Accepted: 07/18/2024] [Indexed: 08/16/2024] Open
Abstract
Background The Phosphatase and Tensin Homolog gene (PTEN) is pivotal in regulating diverse cellular processes, including growth, differentiation, proliferation, and cell survival, mainly by modulating the PI3K/AKT/mTOR pathway. Alterations in the expression of the PTEN gene have been associated with epigenetic mechanisms, particularly the regulation by small non-coding RNAs, such as miRNAs. Modifications in the expression levels of miRNAs that control PTEN have been shown to lead to its underexpression. This underexpression, in turn, impacts the PI3K/AKT/mTOR pathway, thereby influencing crucial mechanisms like proliferation and apoptosis, playing an important role in the initiation and progression of prostate cancer (PCa). Thus, we aimed to systematically reviewed available information concerning the regulation of PTEN mediated by miRNA in PCa. Methods Electronic databases were searched to identify studies assessing PTEN regulation via PCa miRNAs, the search included combination of the words microRNAs, PTEN and prostatic neoplasms. The quality assessment of the articles included was carried out using an adapted version of SYRCLE and CASP tool. Results We included 39 articles that measured the relative gene expression of miRNAs in PCa and their relationship with PTEN regulation. A total of 42 miRNAs were reported involved in the development and progression of PCa via PTEN dysregulation (34 miRNAs up-regulated and eight miRNAs down-regulated). Sixteen miRNAs were shown as the principal regulators for genetic interactions leading to carcinogenesis, being the miR-21 the most reported in PCa associated with PTEN down-regulation. We showed the silencing of PTEN could be promoted by a loop between miR-200b and DNMT1 or by direct targeting of PTEN by microRNAs, leading to the constitutive activation of PI3K/AKT/mTOR and interactions with intermediary genes support apoptosis inhibition, proliferation, invasion, and metastasis in PCa. Conclusion According to our review, dysregulation of PTEN mediated mainly by miR-21, -20a, -20b, -93, -106a, and -106b up-regulation has a central role in PCa development and could be potential biomarkers for diagnosis, prognostic, and therapeutic targets.
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Affiliation(s)
| | | | - Alejandra Martínez-Camberos
- Laboratorio de Biomedicina y Biología Molecular. Lic. en Ciencias Biomédicas, Universidad Autónoma de Occidente. Av del Mar 1200, Tellerías, 82100, Mazatlán, Sinaloa, Mexico
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Tian Y, Zhang M, Liu LX, Wang ZC, Liu B, Huang Y, Wang X, Ling YZ, Wang F, Feng X, Tu Y. Exploring non-coding RNA mechanisms in hepatocellular carcinoma: implications for therapy and prognosis. Front Immunol 2024; 15:1400744. [PMID: 38799446 PMCID: PMC11116607 DOI: 10.3389/fimmu.2024.1400744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Accepted: 04/03/2024] [Indexed: 05/29/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a significant contributor to cancer-related deaths in the world. The development and progression of HCC are closely correlated with the abnormal regulation of non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs). Important biological pathways in cancer biology, such as cell proliferation, death, and metastasis, are impacted by these ncRNAs, which modulate gene expression. The abnormal expression of non-coding RNAs in HCC raises the possibility that they could be applied as new biomarkers for diagnosis, prognosis, and treatment targets. Furthermore, by controlling the expression of cancer-related genes, miRNAs can function as either tumor suppressors or oncogenes. On the other hand, lncRNAs play a role in the advancement of cancer by interacting with other molecules within the cell, which, in turn, affects processes such as chromatin remodeling, transcription, and post-transcriptional processes. The importance of ncRNA-driven regulatory systems in HCC is being highlighted by current research, which sheds light on tumor behavior and therapy response. This research highlights the great potential of ncRNAs to improve patient outcomes in this difficult disease landscape by augmenting the present methods of HCC care through the use of precision medicine approaches.
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Affiliation(s)
- Yu Tian
- Research Center, The Huizhou Central People’s Hospital, Guangdong Medical University, Huizhou, Guangdong, China
- School of Public Health, Benedictine University, Lisle, IL, United States
| | - Meng Zhang
- Department of Hepatobiliary Surgery, Affiliated Hospital of Hebei University, Baoding, China
| | - Li-xia Liu
- Department of Ultrasound, Hebei Key Laboratory of Precise Imaging of Inflammation Related Tumors, Affiliated Hospital of Hebei University, Baoding, Hebei, China
| | - Zi-chao Wang
- Department of Ultrasound, Hebei Key Laboratory of Precise Imaging of Inflammation Related Tumors, Affiliated Hospital of Hebei University, Baoding, Hebei, China
| | - Bin Liu
- Central Laboratory, Hebei Key Laboratory of Cancer Radiotherapy and Chemotherapy, Affiliated Hospital of Hebei University, Baoding, Hebei, China
| | - Youcai Huang
- Research Center, The Huizhou Central People’s Hospital, Guangdong Medical University, Huizhou, Guangdong, China
| | - Xiaoling Wang
- Research Center, The Huizhou Central People’s Hospital, Guangdong Medical University, Huizhou, Guangdong, China
| | - Yun-zhi Ling
- Research Center, The Huizhou Central People’s Hospital, Guangdong Medical University, Huizhou, Guangdong, China
| | - Furong Wang
- Department of Pathology, The Huizhou Central People’s Hospital, Guangdong Medical University, Huizhou, Guangdong, China
| | - Xiaoqiang Feng
- Center of Stem Cell and Regenerative Medicine, Gaozhou People’s Hospital, Gaozhou, Guangdong, China
| | - Yanyang Tu
- Research Center, The Huizhou Central People’s Hospital, Guangdong Medical University, Huizhou, Guangdong, China
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Diao Z, Molludi J, Latef Fateh H, Moradi S. Comparison of the low-calorie DASH diet and a low-calorie diet on serum TMAO concentrations and gut microbiota composition of adults with overweight/obesity: a randomized control trial. Int J Food Sci Nutr 2024; 75:207-220. [PMID: 38149315 DOI: 10.1080/09637486.2023.2294685] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Accepted: 12/09/2023] [Indexed: 12/28/2023]
Abstract
This study compares two diets, Dietary Approaches to Stop Hypertension (DASH) and a Low-Calorie Diet on Trimethylamine N-oxide (TMAO) levels and gut microbiota. 120 obese adults were randomly allocated to these three groups: a low-calorie DASH diet, a Low-Calorie diet, or a control group for 12 weeks. Outcomes included plasma TMAO, lipopolysaccharides (LPS), and gut microbiota profiles. After the intervention, the low-calorie DASH diet group demonstrated a greater decrease in TMAO levels (-20 ± 8.1 vs. -10.63 ± 4.6 μM) and a significant decrease in LPS concentration (-19.76 ± 4.2 vs. -5.68 ± 2.3) compared to the low-calorie diet group. Furthermore, the low-calorie DASH diet showed a higher decrease in the Firmicutes and Bactericides (F/B) ratio, which influenced TMAO levels, compared to the Low-Calorie diet (p = 0.028). The current study found the low-calorie DASH diet improves TMAO and LPS in comparison to a Low-Calorie diet.
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Affiliation(s)
- Zhipeng Diao
- Tianjin Yite Life Science R&D Co. LTD, Tianjin, China
| | - Jalall Molludi
- Research Center for Environmental Determinants of Health (RCEDH), Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Hawal Latef Fateh
- Nursing Department, Kalar Technical College, Sulaimani Polytechnic University, Sulaymaniyah, Iraq
- Nursing Department, Kalar Technical College, Garmian Polytechnic University, Kalar, Iraq
| | - Sara Moradi
- Research Center for Environmental Determinants of Health (RCEDH), Kermanshah University of Medical Sciences, Kermanshah, Iran
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Mohan S, Hakami MA, Dailah HG, Khalid A, Najmi A, Zoghebi K, Halawi MA, Alotaibi TM. From inflammation to metastasis: The central role of miR-155 in modulating NF-κB in cancer. Pathol Res Pract 2024; 253:154962. [PMID: 38006837 DOI: 10.1016/j.prp.2023.154962] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Revised: 11/16/2023] [Accepted: 11/16/2023] [Indexed: 11/27/2023]
Abstract
Cancer is a multifaceted, complex disease characterized by unchecked cell growth, genetic mutations, and dysregulated signalling pathways. These factors eventually cause evasion of apoptosis, sustained angiogenesis, tissue invasion, and metastasis, which makes it difficult for targeted therapeutic interventions to be effective. MicroRNAs (miRNAs) are essential gene expression regulators linked to several biological processes, including cancer and inflammation. The NF-κB signalling pathway, a critical regulator of inflammatory reactions and oncogenesis, has identified miR-155 as a significant participant in its modulation. An intricate network of transcription factors known as the NF-κB pathway regulates the expression of genes related to inflammation, cell survival, and immunological responses. The NF-κB pathway's dysregulation contributes to many cancer types' development, progression, and therapeutic resistance. In numerous cancer models, the well-studied miRNA miR-155 has been identified as a crucial regulator of NF-κB signalling. The p65 subunit and regulatory molecules like IκB are among the primary targets that miR-155 directly targets to alter NF-κB activity. The molecular processes by which miR-155 affects the NF-κB pathway are discussed in this paper. It also emphasizes the miR-155's direct and indirect interactions with important NF-κB cascade elements to control the expression of NF-κB subunits. We also investigate how miR-155 affects NF-κB downstream effectors in cancer, including inflammatory cytokines and anti-apoptotic proteins.
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Affiliation(s)
- Syam Mohan
- Substance Abuse and Toxicology Research Centre, Jazan University, Jazan 45142, Saudi Arabia; School of Health Sciences, University of Petroleum and Energy Studies, Dehradun, Uttarakhand, India; Center for Global Health Research, Saveetha Medical College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, India.
| | - Mohammed Ageeli Hakami
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Al, Quwayiyah, Shaqra University, Riyadh, Saudi Arabia.
| | - Hamad Ghaleb Dailah
- Research and Scientific Studies Unit, College of Nursing, Jazan University, Jazan 45142, Saudi Arabia
| | - Asaad Khalid
- Substance Abuse and Toxicology Research Centre, Jazan University, Jazan 45142, Saudi Arabia
| | - Asim Najmi
- Department of Pharmaceutical Chemistry and Pharmacognosy, College of Pharmacy, Jazan University, Jazan 45142, Saudi Arabia
| | - Khalid Zoghebi
- Department of Pharmaceutical Chemistry and Pharmacognosy, College of Pharmacy, Jazan University, Jazan 45142, Saudi Arabia
| | - Maryam A Halawi
- Department of Clinical Pharmacy, College of Pharmacy, Jazan University, Jazan 45142, Saudi Arabia
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Kozlov D, Rodimova S, Kuznetsova D. The Role of MicroRNAs in Liver Functioning: from Biogenesis to Therapeutic Approaches (Review). Sovrem Tekhnologii Med 2023; 15:54-79. [PMID: 39967915 PMCID: PMC11832066 DOI: 10.17691/stm2023.15.5.06] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Indexed: 01/03/2025] Open
Abstract
Molecular diagnostics based on small non-coding RNA molecules (in particular microRNA) is a new direction in modern biomedicine and is considered a promising method for identification of a wide range of pathologies at an early stage, clinical phenotype assessment, as well as monitoring the course of the disease, evaluation of therapy efficacy and the risk of the disease recurrence. Currently, the role of microRNAs as the most important epigenetic regulator in cancer development has been proven within the studies of normal and pathogenic processes. However, currently, there are insignificant studies devoted to studying the role of microRNAs in functioning of other organs and tissues, as well as to development of possible therapeutic approaches based on microRNAs. A huge number of metabolic processes in the liver are controlled by microRNAs, which creates enormous potential for the use of microRNAs as a diagnostic marker and makes it a target for therapeutic intervention in metabolic, oncological, and even viral diseases of this organ. This review examines various aspects of biological functions of microRNAs in different types of liver cells. Both canonical and non-canonical pathways of biogenesis, epigenetic regulation mediated by microRNAs, as well as the microRNAs role in intercellular communication and the course of viral diseases are shown. The potential of microRNAs as a diagnostic marker for various liver pathologies is described, as well as therapeutic approaches and medicines based on microRNAs, which are approved for clinical use and currently being developed.
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Affiliation(s)
- D.S. Kozlov
- Laboratory Assistant, Scientific Laboratory of Molecular Biotechnologies, I Research Institute of Experimental Oncology and Biomedical Technologies; Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Square, Nizhny Novgorod, 603005, Russia; Student, Institute of Biology and Biomedicine; National Research Lobachevsky State University of Nizhny Novgorod, 23 Prospekt Gagarina, Nizhny Novgorod, 603022, Russia
| | - S.A. Rodimova
- Junior Researcher, Laboratory of Regenerative Medicine; Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Square, Nizhny Novgorod, 603005, Russia; Junior Researcher, Scientific Laboratory of Molecular Biotechnologies, Research Institute of Experimental Oncology and Biomedical Technologies; Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Square, Nizhny Novgorod, 603005, Russia
| | - D.S. Kuznetsova
- PhD, Head of the Scientific Laboratory of Molecular Biotechnologies, Research Institute of Experimental Oncology and Biomedical Technologies; Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Square, Nizhny Novgorod, 603005, Russia; Head of the Research Laboratory for Molecular Genetic Researches, Institute of Clinical Medicine; National Research Lobachevsky State University of Nizhny Novgorod, 23 Prospekt Gagarina, Nizhny Novgorod, 603022, Russia
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9
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Romeo M, Dallio M, Scognamiglio F, Ventriglia L, Cipullo M, Coppola A, Tammaro C, Scafuro G, Iodice P, Federico A. Role of Non-Coding RNAs in Hepatocellular Carcinoma Progression: From Classic to Novel Clinicopathogenetic Implications. Cancers (Basel) 2023; 15:5178. [PMID: 37958352 PMCID: PMC10647270 DOI: 10.3390/cancers15215178] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Accepted: 10/25/2023] [Indexed: 11/15/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a predominant malignancy with increasing incidences and mortalities worldwide. In Western countries, the progressive affirmation of Non-alcoholic Fatty Liver Disease (NAFLD) as the main chronic liver disorder in which HCC occurrence is appreciable even in non-cirrhotic stages, constitutes a real health emergency. In light of this, a further comprehension of molecular pathways supporting HCC onset and progression represents a current research challenge to achieve more tailored prognostic models and appropriate therapeutic approaches. RNA non-coding transcripts (ncRNAs) are involved in the regulation of several cancer-related processes, including HCC. When dysregulated, these molecules, conventionally classified as "small ncRNAs" (sncRNAs) and "long ncRNAs" (lncRNAs) have been reported to markedly influence HCC-related progression mechanisms. In this review, we describe the main dysregulated ncRNAs and the relative molecular pathways involved in HCC progression, analyzing their implications in certain etiologically related contexts, and their applicability in clinical practice as novel diagnostic, prognostic, and therapeutic tools. Finally, given the growing evidence supporting the immune system response, the oxidative stress-regulated mechanisms, and the gut microbiota composition as relevant emerging elements mutually influencing liver-cancerogenesis processes, we investigate the relationship of ncRNAs with this triad, shedding light on novel pathogenetic frontiers of HCC progression.
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Affiliation(s)
- Mario Romeo
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (M.R.); (F.S.); (L.V.); (M.C.); (A.C.); (A.F.)
| | - Marcello Dallio
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (M.R.); (F.S.); (L.V.); (M.C.); (A.C.); (A.F.)
| | - Flavia Scognamiglio
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (M.R.); (F.S.); (L.V.); (M.C.); (A.C.); (A.F.)
| | - Lorenzo Ventriglia
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (M.R.); (F.S.); (L.V.); (M.C.); (A.C.); (A.F.)
| | - Marina Cipullo
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (M.R.); (F.S.); (L.V.); (M.C.); (A.C.); (A.F.)
| | - Annachiara Coppola
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (M.R.); (F.S.); (L.V.); (M.C.); (A.C.); (A.F.)
| | - Chiara Tammaro
- Biochemistry Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (C.T.); (G.S.)
| | - Giuseppe Scafuro
- Biochemistry Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (C.T.); (G.S.)
| | - Patrizia Iodice
- Division of Medical Oncology, AORN Azienda dei Colli, Monaldi Hospital, Via Leonardo Bianchi, 80131 Naples, Italy
| | - Alessandro Federico
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (M.R.); (F.S.); (L.V.); (M.C.); (A.C.); (A.F.)
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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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11
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Rodrigues PM, Afonso MB, Simão AL, Islam T, Gaspar MM, O'Rourke CJ, Lewinska M, Andersen JB, Arretxe E, Alonso C, Santos-Laso Á, Izquierdo-Sanchez L, Jimenez-Agüero R, Eizaguirre E, Bujanda L, Pareja MJ, Prip-Buus C, Banales JM, Rodrigues CMP, Castro RE. miR-21-5p promotes NASH-related hepatocarcinogenesis. Liver Int 2023; 43:2256-2274. [PMID: 37534739 DOI: 10.1111/liv.15682] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 06/03/2023] [Accepted: 07/17/2023] [Indexed: 08/04/2023]
Abstract
BACKGROUND AND AIMS The mechanisms governing the progression of non-alcoholic fatty liver disease (NAFLD) towards steatohepatitis (NASH) and hepatocellular carcinoma (HCC) remain elusive. Here, we evaluated the role of hsa-miRNA-21-5p in NASH-related hepatocarcinogenesis. METHODS Hepatic hsa-miR-21-5p expression was evaluated in two cohorts of patients with biopsy-proven NAFLD (n = 199) or HCC (n = 366 HCC and n = 11 NAFLD-HCC). Serum/liver metabolomic profiles were correlated with hsa-miR-21-5p in NAFLD obese patients. Wild-type (WT) and Mir21 KO mice were fed a choline-deficient, amino acid-defined (CDAA) diet for 32 and 66 weeks to induce NASH and NASH-HCC, respectively. RESULTS In obese individuals, hsa-miR-21-5p expression increased with NAFLD severity and associated with a hepatic lipotoxic profile. CDAA-fed WT mice displayed increased hepatic mmu-miR-21-5p levels and progressively developed NASH and fibrosis, with livers presenting macroscopically discernible pre-neoplastic nodules, hyperplastic foci and deregulated cancer-related pathways. Mir21 KO mice exhibited peroxisome-proliferator-activated receptor α (PPARα) activation, augmented mitochondrial activity, reduced liver injury and NAS below the threshold for NASH diagnosis, with the pro-inflammatory/fibrogenic milieu reversing to baseline levels. In parallel, Mir21 KO mice displayed reduced number of pre-neoplastic nodules, hepatocyte proliferation and activation of oncogenic signalling, being protected from NASH-associated carcinogenesis. The hsa-miRNA-21-5p/PPARα pathway was similarly deregulated in patients with HCC- or NASH-related HCC, correlating with HCC markers and worse prognosis. CONCLUSIONS Hsa-miR-21-5p is a key inducer of whole-spectrum NAFLD progression, from simple steatosis to NASH and NASH-associated carcinogenesis. The inhibition of hsa-miR-21-5p, leading to a pro-metabolic profile, might constitute an appealing therapeutic approach to ameliorate NASH and prevent progression towards HCC.
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Affiliation(s)
- Pedro M Rodrigues
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
- Centre for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
- IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
| | - Marta B Afonso
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - André L Simão
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Tawhidul Islam
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Maria M Gaspar
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Colm J O'Rourke
- Biotech Research and Innovation Centre, Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Monika Lewinska
- Biotech Research and Innovation Centre, Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jesper B Andersen
- Biotech Research and Innovation Centre, Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | | | | | - Álvaro Santos-Laso
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
| | - Laura Izquierdo-Sanchez
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
| | - Raúl Jimenez-Agüero
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
| | - Emma Eizaguirre
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
| | - Luis Bujanda
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
- Centre for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | | | - Carina Prip-Buus
- Université Paris Descartes UMR-S1016, Institut Cochin, Paris, France
| | - Jesus M Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
- Centre for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
- IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
- Department of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona, Spain
| | - Cecília M P Rodrigues
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Rui E Castro
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
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12
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Tan S, Tang H, Wang Y, Xie P, Li H, Zhang Z, Zhou J. Tumor cell-derived exosomes regulate macrophage polarization: Emerging directions in the study of tumor genesis and development. Heliyon 2023; 9:e19296. [PMID: 37662730 PMCID: PMC10474436 DOI: 10.1016/j.heliyon.2023.e19296] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Revised: 08/08/2023] [Accepted: 08/11/2023] [Indexed: 09/05/2023] Open
Abstract
As an extracellular vesicle, exosomes play an important role in intercellular information transmission, delivering cargos of the parent cell, such as RNA, DNA, proteins, and lipids, activating different signaling pathways in the target cell and regulating inflammation, angiogenesis, and tumor progression. In particular, exosomes secreted by tumor cells can change the function of surrounding cells, creating a microenvironment conducive to tumor growth and metastasis. For example, after macrophages phagocytose exosomes and accept their cargos, they activate macrophage polarization-related signaling pathways and polarize macrophages into M1 or M2 types to exert antitumor or protumor functions. Currently, the study of exosomes affecting the polarization of macrophages has attracted increasing attention. Therefore, this paper reviews relevant studies in this field to better understand the mechanism of exosome-induced macrophage polarization and provide evidence for exploring novel targets for tumor therapy and new diagnostic markers in the future.
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Affiliation(s)
- Siyuan Tan
- Department of Surgery, School of Medicine, Southeast University, Nanjing, 210009, Jiangsu Province, China
| | - Haodong Tang
- Department of Surgery, School of Medicine, Southeast University, Nanjing, 210009, Jiangsu Province, China
| | - Yang Wang
- Department of Surgery, School of Medicine, Southeast University, Nanjing, 210009, Jiangsu Province, China
- Department of Hepato-Pancreatico-Biliary Surgery, Zhongda Hospital Southeast University, Nanjing, 210009, Jiangsu Province, China
| | - Peng Xie
- Department of Surgery, School of Medicine, Southeast University, Nanjing, 210009, Jiangsu Province, China
- Department of Hepato-Pancreatico-Biliary Surgery, Zhongda Hospital Southeast University, Nanjing, 210009, Jiangsu Province, China
| | - Haifeng Li
- Department of Surgery, School of Medicine, Southeast University, Nanjing, 210009, Jiangsu Province, China
- Department of Hepato-Pancreatico-Biliary Surgery, Zhongda Hospital Southeast University, Nanjing, 210009, Jiangsu Province, China
| | - Zheng Zhang
- Department of Surgery, School of Medicine, Southeast University, Nanjing, 210009, Jiangsu Province, China
| | - Jiahua Zhou
- Department of Surgery, School of Medicine, Southeast University, Nanjing, 210009, Jiangsu Province, China
- Department of Hepato-Pancreatico-Biliary Surgery, Zhongda Hospital Southeast University, Nanjing, 210009, Jiangsu Province, China
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13
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Li J, Wang X, Ren M, He S, Zhao Y. Advances in experimental animal models of hepatocellular carcinoma. Cancer Med 2023; 12:15261-15276. [PMID: 37248746 PMCID: PMC10417182 DOI: 10.1002/cam4.6163] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 05/08/2023] [Accepted: 05/17/2023] [Indexed: 05/31/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a common malignant tumor with insidious early symptoms, easy metastasis, postoperative recurrence, poor drug efficacy, and a high drug resistance rate when surgery is missed, leading to a low 5-year survival rate. Research on the pathogenesis and drugs is particularly important for clinical treatment. Animal models are crucial for basic research, which is conducive to studying pathogenesis and drug screening more conveniently and effectively. An appropriate animal model can better reflect disease occurrence and development, and the process of anti-tumor immune response in the human body. This review summarizes the classification, characteristics, and advances in experimental animal models of HCC to provide a reference for researchers on model selection.
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Affiliation(s)
- Jing Li
- Department of GastroenterologyThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anPeople's Republic of China
| | - Xin Wang
- Department of GastroenterologyThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anPeople's Republic of China
| | - Mudan Ren
- Department of GastroenterologyThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anPeople's Republic of China
| | - Shuixiang He
- Department of GastroenterologyThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anPeople's Republic of China
| | - Yan Zhao
- Department of GastroenterologyThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anPeople's Republic of China
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14
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Hwang DB, Seo Y, Lee E, Won DH, Kim C, Kang M, Jeon Y, Kim HS, Park JW, Yun JW. Diagnostic potential of serum miR-532-3p as a circulating biomarker for experimental intrinsic drug-induced liver injury by acetaminophen and cisplatin in rats. Food Chem Toxicol 2023:113890. [PMID: 37308052 DOI: 10.1016/j.fct.2023.113890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Revised: 06/07/2023] [Accepted: 06/09/2023] [Indexed: 06/14/2023]
Abstract
Evaluating tissue injury largely depends on serum biochemical analysis despite insufficient tissue specificity and low sensitivity. Therefore, attention has been paid to the potential of microRNAs (miRNAs) to overcome the limitations of the current diagnostic tools, as tissue-enriched miRNAs are detected in the blood upon tissue injury. First, using a cisplatin-injected rats, we screened a specific pattern of altered hepatic miRNAs and their target mRNAs. Subsequently, we identified novel liver-specific circulating miRNAs for drug-induced liver injury by comparing miRNA expression changes in organs and serum. RNA sequencing revealed that 32 hepatic miRNAs were differentially expressed (DE) in the cisplatin-treated group. Furthermore, among the 1217 targets predicted using miRDB on these DE-miRNAs, 153 hepatic genes involved in different liver function-related pathways and processes were found to be dysregulated by cisplatin. Next, comparative analyses of the liver, kidneys, and serum DE-miRNAs were conducted to select circulating miRNA biomarker candidates reflecting drug-induced liver injury. Finally, among the four liver-specific circulating miRNAs selected based on their expression patterns in tissue and serum, miR-532-3p was increased in the serum after cisplatin or acetaminophen administration. Our findings suggest that miR-532-3p is potential as a serum biomarker for identifying drug-induced liver injury, leading to the accurate diagnosis.
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Affiliation(s)
- Da-Bin Hwang
- Department of Biotechnology, The Catholic University of Korea, Bucheon, 14662, Republic of Korea
| | - Yoojin Seo
- Department of Oral Biochemistry, Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan, 50612, Republic of Korea
| | - Eunji Lee
- Laboratory of Veterinary Toxicology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul, 08826, Republic of Korea
| | - Dong-Hoon Won
- Department of Biotechnology, The Catholic University of Korea, Bucheon, 14662, Republic of Korea
| | - Changuk Kim
- Department of Biotechnology, The Catholic University of Korea, Bucheon, 14662, Republic of Korea
| | - MinHwa Kang
- Laboratory of Veterinary Toxicology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul, 08826, Republic of Korea
| | - Young Jeon
- Laboratory of Veterinary Toxicology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul, 08826, Republic of Korea
| | - Hyung-Sik Kim
- Department of Oral Biochemistry, Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan, 50612, Republic of Korea
| | - Jun Won Park
- Division of Biomedical Convergence, College of Biomedical Science, Kangwon National University, Chuncheon, 24341, Republic of Korea
| | - Jun-Won Yun
- Laboratory of Veterinary Toxicology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul, 08826, Republic of Korea.
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15
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Yang S, Luo J, Zhang L, Feng L, He Y, Gao X, Xie S, Gao M, Luo D, Chang K, Chen M. A Smart Nano-Theranostic Platform Based on Dual-microRNAs Guided Self-Feedback Tetrahedral Entropy-Driven DNA Circuit. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023:e2301814. [PMID: 37085743 DOI: 10.1002/advs.202301814] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 04/03/2023] [Indexed: 05/03/2023]
Abstract
MicroRNAs (miRNAs) can act as oncogenes or tumor suppressors, capable of up or down-regulating gene expression during tumorigenesis; they are diagnostic biomarkers or therapeutic targets for tumors. To detect low abundance of intracellular oncogenic miRNAs (onco-miRNAs) and realize synergistic gene therapy of onco-miRNAs and tumor suppressors, a smart nano-theranostic platform based on dual-miRNAs guided self-feedback tetrahedral entropy-driven DNA circuit is created. The platform as a delivery vehicle is a DNA tetrahedral framework, in which the entropy-driven DNA circuit achieves a dual-miRNAs guided self-feedback, between an in situ amplification of the onco-miRNAs and activation of suppressor miRNAs release. To test this platform, dual-miRNAs are selected, miRNA-155, an up-regulated miRNA, as cancer indicators, and miRNA-122, a down-regulated miRNA as therapy targets in hepatocellular carcinoma, respectively. Through the circuit, the platform to detect onco-miRNAs at femtomolar level as well as visualized miRNAs inside cells, fixed tissues, and mice is programmed. Furthermore, triggered by miRNA-155, preloaded miRNA-122 is amplified via the self-feedback and released into target cells; the sudden increase of miRNA-122 and simultaneous decrease of miRNA-155 synergistically served as therapeutic drugs for gene regulation with enhanced antitumor efficacy and superior biosafety. It is envisioned that this nano-theranostic platform will initiate an essential step toward tumor theranostics in personalized/precise medicine.
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Affiliation(s)
- Sha Yang
- Department of Clinical Laboratory Medicine, Southwest Hospital, Third Military Medical University (Army Medical University), 30 Gaotanyan, Shapingba District, Chongqing, 400038, P. R. China
| | - Jie Luo
- Department of Clinical Laboratory Medicine, Southwest Hospital, Third Military Medical University (Army Medical University), 30 Gaotanyan, Shapingba District, Chongqing, 400038, P. R. China
| | - Ligai Zhang
- Department of Clinical Laboratory Medicine, Southwest Hospital, Third Military Medical University (Army Medical University), 30 Gaotanyan, Shapingba District, Chongqing, 400038, P. R. China
| | - Liu Feng
- Department of Clinical Laboratory Medicine, Southwest Hospital, Third Military Medical University (Army Medical University), 30 Gaotanyan, Shapingba District, Chongqing, 400038, P. R. China
| | - Yuan He
- Department of Clinical Laboratory Medicine, Southwest Hospital, Third Military Medical University (Army Medical University), 30 Gaotanyan, Shapingba District, Chongqing, 400038, P. R. China
| | - Xueping Gao
- Department of Clinical Laboratory Medicine, Southwest Hospital, Third Military Medical University (Army Medical University), 30 Gaotanyan, Shapingba District, Chongqing, 400038, P. R. China
| | - Shuang Xie
- Department of Clinical Laboratory Medicine, Southwest Hospital, Third Military Medical University (Army Medical University), 30 Gaotanyan, Shapingba District, Chongqing, 400038, P. R. China
| | - Mingxuan Gao
- Department of Clinical Laboratory Medicine, Southwest Hospital, Third Military Medical University (Army Medical University), 30 Gaotanyan, Shapingba District, Chongqing, 400038, P. R. China
| | - Dan Luo
- Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY, 14853-5701, USA
| | - Kai Chang
- Department of Clinical Laboratory Medicine, Southwest Hospital, Third Military Medical University (Army Medical University), 30 Gaotanyan, Shapingba District, Chongqing, 400038, P. R. China
| | - Ming Chen
- Department of Clinical Laboratory Medicine, Southwest Hospital, Third Military Medical University (Army Medical University), 30 Gaotanyan, Shapingba District, Chongqing, 400038, P. R. China
- College of Pharmacy and Laboratory Medicine, Third Military Medical University (Army Medical University), 30 Gaotanyan, Shapingba District, Chongqing, 400038, P. R. China
- State Key Laboratory of Trauma, Burn and Combined Injury, Third Military Medical University (Army Medical University), 30 Gaotanyan, Shapingba District, Chongqing, 400038, P. R. China
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16
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Lu X, Li Y, Li Y, Zhang X, Shi J, Feng H, Gao Y, Yu Z. Advances of multi-omics applications in hepatic precancerous lesions and hepatocellular carcinoma: The role of extracellular vesicles. Front Mol Biosci 2023; 10:1114594. [PMID: 37006626 PMCID: PMC10060991 DOI: 10.3389/fmolb.2023.1114594] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Accepted: 03/06/2023] [Indexed: 03/18/2023] Open
Abstract
Due to the lack of distinct early symptoms and specific biomarkers, most patients with hepatocellular carcinoma (HCC) are usually diagnosed at advanced stages, rendering the treatment ineffective and useless. Therefore, recognition of the malady at precancerous lesions and early stages is particularly important for improving patient outcomes. The interest in extracellular vesicles (EVs) has been growing in recent years with the accumulating knowledge of their multiple cargoes and related multipotent roles in the modulation of immune response and tumor progression. By virtue of the rapid advancement of high-throughput techniques, multiple omics, including genomics/transcriptomics, proteomics, and metabolomics/lipidomics, have been widely integrated to analyze the role of EVs. Comprehensive analysis of multi-omics data will provide useful insights for discovery of new biomarkers and identification of therapeutic targets. Here, we review the attainment of multi-omics analysis to the finding of the potential role of EVs in early diagnosis and the immunotherapy in HCC.
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Affiliation(s)
- Xiaona Lu
- Department of Liver Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yuyao Li
- Department of Liver Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yue Li
- Department of Liver Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xuemei Zhang
- Department of Liver Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jia Shi
- Department of Liver Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hai Feng
- Institute of Infectious Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- *Correspondence: Hai Feng, ; Yueqiu Gao, ; Zhuo Yu,
| | - Yueqiu Gao
- Department of Liver Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Infectious Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- *Correspondence: Hai Feng, ; Yueqiu Gao, ; Zhuo Yu,
| | - Zhuo Yu
- Department of Liver Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- *Correspondence: Hai Feng, ; Yueqiu Gao, ; Zhuo Yu,
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Behrooz M, Hajjarzadeh S, Kahroba H, Ostadrahimi A, Bastami M. Expression pattern of miR-193a, miR122, miR155, miR-15a, and miR146a in peripheral blood mononuclear cells of children with obesity and their relation to some metabolic and inflammatory biomarkers. BMC Pediatr 2023; 23:95. [PMID: 36859176 PMCID: PMC9976520 DOI: 10.1186/s12887-023-03867-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Accepted: 01/25/2023] [Indexed: 03/03/2023] Open
Abstract
BACKGROUND The widespread presence of childhood obesity has increased considerably over three decades. The present study was designed to investigate expression patterns of miR-146a, miR-155, miR-15a, miR-193a, and miR-122 in peripheral blood mononuclear cells (PBMCs) in children who are obese along with their association with metabolic and inflammatory biomarkers. METHODS Ninety test subjects were admitted. The profile of blood pressure, resting energy expenditure (REE), anthropometric measures, body composition, dietary intakes, physical activity levels, insulin, and lipid profile, fasting blood glucose (FBG), high-sensitivity C-reactive protein (hs-CRP), and pubertal stage have been measured. Total RNA (including small RNAs) was extracted from PBMCs. The expression levels of miRNAs were measured by stem-loop RT-qPCR. RESULTS The miR-155a expression level was significantly lower in obese children, children with high hs-CRP, and children with high-fat mass. Obese girls had significantly higher PBMC levels of miR-122. MiR-155a had a significant negative association with fasting insulin, HOMA-IR, and hs-CRP. There were significant positive associations between miR-193a and miR-122 expression levels and fasting insulin, HOMA-IR, and TG. MiR-15a was positively correlated with fasting insulin and HOMA-IR. Children with metabolic syndrome, insulin resistance, and high-fat mass had higher PBMC levels of miR-122 and miR-193a. Higher miR-193a and miR-122 levels were also detected in PBMCs of children with fast REE, compared to those with slow REE, and the subjects with high hs-CRP, respectively. CONCLUSION lower level of miR-155 expression in obese subjects and significant associations unfolds the need for more studies to detect the possible underlying mechanisms.
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Affiliation(s)
- Maryam Behrooz
- Department of Clinical Nutrition, School of Nutrition & Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.,Pediatric Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Samaneh Hajjarzadeh
- Student of Nutrition Sciences. Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Houman Kahroba
- Department of Toxicogenomics, GROW School of Oncology and Development Biology, Maastricht University, Maastricht, Netherlands.,Centre for Environmental Sciences, Hasselt University, Hasselt, Belgium
| | - Alireza Ostadrahimi
- Department of Clinical Nutrition, Nutrition Research Center, School of Nutrition & Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Milad Bastami
- Department of Medical Genetics, Tabriz University of Medical Sciences, Golgasht St, Attar Neyshabouri Av, Tabriz, Iran.
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18
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Gutiérrez-Cuevas J, Lucano-Landeros S, López-Cifuentes D, Santos A, Armendariz-Borunda J. Epidemiologic, Genetic, Pathogenic, Metabolic, Epigenetic Aspects Involved in NASH-HCC: Current Therapeutic Strategies. Cancers (Basel) 2022; 15:23. [PMID: 36612019 PMCID: PMC9818030 DOI: 10.3390/cancers15010023] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 12/12/2022] [Accepted: 12/14/2022] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and is the sixth most frequent cancer in the world, being the third cause of cancer-related deaths. Nonalcoholic steatohepatitis (NASH) is characterized by fatty infiltration, oxidative stress and necroinflammation of the liver, with or without fibrosis, which can progress to advanced liver fibrosis, cirrhosis and HCC. Obesity, metabolic syndrome, insulin resistance, and diabetes exacerbates the course of NASH, which elevate the risk of HCC. The growing prevalence of obesity are related with increasing incidence of NASH, which may play a growing role in HCC epidemiology worldwide. In addition, HCC initiation and progression is driven by reprogramming of metabolism, which indicates growing appreciation of metabolism in the pathogenesis of this disease. Although no specific preventive pharmacological treatments have recommended for NASH, dietary restriction and exercise are recommended. This review focuses on the molecular connections between HCC and NASH, including genetic and risk factors, highlighting the metabolic reprogramming and aberrant epigenetic alterations in the development of HCC in NASH. Current therapeutic aspects of NASH/HCC are also reviewed.
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Affiliation(s)
- Jorge Gutiérrez-Cuevas
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, University of Guadalajara, CUCS, Guadalajara 44340, Jalisco, Mexico
| | - Silvia Lucano-Landeros
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, University of Guadalajara, CUCS, Guadalajara 44340, Jalisco, Mexico
| | - Daniel López-Cifuentes
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, University of Guadalajara, CUCS, Guadalajara 44340, Jalisco, Mexico
| | - Arturo Santos
- Tecnologico de Monterrey, EMCS, Campus Guadalajara, Zapopan 45201, Jalisco, Mexico
| | - Juan Armendariz-Borunda
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, University of Guadalajara, CUCS, Guadalajara 44340, Jalisco, Mexico
- Tecnologico de Monterrey, EMCS, Campus Guadalajara, Zapopan 45201, Jalisco, Mexico
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19
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Boycott C, Beetch M, Yang T, Lubecka K, Ma Y, Zhang J, Kurzava Kendall L, Ullmer M, Ramsey BS, Torregrosa-Allen S, Elzey BD, Cox A, Lanman NA, Hui A, Villanueva N, de Conti A, Huan T, Pogribny I, Stefanska B. Epigenetic aberrations of gene expression in a rat model of hepatocellular carcinoma. Epigenetics 2022; 17:1513-1534. [PMID: 35502615 PMCID: PMC9586690 DOI: 10.1080/15592294.2022.2069386] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 03/22/2022] [Accepted: 04/14/2022] [Indexed: 11/15/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is mostly triggered by environmental and life-style factors and may involve epigenetic aberrations. However, a comprehensive documentation of the link between the dysregulated epigenome, transcriptome, and liver carcinogenesis is lacking. In the present study, Fischer-344 rats were fed a choline-deficient (CDAA, cancer group) or choline-sufficient (CSAA, healthy group) L-amino acid-defined diet. At the end of 52 weeks, transcriptomic alterations in livers of rats with HCC tumours and healthy livers were investigated by RNA sequencing. DNA methylation and gene expression were assessed by pyrosequencing and quantitative reverse-transcription PCR (qRT-PCR), respectively. We discovered 1,848 genes that were significantly differentially expressed in livers of rats with HCC tumours (CDAA) as compared with healthy livers (CSAA). Upregulated genes in the CDAA group were associated with cancer-related functions, whereas macronutrient metabolic processes were enriched by downregulated genes. Changes of highest magnitude were detected in numerous upregulated genes that govern key oncogenic signalling pathways, including Notch, Wnt, Hedgehog, and extracellular matrix degradation. We further detected perturbations in DNA methylating and demethylating enzymes, which was reflected in decreased global DNA methylation and increased global DNA hydroxymethylation. Four selected upregulated candidates, Mmp12, Jag1, Wnt4, and Smo, demonstrated promoter hypomethylation with the most profound decrease in Mmp12. MMP12 was also strongly overexpressed and hypomethylated in human HCC HepG2 cells as compared with primary hepatocytes, which coincided with binding of Ten-eleven translocation 1 (TET1). Our findings provide comprehensive evidence for gene expression changes and dysregulated epigenome in HCC pathogenesis, potentially revealing novel targets for HCC prevention/treatment.
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Affiliation(s)
- Cayla Boycott
- Food, Nutrition and Health Program, Faculty of Land and Food Systems, University of British Columbia, Vancouver, British Columbia, Canada
| | - Megan Beetch
- Food, Nutrition and Health Program, Faculty of Land and Food Systems, University of British Columbia, Vancouver, British Columbia, Canada
| | - Tony Yang
- Food, Nutrition and Health Program, Faculty of Land and Food Systems, University of British Columbia, Vancouver, British Columbia, Canada
| | - Katarzyna Lubecka
- Department of Biomedical Chemistry, Faculty of Health Sciences, Medical University of Lodz, Lodz, Poland
| | - Yuexi Ma
- Food, Nutrition and Health Program, Faculty of Land and Food Systems, University of British Columbia, Vancouver, British Columbia, Canada
| | - Jiaxi Zhang
- Food, Nutrition and Health Program, Faculty of Land and Food Systems, University of British Columbia, Vancouver, British Columbia, Canada
| | - Lucinda Kurzava Kendall
- Department of Nutrition Science, College of Health and Human Sciences, Purdue University, Indiana, USA
- Department of Internal Medicine, Ascension St. Vincent Hospital, Indianapolis, Indiana, USA
| | - Melissa Ullmer
- Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Benjamin S. Ramsey
- Purdue University Center for Cancer Research, Purdue University, West Lafayette, Indiana, USA
| | - Sandra Torregrosa-Allen
- Purdue University Center for Cancer Research, Purdue University, West Lafayette, Indiana, USA
| | - Bennett D. Elzey
- Purdue University Center for Cancer Research, Purdue University, West Lafayette, Indiana, USA
- Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, Indiana, USA
| | - Abigail Cox
- Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, Indiana, USA
| | - Nadia Atallah Lanman
- Purdue University Center for Cancer Research, Purdue University, West Lafayette, Indiana, USA
- Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, Indiana, USA
| | - Alisa Hui
- Department of Chemistry, Faculty of Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - Nathaniel Villanueva
- Department of Chemistry, Faculty of Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - Aline de Conti
- Division of Biochemical Toxicology, FDA-National Center for Toxicological Research, Jefferson, Arkansas, USA
| | - Tao Huan
- Department of Chemistry, Faculty of Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - Igor Pogribny
- Division of Biochemical Toxicology, FDA-National Center for Toxicological Research, Jefferson, Arkansas, USA
| | - Barbara Stefanska
- Food, Nutrition and Health Program, Faculty of Land and Food Systems, University of British Columbia, Vancouver, British Columbia, Canada
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20
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Rusu I, Pirlog R, Chiroi P, Nutu A, Puia VR, Fetti AC, Rusu DR, Berindan-Neagoe I, Al Hajjar N. The Implications of Noncoding RNAs in the Evolution and Progression of Nonalcoholic Fatty Liver Disease (NAFLD)-Related HCC. Int J Mol Sci 2022; 23:12370. [PMID: 36293225 PMCID: PMC9603983 DOI: 10.3390/ijms232012370] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 10/12/2022] [Accepted: 10/13/2022] [Indexed: 11/07/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver pathology worldwide. Meanwhile, liver cancer represents the sixth most common malignancy, with hepatocellular carcinoma (HCC) as the primary, most prevalent subtype. Due to the rising incidence of metabolic disorders, NAFLD has become one of the main contributing factors to HCC development. However, although NAFLD might account for about a fourth of HCC cases, there is currently a significant gap in HCC surveillance protocols regarding noncirrhotic NAFLD patients, so the majority of NAFLD-related HCC cases were diagnosed in late stages when survival chances are minimal. However, in the past decade, the focus in cancer genomics has shifted towards the noncoding part of the genome, especially on the microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), which have proved to be involved in the regulation of several malignant processes. This review aims to summarize the current knowledge regarding some of the main dysregulated, noncoding RNAs (ncRNAs) and their implications for NAFLD and HCC development. A central focus of the review is on miRNA and lncRNAs that can influence the progression of NAFLD towards HCC and how they can be used as potential screening tools and future therapeutic targets.
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Affiliation(s)
- Ioana Rusu
- Department of Pathology, Regional Institute of Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania
- 3rd Department of General Surgery, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400186 Cluj-Napoca, Romania
| | - Radu Pirlog
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania
| | - Paul Chiroi
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania
| | - Andreea Nutu
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania
| | - Vlad Radu Puia
- 3rd Department of General Surgery, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400186 Cluj-Napoca, Romania
- Department of Surgery, Regional Institute of Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania
| | - Alin Cornel Fetti
- 3rd Department of General Surgery, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400186 Cluj-Napoca, Romania
- Department of Surgery, Regional Institute of Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania
| | - Daniel Radu Rusu
- Department of Pathology, Regional Institute of Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania
| | - Ioana Berindan-Neagoe
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania
| | - Nadim Al Hajjar
- 3rd Department of General Surgery, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400186 Cluj-Napoca, Romania
- Department of Surgery, Regional Institute of Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania
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21
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Lee Y, Kim JH. The emerging roles of extracellular vesicles as intercellular messengers in liver physiology and pathology. Clin Mol Hepatol 2022; 28:706-724. [PMID: 35232008 PMCID: PMC9597227 DOI: 10.3350/cmh.2021.0390] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Accepted: 02/25/2022] [Indexed: 01/05/2023] Open
Abstract
Extracellular vesicles (EVs) are membrane-enclosed particles released from almost all cell types. EVs mediate intercellular communication by delivering their surface and luminal cargoes, including nucleic acids, proteins, and lipids, which reflect the pathophysiological conditions of their cellular origins. Hepatocytes and hepatic non-parenchymal cells utilize EVs to regulate a wide spectrum of biological events inside the liver and transfer them to distant organs through systemic circulation. The liver also receives EVs from multiple organs and integrates these extrahepatic signals that participate in pathophysiological processes. EVs have recently attracted growing attention for their crucial roles in maintaining and regulating hepatic homeostasis. This review summarizes the roles of EVs in intrahepatic and interorgan communications under different pathophysiological conditions of the liver, with a focus on chronic liver diseases including nonalcoholic steatohepatitis, alcoholic hepatitis, viral hepatitis, liver fibrosis, and hepatocellular carcinoma. This review also discusses recent progress for potential therapeutic applications of EVs by targeting or enhancing EV-mediated cellular communication for the treatment of liver diseases.
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Affiliation(s)
- Youngseok Lee
- Laboratory of Stem Cells and Tissue Regeneration, Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Korea
| | - Jong-Hoon Kim
- Laboratory of Stem Cells and Tissue Regeneration, Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Korea,Corresponding author : Jong-Hoon Kim Laboratory of Stem Cells and Tissue Regeneration, Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Korea Tel: +82-2-3290-3007, Fax: +82-2-3290-3040, E-mail:
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22
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Czaja AJ. Examining micro-ribonucleic acids as diagnostic and therapeutic prospects in autoimmune hepatitis. Expert Rev Clin Immunol 2022; 18:591-607. [PMID: 35510750 DOI: 10.1080/1744666x.2022.2074839] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Micro-ribonucleic acids modulate the immune response by affecting the post-transcriptional expression of genes that influence the proliferation and function of activated immune cells, including regulatory T cells. Individual expressions or patterns in peripheral blood and liver tissue may have diagnostic value, reflect treatment response, or become therapeutic targets. The goals of this review are to present the properties and actions of micro-ribonucleic acids, indicate the key individual expressions in autoimmune hepatitis, and describe prospective clinical applications in diagnosis and management. AREAS COVERED Abstracts were identified in PubMed using the search words "microRNAs", "microRNAs in liver disease", and "microRNAs in autoimmune hepatitis". The number of abstracts reviewed exceeded 2000, and the number of full-length articles reviewed was 108. EXPERT OPINION Individual micro-ribonucleic acids, miR-21, miR-122, and miR-155, have been associated with biochemical severity, histological grade of inflammation, and pivotal pathogenic mechanisms in autoimmune hepatitis. Antisense oligonucleotides that down-regulate deleterious individual gene expressions, engineered molecules that impair targeting of gene products, and drugs that non-selectively up-regulate the biogenesis of potentially deficient gene regulators are feasible treatment options. Micro-ribonucleic acids constitute an under-evaluated area in autoimmune hepatitis that promises to improve diagnosis, pathogenic concepts, and therapy.
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Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
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23
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Zou H, Wang L, Zhao J, Yuan Y, Wang T, Bian J, Liu Z. MiR-155 promotes cadmium-induced autophagy in rat hepatocytes by suppressing Rheb expression. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2021; 227:112895. [PMID: 34673407 DOI: 10.1016/j.ecoenv.2021.112895] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/04/2021] [Revised: 10/02/2021] [Accepted: 10/10/2021] [Indexed: 06/13/2023]
Abstract
Cadmium is an environmental pollutant that threatens the health of both humans and animals. Current studies have shown that while hepatotoxic damage induced by cadmium is closely related to autophagy, its intrinsic mechanism has not been elucidated. MicroRNA plays a regulatory role on different stages of autophagy. In this study, we investigated the mechanisms by which microRNA-155 (miR-155) regulate cadmium-induced hepatotoxicity in rat hepatocytes (BRL 3A cells) and in vivo. We found that cadmium exposure could cause liver injury in rats, resulting in a decreased liver index, increased alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) activity, hepatocyte steatosis, and ultrastructure damage. Cadmium exposure also induced autophagy in hepatocytes, resulting in increased expression of ATG5, Belin1, LC3II, and an increased number of autophagosomes. In addition, cadmium exposure upregulated miR-155 expression, downregulated Rheb mRNA expression, and downregulated the level of protein expression in the Rheb/mTOR signaling pathway in rat hepatocytes. The overexpression of miR-155 followed by cadmium exposure upregulated the level of autophagy in BRL3A cells, whereas miR-155 inhibition had the opposite effect. In addition, miR-155 negatively regulated Rheb. A dual-luciferase reporter assay verified the negative regulatory effect of miR-155 on Rheb targeting. Knockdown of Rheb downregulated cadmium-induced autophagy. Therefore, the Rheb/mTOR signaling can negatively regulate autophagy. The present study demonstrates that miR-155 promotes cadmium-induced autophagy in rat hepatocytes by suppressing Rheb expression.
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Affiliation(s)
- Hui Zou
- College of Veterinary Medicine, Yangzhou University, and Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, PR China
| | - Ling Wang
- College of Veterinary Medicine, Yangzhou University, and Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, PR China
| | - Jianya Zhao
- College of Veterinary Medicine, Yangzhou University, and Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, PR China; College of Public Health, Nantong University, Nantong, Jiangsu 226000, PR China
| | - Yan Yuan
- College of Veterinary Medicine, Yangzhou University, and Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, PR China
| | - Tao Wang
- College of Veterinary Medicine, Yangzhou University, and Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, PR China
| | - Jianchun Bian
- College of Veterinary Medicine, Yangzhou University, and Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, PR China
| | - Zongping Liu
- College of Veterinary Medicine, Yangzhou University, and Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, PR China.
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24
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Li Y, Guo L, Hou Z, Gong H, Yan M, Zhang B. Role of MicroRNA-155 in Triptolide-induced hepatotoxicity via the Nrf2-Dependent pathway. JOURNAL OF ETHNOPHARMACOLOGY 2021; 281:114489. [PMID: 34363931 DOI: 10.1016/j.jep.2021.114489] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Revised: 08/03/2021] [Accepted: 08/03/2021] [Indexed: 06/13/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Triptolide (TP), the main bioactive and toxic ingredient of Tripterygium wilfordii Hook F, causes severe toxicity, particularly for hepatotoxicity. However, the underlying mechanisms for its hepatotoxicity are not entirely clear. AIM OF THE STUDY The purpose of the study was to explore the role of miR-155, a microRNA closely related to various liver injuries and a regulator of the nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant pathway, in TP-induced liver injury in vitro and in vivo. MATERIALS AND METHODS First, in vitro L02 cells were treated with different concentrations of TP. The protein levels of Nrf2 and its downstream genes Heme oxygenase1 (HO-1) were determined by Western blot. The mRNA expression of miR-155, Nrf2, NAD(P)H: quinone oxidoreductase 1 (NQO1) and HO-1 were measured using qRT-PCR. And we transfected miR-155 inhibitor and miminc before TP treatment to determine the mRNA and/or protein levels of miR-155, Nrf2 and HO-1. Then, we further confirmed the interaction between miR-155 and Nrf2 pathway in TP-induced hepatic injury in BALB/C mice. The degree of liver injury was determined by HE staining and serum biochemical. The mRNA expression of miR-155 was examined with qRT-PCR and Nrf2 and HO-1 gene expression in liver were evaluated by immunohistochemistry and/or Western blot. RESULTS The results showed that TP significantly induced the expression of miR-155 both in L02 cells and in rodents liver tissue, and the inhibition of miR-155 could mitigate the hepatic damages caused by TP. Further experiments demonstrated that the inhibition of miR-155 reversed the down-regulation of Nrf2 and HO-1 by TP, while the miR-155 mimic enhanced the effects of TP. Animal experiments also showed that the inhibition of miR-155 by miR-155 antagomir reversed the decrease of Nrf2 induced by TP administration. CONCLUSIONS These results indicated that miR-155 played an important role in TP-induced hepatotoxicity by regulating the Nrf2 signaling pathway.
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Affiliation(s)
- Yao Li
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
| | - Lin Guo
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
| | - Zhenyan Hou
- Department of Pharmacy, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, 264000, China
| | - Hui Gong
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
| | - Miao Yan
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China.
| | - Bikui Zhang
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China.
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25
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Afonso MB, Rodrigues PM, Mateus-Pinheiro M, Simão AL, Gaspar MM, Majdi A, Arretxe E, Alonso C, Santos-Laso A, Jimenez-Agüero R, Eizaguirre E, Bujanda L, Pareja MJ, Banales JM, Ratziu V, Gautheron J, Castro RE, Rodrigues CMP. RIPK3 acts as a lipid metabolism regulator contributing to inflammation and carcinogenesis in non-alcoholic fatty liver disease. Gut 2021; 70:2359-2372. [PMID: 33361348 PMCID: PMC8588316 DOI: 10.1136/gutjnl-2020-321767] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Revised: 09/22/2020] [Accepted: 11/25/2020] [Indexed: 12/24/2022]
Abstract
OBJECTIVE Receptor-interacting protein kinase 3 (RIPK3) is a key player in necroptosis execution and an emerging metabolic regulator, whose contribution to non-alcoholic fatty liver disease (NAFLD) is controversial. We aimed to clarify the impact of RIPK3 signalling in the pathogenesis of human and experimental NAFLD. DESIGN RIPK3 levels were evaluated in two large independent cohorts of patients with biopsy proven NAFLD diagnosis and correlated with clinical and biochemical parameters. Wild-type (WT) or Ripk3-deficient (Ripk3-/-) mice were fed a choline-deficient L-amino acid-defined diet (CDAA) or an isocaloric control diet for 32 and 66 weeks. RESULTS RIPK3 increased in patients with non-alcoholic steatohepatitis (NASH) in both cohorts, correlating with hepatic inflammation and fibrosis. Accordingly, Ripk3 deficiency ameliorated CDAA-induced inflammation and fibrosis in mice at both 32 and 66 weeks. WT mice on the CDAA diet for 66 weeks developed preneoplastic nodules and displayed increased hepatocellular proliferation, which were reduced in Ripk3-/- mice. Furthermore, Ripk3 deficiency hampered tumourigenesis. Intriguingly, Ripk3-/- mice displayed increased body weight gain, while lipidomics showed that deletion of Ripk3 shifted hepatic lipid profiles. Peroxisome proliferator-activated receptor γ (PPARγ) was increased in Ripk3-/- mice and negatively correlated with hepatic RIPK3 in patients with NAFLD. Mechanistic studies established a functional link between RIPK3 and PPARγ in controlling fat deposition and fibrosis. CONCLUSION Hepatic RIPK3 correlates with NAFLD severity in humans and mice, playing a key role in managing liver metabolism, damage, inflammation, fibrosis and carcinogenesis. Targeting RIPK3 and its intricate signalling arises as a novel promising approach to treat NASH and arrest disease progression.
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Affiliation(s)
- Marta B Afonso
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Pedro M Rodrigues
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Miguel Mateus-Pinheiro
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - André L Simão
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Maria M Gaspar
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Amine Majdi
- Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine (CRSA), Paris, France
- Institute of Cardiometabolism and Nutrition (ICAN), Paris, France
| | - Enara Arretxe
- OWL Metabolomics, Bizkaia Technology Park, Derio, Spain
| | | | - Alvaro Santos-Laso
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), Ikerbasque, CIBERehd, San Sebastian, Spain
| | - Raul Jimenez-Agüero
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), Ikerbasque, CIBERehd, San Sebastian, Spain
| | - Emma Eizaguirre
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), Ikerbasque, CIBERehd, San Sebastian, Spain
| | - Luis Bujanda
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), Ikerbasque, CIBERehd, San Sebastian, Spain
| | | | - Jesus M Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), Ikerbasque, CIBERehd, San Sebastian, Spain
| | - Vlad Ratziu
- Institute of Cardiometabolism and Nutrition (ICAN), Paris, France
- Department of Hepatology, Assistance Publique-Hôpitaux de Paris (AP-HP), Pitié-Salpêtrière Hospital, Paris, France
- Sorbonne Université, Inserm, Centre de Recherche des Cordeliers (CRC), Paris, France
| | - Jeremie Gautheron
- Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine (CRSA), Paris, France
- Institute of Cardiometabolism and Nutrition (ICAN), Paris, France
| | - Rui E Castro
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Cecília M P Rodrigues
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
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Duan Y, Chen Z, Li H, Shen W, Zeng Y, Peng M, Hu P. Potential Molecular Targets of Tenofovir Disoproxil Fumarate for Alleviating Chronic Liver Diseases via a Non-Antiviral Effect in a Normal Mouse Model. Front Mol Biosci 2021; 8:763150. [PMID: 34869594 PMCID: PMC8635150 DOI: 10.3389/fmolb.2021.763150] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Accepted: 10/25/2021] [Indexed: 12/20/2022] Open
Abstract
Accumulating evidence suggests that tenofovir disoproxil fumarate (TDF) can attenuate liver fibrosis directly, the mechanism of which, however, has not been fully elucidated, and there is a paucity of data concerning whether TDF can also mitigate other chronic liver diseases (CLDs). We aimed to identify the molecular targets and potential mechanism of TDF itself in ameliorating CLDs. RNA-sequencing was performed on mouse liver tissues treated with TDF or normal saline. Then the differentially expressed genes (DEGs) were screened, and enrichment analyses of the function and signaling pathways of DEGs were performed with Database for Annotation, Visualization, and Integrated Discovery (DAVID) and Metascape. Next, protein-protein interaction (PPI) networks were constructed and module analyses were utilized to identify significant genes. Subsequently, the DisGeNET platform was used to identify the potential target genes of TDF in mitigating these diseases. Finally, prediction of the transcription factors (TFs) and microRNAs (miRNAs) of the target genes was done to conjecture the underlying mechanism by which TDF relieved CLDs. As a result, a total of 854 DEGs were identified, and the DEGs were involved mainly in "immunity," "inflammation," and "metabolism" processes. In addition, 50 significant genes were obtained via PPI construction and module analyses. Furthermore, by means of DisGeNET, 19 genes (Adra2a, Cxcl1, Itgam, Cxcl2, Ccr1, Ccl5, Cxcl5, Fabp5, Sell, Lilr4b, Ccr2, Tlr2, Lilrb4a, Tnf, Itgb2, Lgals3, Cxcr4, Sucnr1, and Mme) were identified to be associated with nine CLDs. Finally, 34 miRNAs (especially mmu-miR-155-5p) and 12 TFs (especially Nfkb1) were predicted to be upstream of the nine target genes (Cxcl1, Cxcl2, Ccl5, Ccr2, Sell, Tlr2, Tnf, Cxcr4, and Mme) of TDF in ameliorating CLDs. In conclusion, our study suggests that TDF have the potential to ameliorate CLDs independently of its antiviral activity by affecting the expression of genes involved in hepatic immune, inflammatory, and metabolic processes via mmu-miR-155-5p-NF-κB signaling. These findings provided prima facie evidence for using TDF in CHB patients with concurrent CLDs.
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Affiliation(s)
| | | | | | | | | | | | - Peng Hu
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Tan H, Wang N, Zhang C, Chan Y, Yuen M, Feng Y. Lysyl Oxidase-Like 4 Fosters an Immunosuppressive Microenvironment During Hepatocarcinogenesis. Hepatology 2021; 73:2326-2341. [PMID: 33068461 PMCID: PMC8251926 DOI: 10.1002/hep.31600] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2020] [Revised: 09/03/2020] [Accepted: 09/20/2020] [Indexed: 12/20/2022]
Abstract
BACKGROUND AND AIMS Lysyl oxidase-like 4 (LOXL4) is an amine oxidase that is primarily involved in extracellular matrix remodeling and is highly expressed in HCC tissues, but its functional role in mediating liver carcinogenesis is poorly understood. Therefore, we aimed to investigate the role of LOXL4 in hepatocarcinogenesis. APPROACH AND RESULTS Here, we demonstrate that hepatic LOXL4 expression was increased during the liver carcinogenesis in mice concomitantly fed a choline-deficient, l-amino acid-defined diet. LOXL4 was secreted by the neoplastic cells and primarily localized within hepatic macrophages through exosome internalization. Supplementation of LOXL4 had minimal effect on neoplastic cells. In vitro exposure of macrophages to LOXL4 invoked an immunosuppressive phenotype and activated programmed death ligand 1 (PD-L1) expression, which further suppressed the function of CD8+ T cells. Injection of LOXL4 promoted macrophages infiltration into the liver and accelerated tumor growth, which was further abolished by adoptive T-cell transfer or PD-L1 neutralization. Label-free proteomics analysis revealed that the immunosuppressive function of LOXL4 on macrophages primarily relied on interferon (IFN)-mediated signal transducer and activator of transcription-dependent PD-L1 activation. Hydrogen peroxide scavenger or copper chelation on macrophages abolished the IFN-mediated PD-L1 presentation by LOXL4. In human HCC tissue, expression of LOXL4 in CD68+ cells was positively correlated with PD-L1 level. High expression of LOXL4 in CD68+ cells and low expression of CD8A in tumor tissue cooperatively predict poor survival of patients with HCC. CONCLUSIONS LOXL4 facilitates immune evasion by tumor cells and leads to hepatocarcinogenesis. Our study unveils the role of LOXL4 in fostering an immunosuppressive microenvironment during hepatocarcinogenesis.
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Affiliation(s)
- Hor‐Yue Tan
- School of Chinese MedicineLi Ka Shing Faculty of MedicineThe University of Hong KongHong Kong SARChina
| | - Ning Wang
- School of Chinese MedicineLi Ka Shing Faculty of MedicineThe University of Hong KongHong Kong SARChina
| | - Cheng Zhang
- School of Chinese MedicineLi Ka Shing Faculty of MedicineThe University of Hong KongHong Kong SARChina
| | - Yau‐Tuen Chan
- School of Chinese MedicineLi Ka Shing Faculty of MedicineThe University of Hong KongHong Kong SARChina
| | - Man‐Fung Yuen
- Division of Gastroenterology and HepatologyDepartment of MedicineLi Ka Shing Faculty of MedicineThe University of Hong KongHong Kong SARChina
| | - Yibin Feng
- School of Chinese MedicineLi Ka Shing Faculty of MedicineThe University of Hong KongHong Kong SARChina
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Alimoradi N, Firouzabadi N, Fatehi R. Metformin and insulin-resistant related diseases: Emphasis on the role of microRNAs. Biomed Pharmacother 2021; 139:111662. [PMID: 34243629 DOI: 10.1016/j.biopha.2021.111662] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 04/16/2021] [Accepted: 04/22/2021] [Indexed: 12/14/2022] Open
Abstract
Metformin is one of the most prescribed drugs in type II diabetes (T2DM) which has recently found new applications in the prevention and treatment of various illnesses, from metabolic disorders to cardiovascular and age-related diseases. Metformin improves insulin resistance (IR) by modulating metabolic mechanisms and mitochondrial biogenesis. Alternation of microRNAs (miRs) in the treatment of IR-related illnesses has been observed by metformin therapy. MiRs are small non-coding RNAs that play important roles in RNA silencing, targeting the 3'untranslated region (3'UTR) of most mRNAs and inhibiting the translation of related proteins. As a result, their dysregulation is associated with many diseases. Metformin may alter miRs levels in the treatment of various diseases by AMPK-dependent or AMPK-independent mechanisms. Here, we summarized the therapeutic role of metformin by modifying the aberrant expression of miRs as potential biomarkers or therapeutic targets in diseases in which IR plays a key role.
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Affiliation(s)
- Nahid Alimoradi
- Department of Pharmacology & Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Negar Firouzabadi
- Department of Pharmacology & Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Reihaneh Fatehi
- Department of Pharmacology & Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
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29
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Sartorius K, An P, Winkler C, Chuturgoon A, Li X, Makarova J, Kramvis A. The Epigenetic Modulation of Cancer and Immune Pathways in Hepatitis B Virus-Associated Hepatocellular Carcinoma: The Influence of HBx and miRNA Dysregulation. Front Immunol 2021; 12:661204. [PMID: 33995383 PMCID: PMC8117219 DOI: 10.3389/fimmu.2021.661204] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 04/15/2021] [Indexed: 12/24/2022] Open
Abstract
Hepatitis B virus (HBV)-associated hepatocellular carcinoma (HBV-HCC) pathogenesis is fueled by persistent HBV infection that stealthily maintains a delicate balance between viral replication and evasion of the host immune system. HBV is remarkably adept at using a combination of both its own, as well as host machinery to ensure its own replication and survival. A key tool in its arsenal, is the HBx protein which can manipulate the epigenetic landscape to decrease its own viral load and enhance persistence, as well as manage host genome epigenetic responses to the presence of viral infection. The HBx protein can initiate epigenetic modifications to dysregulate miRNA expression which, in turn, can regulate downstream epigenetic changes in HBV-HCC pathogenesis. We attempt to link the HBx and miRNA induced epigenetic modulations that influence both the HBV and host genome expression in HBV-HCC pathogenesis. In particular, the review investigates the interplay between CHB infection, the silencing role of miRNA, epigenetic change, immune system expression and HBV-HCC pathogenesis. The review demonstrates exactly how HBx-dysregulated miRNA in HBV-HCC pathogenesis influence and are influenced by epigenetic changes to modulate both viral and host genome expression. In particular, the review identifies a specific subset of HBx induced epigenetic miRNA pathways in HBV-HCC pathogenesis demonstrating the complex interplay between HBV infection, epigenetic change, disease and immune response. The wide-ranging influence of epigenetic change and miRNA modulation offers considerable potential as a therapeutic option in HBV-HCC.
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Affiliation(s)
- Kurt Sartorius
- Hepatitis Virus Diversity Research Unit, School of Internal Medicine, University of the Witwatersrand, Johannesburg, South Africa.,Department of Public Health Medicine, School of Nursing and Public Health, University of KwaZulu-Natal, Durban, South Africa.,Department of Surgery, University of KwaZulu-Natal Gastrointestinal Cancer Research Centre, Durban, South Africa
| | - Ping An
- Basic Research Laboratory, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, United States
| | - Cheryl Winkler
- Basic Research Laboratory, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, United States
| | - Anil Chuturgoon
- Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Sciences, College of Health Science, University of KwaZulu-Natal, Durban, South Africa
| | - Xiaodong Li
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, China.,Department of Nutrition and Food Hygiene, School of Public Health, Soochow University, Suzhou, China
| | - Julia Makarova
- Faculty of Biology and Biotechnology, National Research University Higher School of Economics, Moscow, Russia.,Higher School of Economics University, Moscow, Russia
| | - Anna Kramvis
- Hepatitis Virus Diversity Research Unit, School of Internal Medicine, University of the Witwatersrand, Johannesburg, South Africa
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30
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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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31
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Ju C, Wang M, Tak E, Kim B, Emontzpohl C, Yang Y, Yuan X, Kutay H, Liang Y, Hall DR, Dar WA, Bynon JS, Carmeliet P, Ghoshal K, Eltzschig HK. Hypoxia-inducible factor-1α-dependent induction of miR122 enhances hepatic ischemia tolerance. J Clin Invest 2021; 131:140300. [PMID: 33792566 PMCID: PMC8011886 DOI: 10.1172/jci140300] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Accepted: 02/10/2021] [Indexed: 12/29/2022] Open
Abstract
Hepatic ischemia and reperfusion (IR) injury contributes to the morbidity and mortality associated with liver transplantation. microRNAs (miRNAs) constitute a family of noncoding RNAs that regulate gene expression at the posttranslational level through the repression of specific target genes. Here, we hypothesized that miRNAs could be targeted to enhance hepatic ischemia tolerance. A miRNA screen in a murine model of hepatic IR injury pointed us toward the liver-specific miRNA miR122. Subsequent studies in mice with hepatocyte-specific deletion of miR122 (miR122loxP/loxP Alb-Cre+ mice) during hepatic ischemia and reperfusion revealed exacerbated liver injury. Transcriptional studies implicated hypoxia-inducible factor-1α (HIF1α) in the induction of miR122 and identified the oxygen-sensing prolyl hydroxylase domain 1 (PHD1) as a miR122 target. Further studies indicated that HIF1α-dependent induction of miR122 participated in a feed-forward pathway for liver protection via the enhancement of hepatic HIF responses through PHD1 repression. Moreover, pharmacologic studies utilizing nanoparticle-mediated miR122 overexpression demonstrated attenuated liver injury. Finally, proof-of-principle studies in patients undergoing orthotopic liver transplantation showed elevated miR122 levels in conjunction with the repression of PHD1 in post-ischemic liver biopsies. Taken together, the present findings provide molecular insight into the functional role of miR122 in enhancing hepatic ischemia tolerance and suggest the potential utility of pharmacologic interventions targeting miR122 to dampen hepatic injury during liver transplantation.
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Affiliation(s)
- Cynthia Ju
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Texas, USA
| | - Meng Wang
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Texas, USA
| | - Eunyoung Tak
- Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Boyun Kim
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Texas, USA
| | - Christoph Emontzpohl
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Texas, USA
| | - Yang Yang
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Texas, USA
| | - Xiaoyi Yuan
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Texas, USA
| | - Huban Kutay
- Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
| | - Yafen Liang
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Texas, USA
| | - David R. Hall
- Department of Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Wasim A. Dar
- Department of Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - J. Steve Bynon
- Department of Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Peter Carmeliet
- Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, and
- Center for Cancer Biology, Department of Oncology, Katholieke University Leuven, Leuven, Belgium
| | - Kalpana Ghoshal
- Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
- Department of Pathology, The Ohio State University, Columbus, Ohio, USA
| | - Holger K. Eltzschig
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Texas, USA
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32
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Morishita A, Oura K, Tadokoro T, Fujita K, Tani J, Masaki T. MicroRNAs in the Pathogenesis of Hepatocellular Carcinoma: A Review. Cancers (Basel) 2021; 13:cancers13030514. [PMID: 33572780 PMCID: PMC7866004 DOI: 10.3390/cancers13030514] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 01/22/2021] [Accepted: 01/25/2021] [Indexed: 12/11/2022] Open
Abstract
Simple Summary Hepatocellular carcinoma (HCC) is one of the most frequently occurring cancers, and the prognosis for late-stage HCC remains poor. A better understanding of the pathogenesis of HCC is expected to improve outcomes. MicroRNAs (miRNAs) are small, noncoding, single-stranded RNAs that regulate the expression of various target genes, including those in cancer-associated genomic regions or fragile sites in various human cancers. We summarize the central roles of miRNAs in the pathogenesis of HCC and discuss their potential utility as valuable biomarkers and new therapeutic agents for HCC. Abstract Hepatocellular carcinoma (HCC) is the seventh most frequent cancer and the fourth leading cause of cancer mortality worldwide. Despite substantial advances in therapeutic strategies, the prognosis of late-stage HCC remains dismal because of the high recurrence rate. A better understanding of the etiology of HCC is therefore necessary to improve outcomes. MicroRNAs (miRNAs) are small, endogenous, noncoding, single-stranded RNAs that modulate the expression of their target genes at the posttranscriptional and translational levels. Aberrant expression of miRNAs has frequently been detected in cancer-associated genomic regions or fragile sites in various human cancers and has been observed in both HCC cells and tissues. The precise patterns of aberrant miRNA expression differ depending on disease etiology, including various causes of hepatocarcinogenesis, such as viral hepatitis, alcoholic liver disease, or nonalcoholic steatohepatitis. However, little is known about the underlying mechanisms and the association of miRNAs with the pathogenesis of HCC of various etiologies. In the present review, we summarize the key mechanisms of miRNAs in the pathogenesis of HCC and emphasize their potential utility as valuable diagnostic and prognostic biomarkers, as well as innovative therapeutic targets, in HCC diagnosis and treatment.
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Zeng J, Zhang D, Wan X, Bai Y, Yuan C, Wang T, Yuan D, Zhang C, Liu C. Chlorogenic Acid Suppresses miR-155 and Ameliorates Ulcerative Colitis through the NF-κB/NLRP3 Inflammasome Pathway. Mol Nutr Food Res 2020; 64:e2000452. [PMID: 33078870 DOI: 10.1002/mnfr.202000452] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Revised: 10/08/2020] [Indexed: 12/12/2022]
Abstract
SCOPE The over-activation of the nucleotide-binding domain like receptor protein 3 (NLRP3) inflammasome plays an important role in the pathogenesis of ulcerative colitis (UC). Chlorogenic acid (CGA) exposure is identified as an effective strategy for repressing inflammatory responses. METHODS AND RESULTS In this study, the NLRP3 inflammasome model with LPS/ATP-induced RAW264.7 cells in vitro and dextran-sulfate-sodium (DSS)-induced colitis in mice are used to evaluate the effect of CGA on NLRP3 inflammasome-related signaling. The results suggest that CGA suppressed the expression of NLRP3 inflammasome-related genes (apoptosis-associated speck-like protein containing CARD (ASC), cysteine-requiring aspartate protease (Caspase)-1 p45, Caspase-1 p20, pro-/cleaved-interleukin (IL)-1β, pro-/cleaved-IL-18), p-nuclear factor kappa B (NF-κB) protein, and miR-155 in mice with colitis. Gain- and loss-of-function studies of miR-155 are performed to elucidate its role in inflammation. Moreover, activation of the NF-κB/NLRP3 inflammasome pathway and miR-155 expression is investigated. CGA exposure in lipopolysaccharide (LPS)/adenosine triphosphate (ATP)-stimulated RAW264.7 cells leads to a decrease in p-NK-κB and NLRP3 inflammasome-related proteins, which is dependent on the downregulation of miR-155 expression. CONCLUSIONS These findings indicate that CGA prevented colitis by downregulating miR-155 expression and inactivating the NF-κB/NLRP3 inflammasome pathway in macrophages. The current study has promising therapeutic implications in the treatment of UC.
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Affiliation(s)
- Junhao Zeng
- College of Medical Science, China Three Gorges University, Yichang, Hubei, 443000, China
| | - Dengqing Zhang
- College of Medical Science, China Three Gorges University, Yichang, Hubei, 443000, China
| | - Xiaoyu Wan
- College of Medical Science, China Three Gorges University, Yichang, Hubei, 443000, China
| | - Yuanling Bai
- College of Medical Science, China Three Gorges University, Yichang, Hubei, 443000, China
| | - Chengfu Yuan
- College of Medical Science, China Three Gorges University, Yichang, Hubei, 443000, China
| | - Ting Wang
- College of Medical Science, China Three Gorges University, Yichang, Hubei, 443000, China
| | - Ding Yuan
- College of Medical Science, China Three Gorges University, Yichang, Hubei, 443000, China
| | - Changcheng Zhang
- College of Medical Science, China Three Gorges University, Yichang, Hubei, 443000, China
| | - Chaoqi Liu
- College of Medical Science, China Three Gorges University, Yichang, Hubei, 443000, China
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Molecular and Functional Roles of MicroRNAs in the Progression of Hepatocellular Carcinoma-A Review. Int J Mol Sci 2020; 21:ijms21218362. [PMID: 33171811 PMCID: PMC7664704 DOI: 10.3390/ijms21218362] [Citation(s) in RCA: 78] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2020] [Revised: 11/05/2020] [Accepted: 11/05/2020] [Indexed: 12/11/2022] Open
Abstract
Liver cancer is the fourth leading cause of cancer deaths globally, of which hepatocellular carcinoma (HCC) is the major subtype. Viral hepatitis B and C infections, alcohol abuse, and metabolic disorders are multiple risk factors for liver cirrhosis and HCC development. Although great therapeutic advances have been made in recent decades, the prognosis for HCC patients remains poor due to late diagnosis, chemotherapy failure, and frequent recurrence. MicroRNAs (miRNAs) are endogenous, non-coding RNAs that regulate various molecular biological phenomena by suppressing the translation of target messenger RNAs (mRNAs). miRNAs, which often become dysregulated in malignancy, control cell proliferation, migration, invasion, and development in HCC by promoting or suppressing tumors. Exploring the detailed mechanisms underlying miRNA-mediated HCC development and progression can likely improve the outcomes of patients with HCC. This review summarizes the molecular and functional roles of miRNAs in the pathogenesis of HCC. Further, it elucidates the utility of miRNAs as novel biomarkers and therapeutic targets.
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35
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Yin L, Cai W, Liang Y, Yao J, Wang X, Shen J. In situ self-assembly of Au-antimiR-155 nanocomplexes mediates TLR3-dependent apoptosis in hepatocellular carcinoma cells. Aging (Albany NY) 2020; 13:241-261. [PMID: 33173017 PMCID: PMC7834998 DOI: 10.18632/aging.103799] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Accepted: 07/06/2020] [Indexed: 02/07/2023]
Abstract
MicroRNA 155 (miRNA-155) is frequently dysregulated in hepatocellular carcinoma (HCC) and other cancer types. Toll-like receptor 3 (TLR3), a putative miR-155 target, plays a key role in liver pathophysiology, and its downregulation in HCC cells is associated with apoptosis evasion and poor outcomes. Herein, we examined the ability of in situ self-assembled Au-antimiR-155 nanocomplexes (Au-antimiRNA NCs) to activate TLR3 signaling in HCC cells. Gene expression analysis confirmed an inverse relationship between miR-155 and TLR3 expression in HCC samples, and marked upregulation of miR-155 was observed in HCC cells but not in normal L02 hepatocytes. RNA immunoprecipitation confirmed physical interaction between miR-155 and TLR3, while negative regulation of TLR3 expression by miR-155 was demonstrated by luciferase reporter assays. Au-antimiR-155 NCs were self-assembled within HepG2 HCC cells, but not within control L02 cells. They efficiently silenced miR-155, thereby inhibiting proliferation and migration and inducing apoptosis in HepG2 cells. Molecular analyses suggested these effects are secondary to TLR3 signaling mediating NF-κB transcription, caspase-8 activation, and interleukin-1β (IL-1β) release. Our results provide a basis for future studies examining the in vivo applicability of this novel Au-antimiRNA NCs delivery system to halt HCC progression by activating pro-apoptotic TLR3 signaling.
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Affiliation(s)
- Liang Yin
- Department of Endocrinology, Shunde Hospital of Southern Medical University, The First People's Hospital of Shunde Foshan, Shunde 528300, P. R. China
| | - Weijuan Cai
- State Key Laboratory of Bioelectronics, Chien-Shiung Wu Lab, School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, P. R. China
| | - Yongqian Liang
- Department of Endocrinology, Shunde Hospital of Southern Medical University, The First People's Hospital of Shunde Foshan, Shunde 528300, P. R. China
| | - Jie Yao
- Central Laboratory, Shunde Hospital of Southern Medical University, The First People's Hospital of Shunde Foshan, Shunde 528300, P. R. China
| | - Xuemei Wang
- State Key Laboratory of Bioelectronics, Chien-Shiung Wu Lab, School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, P. R. China
| | - Jie Shen
- Department of Endocrinology, Shunde Hospital of Southern Medical University, The First People's Hospital of Shunde Foshan, Shunde 528300, P. R. China
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36
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Sartorius K, Swadling L, An P, Makarova J, Winkler C, Chuturgoon A, Kramvis A. The Multiple Roles of Hepatitis B Virus X Protein (HBx) Dysregulated MicroRNA in Hepatitis B Virus-Associated Hepatocellular Carcinoma (HBV-HCC) and Immune Pathways. Viruses 2020; 12:v12070746. [PMID: 32664401 PMCID: PMC7412373 DOI: 10.3390/v12070746] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 07/08/2020] [Accepted: 07/09/2020] [Indexed: 12/11/2022] Open
Abstract
Currently, the treatment of hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) [HBV-HCC] relies on blunt tools that are unable to offer effective therapy for later stage pathogenesis. The potential of miRNA to treat HBV-HCC offer a more targeted approach to managing this lethal carcinoma; however, the complexity of miRNA as an ancillary regulator of the immune system remains poorly understood. This review examines the overlapping roles of HBx-dysregulated miRNA in HBV-HCC and immune pathways and seeks to demonstrate that specific miRNA response in immune cells is not independent of their expression in hepatocytes. This interplay between the two pathways may provide us with the possibility of using candidate miRNA to manipulate this interaction as a potential therapeutic option.
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Affiliation(s)
- Kurt Sartorius
- Faculty of Commerce, Law and Management, University of the Witwatersrand, Johannesburg 2050, South Africa
- Department of Public Health Medicine, School of Nursing and Public Health, University of KwaZulu-Natal, Durban 4041, South Africa;
- UKZN Gastrointestinal Cancer Research Centre, Durban 4041, South Africa
- Correspondence:
| | - Leo Swadling
- Division of Infection and Immunity, University College London, London WC1E6BT, UK;
| | - Ping An
- Basic Research Laboratory, Centre for Cancer Research, National Cancer Institute, Leidos Biomedical Research, Inc. Frederick Nat. Lab. for Cancer Research, Frederick, MD 20878, USA; (P.A.); (C.W.)
| | - Julia Makarova
- National Research University Higher School of Economics, Faculty of Biology and Biotechnology, 10100 Moscow, Russia;
| | - Cheryl Winkler
- Basic Research Laboratory, Centre for Cancer Research, National Cancer Institute, Leidos Biomedical Research, Inc. Frederick Nat. Lab. for Cancer Research, Frederick, MD 20878, USA; (P.A.); (C.W.)
| | - Anil Chuturgoon
- Department of Public Health Medicine, School of Nursing and Public Health, University of KwaZulu-Natal, Durban 4041, South Africa;
| | - Anna Kramvis
- Hepatitis Virus Diversity Research Unit, Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2050, South Africa;
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Lee TJ, Yuan X, Kerr K, Yoo JY, Kim DH, Kaur B, Eltzschig HK. Strategies to Modulate MicroRNA Functions for the Treatment of Cancer or Organ Injury. Pharmacol Rev 2020; 72:639-667. [PMID: 32554488 PMCID: PMC7300323 DOI: 10.1124/pr.119.019026] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Cancer and organ injury-such as that occurring in the perioperative period, including acute lung injury, myocardial infarction, and acute gut injury-are among the leading causes of death in the United States and impose a significant impact on quality of life. MicroRNAs (miRNAs) have been studied extensively during the last two decades for their role as regulators of gene expression, their translational application as diagnostic markers, and their potential as therapeutic targets for disease treatment. Despite promising preclinical outcomes implicating miRNA targets in disease treatment, only a few miRNAs have reached clinical trials. This likely relates to difficulties in the delivery of miRNA drugs to their targets to achieve efficient inhibition or overexpression. Therefore, understanding how to efficiently deliver miRNAs into diseased tissues and specific cell types in patients is critical. This review summarizes current knowledge on various approaches to deliver therapeutic miRNAs or miRNA inhibitors and highlights current progress in miRNA-based disease therapy that has reached clinical trials. Based on ongoing advances in miRNA delivery, we believe that additional therapeutic approaches to modulate miRNA function will soon enter routine medical treatment of human disease, particularly for cancer or perioperative organ injury. SIGNIFICANCE STATEMENT: MicroRNAs have been studied extensively during the last two decades in cancer and organ injury, including acute lung injury, myocardial infarction, and acute gut injury, for their regulation of gene expression, application as diagnostic markers, and therapeutic potentials. In this review, we specifically emphasize the pros and cons of different delivery approaches to modulate microRNAs, as well as the most recent exciting progress in the field of therapeutic targeting of microRNAs for disease treatment in patients.
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Affiliation(s)
- Tae Jin Lee
- Departments of Neurosurgery (T.J.L., K.K., J.Y.Y., D.H.K., B.K.) and Anesthesiology (X.Y., H.K.E.), McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas
| | - Xiaoyi Yuan
- Departments of Neurosurgery (T.J.L., K.K., J.Y.Y., D.H.K., B.K.) and Anesthesiology (X.Y., H.K.E.), McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas
| | - Keith Kerr
- Departments of Neurosurgery (T.J.L., K.K., J.Y.Y., D.H.K., B.K.) and Anesthesiology (X.Y., H.K.E.), McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas
| | - Ji Young Yoo
- Departments of Neurosurgery (T.J.L., K.K., J.Y.Y., D.H.K., B.K.) and Anesthesiology (X.Y., H.K.E.), McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas
| | - Dong H Kim
- Departments of Neurosurgery (T.J.L., K.K., J.Y.Y., D.H.K., B.K.) and Anesthesiology (X.Y., H.K.E.), McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas
| | - Balveen Kaur
- Departments of Neurosurgery (T.J.L., K.K., J.Y.Y., D.H.K., B.K.) and Anesthesiology (X.Y., H.K.E.), McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas
| | - Holger K Eltzschig
- Departments of Neurosurgery (T.J.L., K.K., J.Y.Y., D.H.K., B.K.) and Anesthesiology (X.Y., H.K.E.), McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas
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Venniyoor A. PTEN: A Thrifty Gene That Causes Disease in Times of Plenty? Front Nutr 2020; 7:81. [PMID: 32582754 PMCID: PMC7290048 DOI: 10.3389/fnut.2020.00081] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Accepted: 05/06/2020] [Indexed: 12/15/2022] Open
Abstract
The modern obesity epidemic with associated disorders of metabolism and cancer has been attributed to the presence of "thrifty genes". In the distant past, these genes helped the organism to improve energy efficiency and store excess energy safely as fat to survive periods of famine, but in the present day obesogenic environment, have turned detrimental. I propose PTEN as the likely gene as it has functions that span metabolism, cancer and reproduction, all of which are deranged in obesity and insulin resistance. The activity of PTEN can be calibrated in utero by availability of nutrients by the methylation arm of the epigenetic pathway. Deficiency of protein and choline has been shown to upregulate DNA methyltransferases (DNMT), especially 1 and 3a; these can then methylate promoter region of PTEN and suppress its expression. Thus, the gene is tuned like a metabolic rheostat proportional to the availability of specific nutrients, and the resultant "dose" of the protein, which sits astride and negatively regulates the insulin-PI3K/AKT/mTOR pathway, decides energy usage and proliferation. This "fixes" the metabolic capacity of the organism periconceptionally to a specific postnatal level of nutrition, but when faced with a discordant environment, leads to obesity related diseases.
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Affiliation(s)
- Ajit Venniyoor
- Department of Medical Oncology, National Oncology Centre, The Royal Hospital, Muscat, Oman
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Non-Coding RNAs: Regulating Disease Progression and Therapy Resistance in Hepatocellular Carcinoma. Cancers (Basel) 2020; 12:cancers12051243. [PMID: 32429062 PMCID: PMC7281199 DOI: 10.3390/cancers12051243] [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] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 05/12/2020] [Accepted: 05/12/2020] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC), the primary liver cancer arising from hepatocytes, is a universal health problem and one of the most common malignant tumors. Surgery followed by chemotherapy as well as tyrosine kinase inhibitors (TKIs), such as sorafenib, are primary treatment procedures for HCC, but recurrence of disease because of therapy resistance results in high mortality. It is necessary to identify novel regulators of HCC for developing effective targeted therapies that can significantly interfere with progression of the disease process. Non-coding RNAs (ncRNAs) are an abundant group of versatile RNA transcripts that do not translate into proteins, rather serve as potentially functional RNAs. The role of ncRNAs in regulating diverse aspects of the carcinogenesis process are gradually being elucidated. Recent advances in RNA sequencing technology have identified a plethora of ncRNAs regulating all aspects of hepatocarcinogenesis process and serving as potential prognostic or diagnostic biomarkers. The present review provides a comprehensive description of the biological roles of ncRNAs in disease process and therapy resistance, and potential clinical application of these ncRNAs in HCC.
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MiR-155 and MiR-665 Role as Potential Non-invasive Biomarkers for Hepatocellular Carcinoma in Egyptian Patients with Chronic Hepatitis C Virus Infection. J Transl Int Med 2020; 8:32-40. [PMID: 32435610 PMCID: PMC7227164 DOI: 10.2478/jtim-2020-0006] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Background and Objectives Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer associated death globally. Serum micro RNAs are full of potential as noninvasive biomarkers. Here, we aim to assess the performance of serum MicroRNA-155 and MicroRNA-665 as diagnostic biomarker for HCC comparing to AFP. Methods Serum samples were collected from 200 subjects (40 healthy control, 80 chronic hepatitis C patients with cirrhosis and without HCC (LC) and 80 HCC patients currently infected by hepatitis C infection and didn’t start the treatment). The HCC patients didn’t include alcoholic liver disease, nonalcoholic fatty liver disease nor autoimmune liver disease. MicroRNA-155 and MicroRNA-665 expression were measured by real-time quantitative PCR (RT-qPCR), while AFP level was assessed by ELISA method. Results Both miR-155 and miR-665 were significantly elevated in HCC group as compared to both control and LC groups. The comparison between LC and HCC patients revealed that the serum level of miR-155 was a significant increase in HCC patients compared to LC patients; however, the serum level of miR-665 didn’t show any significant difference between the same two groups. MiR-665 expression level showed a direct correlation with tumor size in HCC patients. Conclusions Using measurement against AFP level in serum, miR-665 is considered a promising serum biomarker for the diagnosis of HCC patients among the LC patients without HCC. MiR-155 didn’t provide a better performance than serum AFP as a diagnostic biomarker among the same group. MiR-665 may serve as a good indicator for HCC prognosis.
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Pratedrat P, Chuaypen N, Nimsamer P, Payungporn S, Pinjaroen N, Sirichindakul B, Tangkijvanich P. Diagnostic and prognostic roles of circulating miRNA-223-3p in hepatitis B virus-related hepatocellular carcinoma. PLoS One 2020; 15:e0232211. [PMID: 32330203 PMCID: PMC7182200 DOI: 10.1371/journal.pone.0232211] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Accepted: 04/09/2020] [Indexed: 02/06/2023] Open
Abstract
Background Circulating microRNAs (miRNAs) have been shown to dysregulate in many cancer types including hepatocellular carcinoma (HCC). The purpose of this study was to examine the potential diagnostic or prognostic roles of circulating miRNAs in patients with hepatitis B virus (HBV)-related HCC. Methods Paired cancerous and adjacent non-cancerous liver tissue specimens of patients with HBV-related HCC were used as a discovery set for screening 800 miRNAs by a Nanostring quantitative assay. Differentially expressed miRNAs were then examined by SYBR green quantitative RT-PCR in a validation cohort of serum samples obtained from 70 patients with HBV-related HCC, 70 HBV patients without HCC and 50 healthy controls. Results The discovery set identified miR-223-3p, miR-199a-5p and miR-451a significantly lower expressed in cancerous tissues compared with non-cancerous tissues. In the validated cohort, circulating miR-223-3p levels were significantly lower in the HCC group compared with the other groups. The combined use of serum alpha-fetoprotein and miR-223-3p displayed high sensitivity for detecting early HCC (85%) and intermediate/advanced stage HCC (100%). Additionally, serum miR-223-3p had a negative correlation with tumor size and BCLC stage. On multivariate analysis, serum miR-223-3p was identified as an independent prognostic factor of overall survival in patients with HCC. In contrast, circulating miRNA-199a-5p and miR-451a did not show any clinical benefit for the diagnosis and prognostic prediction of HCC. Conclusions Our results demonstrated that miR-223-3p was differentially expressed in cancerous compared with paired adjacent non-cancerous tissues. In addition, circulating miRNA-223-3p could represent a novel diagnostic and prognostic marker for patients with HBV-related HCC.
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Affiliation(s)
- Pornpitra Pratedrat
- Center of Excellence in Hepatitis and Liver Cancer, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Natthaya Chuaypen
- Center of Excellence in Hepatitis and Liver Cancer, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Pattaraporn Nimsamer
- Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Sunchai Payungporn
- Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Nutcha Pinjaroen
- Department of Radiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | | | - Pisit Tangkijvanich
- Center of Excellence in Hepatitis and Liver Cancer, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
- * E-mail:
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Bandopadhyay M, Bharadwaj M. Exosomal miRNAs in hepatitis B virus related liver disease: a new hope for biomarker. Gut Pathog 2020; 12:23. [PMID: 32346400 PMCID: PMC7183117 DOI: 10.1186/s13099-020-00353-w] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Accepted: 03/31/2020] [Indexed: 02/06/2023] Open
Abstract
The World Health Organisation, in its 2019 progress report on HIV, viral hepatitis and STDs indicates that 257 million people are afflicted with chronic HBV infections, of which, 1 million patients lose their lives every year due to HBV related chronic liver diseases including serious complications such as liver cirrhosis and hepatocellular carcinoma. The course of HBV infection and associated liver injury depend on several host factors, genetic variability of the virus, and the host viral interplay. The challenge of medical science is the early diagnosis/identification of the potential for development of fatal complications like liver cirrhosis and HCC so that timely medical intervention can improve the chances of survival. Currently, neither the vaccination regime nor the diagnostic methods are completely effective as reflected in the high number of annual deaths. It is evident from numerous publications that microRNAs (miRNAs) are the critical regulators of gene expression and various cellular processes like proliferation, development, differentiation, apoptosis and tumorigenesis. Expressions of these diminutive RNAs are significantly affected in cancerous tissues as a result of numerous genomic and epigenetic modifications. Exosomes are membrane-derived vesicles (30–100 nm) secreted by normal as well as malignant cells, and are present in all body fluids. They are recognized as critical molecules in intercellular communication between cells through horizontal transfer of information via their cargo, which includes selective proteins, mRNAs and miRNAs. Exosomal miRNAs are transferred to recipient cells where they can regulate target gene expression. This provides an insight into the elementary biology of cancer progression and therefore the development of therapeutic approaches. This concise review outlines various on-going research on miRNA mediated regulation of HBV pathogenesis with special emphasis on association of exosomal miRNA in advanced stage liver disease like hepatocellular carcinoma. This review also discusses the possible use of exosomal miRNAs as biomarkers in the early detection of HCC and liver cirrhosis.
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Affiliation(s)
- Manikankana Bandopadhyay
- Molecular Genetics and Biochemistry, National Institute of Cancer Prevention and Research (NICPR), Indian Council of Medical Research (ICMR), Noida, Uttar Pradesh 201301 India
| | - Mausumi Bharadwaj
- Molecular Genetics and Biochemistry, National Institute of Cancer Prevention and Research (NICPR), Indian Council of Medical Research (ICMR), Noida, Uttar Pradesh 201301 India
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Chen S, Chen D, Yang H, Wang X, Wang J, Xu C. Uric acid induced hepatocytes lipid accumulation through regulation of miR-149-5p/FGF21 axis. BMC Gastroenterol 2020; 20:39. [PMID: 32070295 PMCID: PMC7027271 DOI: 10.1186/s12876-020-01189-z] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Accepted: 02/11/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Hyperuricemia is a major risk for non-alcoholic fatty liver disease. However, the mechanisms for this phenomenon are not fully understood. This study aimed to investigate whether microRNAs mediated the pathogenic effects of uric acid on non-alcoholic fatty liver disease. METHODS Microarray was used to determine the hepatic miRNA expression profiles of male C57BL/6 mice fed on standard chow diet, high fat diet (HFD), and HFD combined with uric acid-lowering therapy by allopurinol. We validated the expression of the most significant differentially expressed microRNAs and explored its role and downstream target in uric acid-induced hepatocytes lipid accumulation. RESULTS Microarray analysis and subsequent validation showed that miR-149-5p was significantly up-regulated in the livers of HFD-fed mice, while the expression was down-regulated by allopurinol therapy. MiR-149-5p expression was also significantly up-regulated in uric acid-stimulated hepatocytes. Over-expression of miR-149-5p significantly aggregated uric acid-induced triglyceride accumulation in hepatocytes, while inhibiting miR-149-5p ameliorated the triglyceride accumulation. Luciferase report assay confirmed that FGF21 is a target gene of miR-149-5p. Silencing FGF21 abolished the ameliorative effects of miR-149-5p inhibitor on uric acid-induced hepatocytes lipid accumulation, while overexpression of FGF21 prevented the lipid accumulation induced by miR-149-5p mimics. CONCLUSIONS Uric acid significantly up-regulated the expression of miR-149-5p in hepatocytes and induced hepatocytes lipid accumulation via regulation of miR-149-5p/FGF21 axis.
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Affiliation(s)
- Shenghui Chen
- Department of Gastroenterology, the First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310003, Zhejiang Province, China
| | - Dan Chen
- Department of Gastroenterology, the First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310003, Zhejiang Province, China
| | - Hua Yang
- Department of Gastroenterology, the First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310003, Zhejiang Province, China
| | - Xinyu Wang
- Department of Gastroenterology, the First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310003, Zhejiang Province, China
| | - Jinghua Wang
- Department of Gastroenterology, the First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310003, Zhejiang Province, China
| | - Chengfu Xu
- Department of Gastroenterology, the First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310003, Zhejiang Province, China.
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Li S, Jiang L, Yang Y, Cao J, Zhang Q, Zhang J, Wang R, Deng X, Li Y. Siglec1 enhances inflammation through miR-1260-dependent degradation of IκBα in COPD. Exp Mol Pathol 2020; 113:104398. [PMID: 32007531 DOI: 10.1016/j.yexmp.2020.104398] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Revised: 12/24/2019] [Accepted: 01/30/2020] [Indexed: 02/07/2023]
Abstract
It has been documented that sialic acid-binding Ig-like lectin 1 (Siglec1) is a cell surface protein with a variety of functions in the immune system. In the present study, we evaluated whether Siglec1 plays a role in chronic obstructive pulmonary disease (COPD). Results show that the expression of Siglec1 was increased in the lung of COPD rats, and that Siglec1 overexpression greatly enhanced the expression of inflammatory cytokines including tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β) and IL-6 in cigarette smoke extract (CSE)-treated NR8383 cells, a rat lung-derived macrophage cell line. Notably, the proinflammatory effect of Siglec1 was totally inhibited by overexpression of nuclear factor of κ light polypeptide gene enhancer in B-cells inhibitor α (IκBα). Importantly, Siglec1 overexpression increased miR-1260, which then degraded IκBα through its 3' untranslated region (3'UTR). Further study demonstrated that miR-1260 inhibitor attenuated inflammation in CSE-induced rat COPD lung and in CSE-treated NR8383 cells. Finally, the inhibitory effect of miR-1260 on inflammation was totally lost when IκBα was inhibited. In summary, the present study demonstrated that Siglec1 exerts its proinflammatory effects through increasing miR-1260, leading to decreased expression of IκBα.
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Affiliation(s)
- Sensen Li
- School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, Jiangsu, China; Department of Pharmacy, Luohe Central Hospital, Luohe 462000, Henan, China
| | - Longfeng Jiang
- Department of Infectious Diseases, The First Affiliated Hospital with Nanjing Medical University, Nanjing 210002, Jiangsu, China
| | - Yanbing Yang
- Department of Respiratory Medicine, Luohe Central Hospital, Luohe 462000, Henan, China
| | - Juan Cao
- Department of Respiratory Medicine, Luohe Central Hospital, Luohe 462000, Henan, China
| | - Qi Zhang
- Huadong Research Institute for Medicine and Biotechnics, Nanjing 210002, Jiangsu, China
| | - Jinghai Zhang
- Huadong Research Institute for Medicine and Biotechnics, Nanjing 210002, Jiangsu, China
| | - Rui Wang
- Department of Pharmacy, Luohe Central Hospital, Luohe 462000, Henan, China
| | - Xiaozhao Deng
- School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, Jiangsu, China; Huadong Research Institute for Medicine and Biotechnics, Nanjing 210002, Jiangsu, China.
| | - Yaojun Li
- Department of Respiratory Medicine, Luohe Central Hospital, Luohe 462000, Henan, China.
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Abstract
Liver cancer is a particularly aggressive group of malignancies with historically low survival rates. Despite advancements in cancer treatments in general in the last few decades, incidence and mortality have not changed. Even though some phase 1 and 2 studies have shown promising results, many medication have failed to reach a sustainable level of efficacy to move into the clinical setting. Immunotherapy drugs have shown impressive results in the treatment of specific immunogenic cancers, prompting the possibility of their use in liver cancers. Immunotherapy medications approved for other cancers have received FDA accelerated approval for treatment of hepatocellular carcinoma. But, these approvals are contingent upon verification and description of clinical benefit in confirmatory trials. With more treatments in development involving cancer vaccines and natural killer cell-mediated therapy, liver cancer treatment is being reinvigorated with a broad array of new treatment angles. In this review article, we discuss these treatments, focusing on mechanism of action and clinical trials. Much needed advancements in treating late- and early-stage liver cancers will require new and innovative immunotherapeutic treatments.
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Affiliation(s)
- Christoffer Briggs Lambring
- Graduate School of Biomedical Sciences, The University of North Texas Health Science Center, Fort Worth, Texas
| | | | | | - Riyaz Basha
- Graduate School of Biomedical Sciences, The University of North Texas Health Science Center, Fort Worth, Texas
- Department of Pediatrics and Women’s Health, Texas College of Osteopathic Medicine, The University of North Texas Health Science Center, Fort Worth, Texas
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The Regulatory Role of MicroRNA in Hepatitis-B Virus-Associated Hepatocellular Carcinoma (HBV-HCC) Pathogenesis. Cells 2019; 8:cells8121504. [PMID: 31771261 PMCID: PMC6953055 DOI: 10.3390/cells8121504] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 11/11/2019] [Accepted: 11/12/2019] [Indexed: 02/06/2023] Open
Abstract
The incidence and mortality of hepatitis B virus (HBV)-associated hepatocellular carcinoma (HBV-HCC) is an intractable public health problem in developing countries that is compounded by limited early detection and therapeutic options. Despite the early promise of utilizing the regulatory role of miRNA in liver cancer, this field remains largely in the work-in-progress phase. This exploratory review paper adopts a broad focus in order to collate evidence of the regulatory role of miRNA in each stage of the HBV-HCC continuum. This includes the regulatory role of miRNA in early HBV infection, chronic inflammation, fibrosis/cirrhosis, and the onset of HCC. The paper specifically investigates HBV dysregulated miRNA that influence the expression of the host/HBV genome in HBV-HCC pathogenesis and fully acknowledges that this does not cover the full spectrum of dysregulated miRNA. The sheer number of dysregulated miRNA in each phase support a hypothesis that future therapeutic interventions will need to consider incorporating multiple miRNA panels.
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Sun JF, Zhang D, Gao CJ, Zhang YW, Dai QS. Exosome-Mediated MiR-155 Transfer Contributes to Hepatocellular Carcinoma Cell Proliferation by Targeting PTEN. Med Sci Monit Basic Res 2019; 25:218-228. [PMID: 31645540 PMCID: PMC6827328 DOI: 10.12659/msmbr.918134] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND Most eukaryocytes release nano vesicles (30-120 nm), named exosomes, to various biological fluids such as blood, lymph, and milk. Hepatocellular carcinoma (HCC) is one of the tumors with the highest incidence rate in primary malignant carcinoma of the liver. However, the mechanism of HCC proliferation remains elusive. In this study, we aim to explore whether HCC cell-derived exosomes affect the proliferation of cancer cells. MATERIAL AND METHODS Exosomes were isolated from HCC cells by ultracentrifugation and were visualized the phenotype by transmission electron microscopy. Cell proliferation was detected by Cell Counting Kit-8 assays and EdU (5-ethynyl-2-deoxyuridine) incorporation assays. Dual-luciferase assays were performed to validate the paired correlation of miR-155 and 3'-UTR of PTEN (gene of phosphate and tension homology deleted on chromosome 10). A xenograft mice model was constructed to verify the effect of exosome-mediated miR-155 on cell proliferation in vivo. RESULTS Our finding showed that miR-155 was enriched in exosomes released from HCC cells. The exosome-containing miR-155 transferred into new HCC targeted cells and lead to the elevation of HCC cells' proliferation. Besides, the exosomal miR-155 directly bound to 3'-UTR of PTEN leading to the reduction of relevant targets in recipient liver cells. The knockdown of PTEN attenuated the proliferation of HCC cells treated with the exosomal miR-155. Moreover, nude-mouse experiment results revealed a promotional effect of the exosomal miR-155 on HCC cell-acquired xenografts. CONCLUSIONS Our study indicated that exosomal-specific miR-155 transfers to adjacent and/or more distant cells and stimulates the proliferation of HCC cells.
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Affiliation(s)
- Jing-Feng Sun
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Cancer Hospital of Nanjing Medical University and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, Nanjing, Jiangsu, China (mainland)
| | - Dong Zhang
- Department of General Surgery, GuanYun People's Hospital, Guanyun, Jiangsu, China (mainland)
| | - Cai-Jie Gao
- Pediatric Department, The Affiliated Children's Hospital of Nanjing Medical University, Nanjing, Jiangsu, China (mainland)
| | - Ye-Wei Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Cancer Hospital of Nanjing Medical University and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, Nanjing, Jiangsu, China (mainland)
| | - Qing-Song Dai
- Department of General Surgery, The Affiliated Sir RunRun Hospital of Nanjing Medical University, Nanjing, Jiangsu, China (mainland)
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Ha SY, Yu JI, Choi C, Kang SY, Joh JW, Paik SW, Kim S, Kim M, Park HC, Park CK. Prognostic significance of miR-122 expression after curative resection in patients with hepatocellular carcinoma. Sci Rep 2019; 9:14738. [PMID: 31611609 PMCID: PMC6791887 DOI: 10.1038/s41598-019-50594-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Accepted: 09/13/2019] [Indexed: 12/13/2022] Open
Abstract
Downregulation of MicroRNA-122 (miR-122) and its association with cancer progression have been reported in hepatocellular carcinoma (HCC) cell line models and a limited number of HCC samples. Recently, restoration of miR-122 expression by direct delivery of miR-122 yielded promising results in HCCs. However, the prognostic effect of miR-122 expression in human HCC samples is not fully understood. We investigated the expression level of miR-122 by quantitative real-time polymerase chain reaction in 289 curatively resected HCC samples and 20 normal liver samples and evaluated the prognostic effect of miR-122 expression. The relative quantification value of miR-122 was much lower in HCC samples than in normal liver tissues. During a median 119 months of follow-up for survival, the low miR-122 expression group showed shorter recurrence-free survival (RFS) (p = 0.033) and intrahepatic recurrence-free survival (IHRFS) (p = 0.014), and a trend of short distant metastasis-free survival (DMFS) (p = 0.149) than high expression group. On multivariate analysis, miR-122 expression was an independent prognostic factor for RFS, IHRFS and DMFS. Downregulation of miR-122 expression, frequently found in HCC samples, was an independent prognostic factor for RFS after curative resection. Emerging therapeutic approaches targeting miR-122 could be applicable in patients with miR-122 downregulated hepatocellular carcinoma.
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Affiliation(s)
- Sang Yun Ha
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jeong Il Yu
- Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Changhoon Choi
- Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - So Young Kang
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jae-Won Joh
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Seung Woon Paik
- Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Seonwoo Kim
- Statistics and Data Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Minji Kim
- Statistics and Data Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hee Chul Park
- Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
| | - Cheol-Keun Park
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
- Department of Pathology, Anatomic Pathology Reference Lab, Seegene Medical Foundation, Seoul, Korea.
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Simão AL, Afonso MB, Rodrigues PM, Gama-Carvalho M, Machado MV, Cortez-Pinto H, Rodrigues CMP, Castro RE. Skeletal muscle miR-34a/SIRT1:AMPK axis is activated in experimental and human non-alcoholic steatohepatitis. J Mol Med (Berl) 2019; 97:1113-1126. [DOI: 10.1007/s00109-019-01796-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2018] [Revised: 02/22/2019] [Accepted: 05/08/2019] [Indexed: 01/01/2023]
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Yin C, Han Q, Xu D, Zheng B, Zhao X, Zhang J. SALL4-mediated upregulation of exosomal miR-146a-5p drives T-cell exhaustion by M2 tumor-associated macrophages in HCC. Oncoimmunology 2019; 8:1601479. [PMID: 31143524 DOI: 10.1080/2162402x.2019.1601479] [Citation(s) in RCA: 132] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2018] [Revised: 03/03/2019] [Accepted: 03/27/2019] [Indexed: 12/13/2022] Open
Abstract
Emerging evidence indicates that cancer cell-derived exosomes contribute to cancer progression through the modulation of tumor microenvironment, but the underlying mechanisms are not fully elucidated. Here, we reported that hepatocellular carcinoma (HCC)-derived exosomes could remodel macrophages by activating NF-κB signaling and inducing pro-inflammatory factors, and resulted in M2-polarized tumor-associated macrophages. In addition, the expression of IFN-γ and TNF-α was inhibited, while the expression of inhibitory receptors such as PD-1 and CTLA-4 was upregulated in T cells by HCC-derived exosome educated macrophages. Data also revealed that HCC exosomes were enriched with miR-146a-5p and promoted M2-polarization. Further investigation demonstrated that the transcription factor Sal-like protein-4 (SALL4) was critical for regulating miR-146a-5p in HCC exosomes and M2-polarization. Mechanistically, SALL4 could bind to the promoter of miR-146a-5p, and directly controlled its expression in exosomes. Blocking the SALL4/miR-146a-5p interaction in HCC reduced the expression of inhibitory receptors on T cells, reversed T cell exhaustion, and delayed HCC progression in DEN/CCL4-induced HCC mice. In conclusion, identification of a role of the exosomal SALL4/miR-146a-5p regulatory axis in M2-polarization as well as HCC progression provides potential targets for therapeutic and diagnostic applications in liver cancer.
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Affiliation(s)
- Chunlai Yin
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong, China
| | - Qiuju Han
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong, China
| | - Dongqing Xu
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong, China
| | - Bingqing Zheng
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong, China
| | - Xuemei Zhao
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong, China
| | - Jian Zhang
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong, China
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