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Wang X, Li J, Nong J, Deng X, Chen Y, Han B, Zeng L, Huang X. MiR-518b Promotes the Tumorigenesis of Hepatocellular Carcinoma by Targeting EGR1 to Regulate PI3K/AKT/mTOR Signaling Pathway. Cell Biochem Biophys 2025:10.1007/s12013-025-01752-z. [PMID: 40221539 DOI: 10.1007/s12013-025-01752-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/02/2025] [Indexed: 04/14/2025]
Abstract
Hepatocellular carcinoma (HCC) is a prevalent malignancy originating from hepatocytes and is characterized by high invasiveness and fatality. Dysregulation of microRNAs (miRNAs) is frequently observed during HCC progression. This study aimed to investigate the role of miR-518b in HCC cell malignancy and tumor growth. MiR-518b expression in HCC cells was measured by RT-qPCR. The proliferative, migratory and invasive capabilities of Hep3B and SNU-387 were assessed by colony formation, wound healing and transwell assays, respectively. RNA immunoprecipitation and luciferase reporter assays were utilized to verify the binding between miR-518b and its target gene, early growth response factor 1 (EGR1). Results revealed that miR-518b was highly expressed while EGR1 was downregulated in HCC cells. Knockdown of miR-518b significantly repressed cell proliferation, migration and invasion. Moreover, miR-518b bound to 3'untranslated region of EGR1 and negatively regulated its expression in HCC cells. EGR1 knockdown counteracted the inhibitory impact of miR-518b inhibition on malignant cell behaviors. In addition, the silencing of EGR1 activated the PI3K/AKT/mTOR signaling in HCC cells, while miR-518b depletion had the opposite effect. Importantly, the suppressive impact of miR-518b on the pathway was rescued by EGR1 knockdown. In vivo experiments demonstrated that inhibition of miR-518b suppressed HCC tumor growth, reduced EGR1 and Ki67 (a proliferation marker) expression, and inactivated the PI3K/AKT/mTOR signaling. In conclusion, miR-518b promotes HCC tumorigenesis by targeting EGR1 and regulating the PI3K/AKT/mTOR signaling pathway.
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Affiliation(s)
- Xinyuan Wang
- College of Zhuang Medicine, Guangxi University of Chinese Medicine, Nanning, China
| | - Juan Li
- Department of pediatrics, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, China
| | - Jiao Nong
- College of Osteopathy, Guangxi University of Chinese Medicine, Nanning, China
| | - Xin Deng
- School of basic medicine, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, China
| | - Yiping Chen
- Emergency department, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, China
| | - Bing Han
- Guangxi University of Chinese Medicine, Nanning, China
| | - Lin Zeng
- Guangxi University of Chinese Medicine, Nanning, China
| | - Xiabing Huang
- Emergency department, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, China.
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2
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Song G, Yu X, Shi H, Sun B, Amateau S. miRNAs in HCC, pathogenesis, and targets. Hepatology 2024:01515467-990000000-01097. [PMID: 39626210 DOI: 10.1097/hep.0000000000001177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Accepted: 11/22/2024] [Indexed: 12/21/2024]
Abstract
Liver cancer is the third leading cause of cancer-related mortality worldwide. HCC, the most common type of primary liver cancer, is driven by complex genetic, epigenetic, and environmental factors. MicroRNAs, a class of naturally occurring small noncoding RNAs, play crucial roles in HCC by simultaneously modulating the expression of multiple genes in a fine-tuning manner. Significant progress has been made in understanding how miRNAs influence key oncogenic pathways, including cell proliferation, apoptosis, angiogenesis, and epithelial-mesenchymal transition (EMT), as well as their role in modulating the immune microenvironment in HCC. Due to the unexpected stability of miRNAs in the blood and fixed HCC tumors, recent advancements also highlight their potential as noninvasive diagnostic tools. Restoring or inhibiting specific miRNAs has offered promising strategies for targeted HCC treatment by suppressing malignant hepatocyte growth and enhancing antitumor immunity. In this comprehensive review, we consolidate previous research and provide the latest insights into how miRNAs regulate HCC and their therapeutic and diagnostic potential. We delve into the dysregulation of miRNA biogenesis in HCC, the roles of miRNAs in the proliferation and apoptosis of malignant hepatocytes, angiogenesis and metastasis of HCC, the immune microenvironment in HCC, and drug resistance. We also discuss the therapeutic and diagnostic potential of miRNAs and delivery approaches of miRNA drugs to overcome the limitations of current HCC treatment options. By thoroughly summarizing the roles of miRNAs in HCC, our goal is to advance the development of effective therapeutic drugs with minimal adverse effects and to establish precise tools for early diagnosis of HCC.
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Affiliation(s)
- Guisheng Song
- Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA
- Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, Minnesota, USA
| | - Xiaofan Yu
- Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA
| | - Hongtao Shi
- Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA
- Department of Cardiology, the First Hospital of Shanxi Medical University, Taiyuan City, China
| | - Bo Sun
- Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA
| | - Stuart Amateau
- Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA
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Xie C, Zhou X, Wu J, Chen W, Ren D, Zhong C, Meng Z, Shi Y, Zhu J. ZNF652 exerts a tumor suppressor role in lung cancer by transcriptionally downregulating cyclin D3. Cell Death Dis 2024; 15:792. [PMID: 39500884 PMCID: PMC11538260 DOI: 10.1038/s41419-024-07197-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 10/24/2024] [Accepted: 10/30/2024] [Indexed: 11/08/2024]
Abstract
Dysfunction of zinc finger protein 652 (ZNF652) is associated with various malignant tumors. However, the role of ZNF652 in lung cancer (LC) is poorly understood. Here, we identified that ZNF652 was downregulated in human LC tissues and cell lines. Low ZNF652 expression was associated with poor survival in LC patients. Overexpression of ZNF652 inhibited cell viability, proliferation, migration, and invasion of LC cells, whereas ZNF652 knockdown promoted these malignant phenotypes. Using RNA-seq analysis revealed that ZNF652 overexpression resulted in obvious alterations of various biological processes, especially cell cycle and cellular senescence. Subsequently, we confirmed that ZNF652 overexpression arrested the cell cycle at the G1 phase, increased ROS-mediated DNA damage, induced LC cell senescence, and enhanced cisplatin-induced apoptosis in LC cells. Mechanistically, ZNF652 directly bound to the promoter of cyclin D3 (CCND3), inhibited its transcription, thereby arresting the cell cycle at the G1 phase. Ectopic expression of cyclin D3 rescued the decreased cell viability and cell cycle arrest induced by ZNF652. In vivo studies further showed that ZNF652 overexpression suppressed the tumorigenic potential of LC. Collectively, our findings reveal that ZNF652 exerts a tumor suppressor role in lung cancer by inducing cell cycle arrest and cellular senescence via transcriptionally downregulating cyclin D3. Thus, ZNF652 may be a prognostic predictive factor for LC patients.
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Affiliation(s)
- Chunfeng Xie
- Department of Nutrition and Food Safety, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Xu Zhou
- Department of Nutrition and Food Safety, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Jinyi Wu
- Department of Nutrition and Food Safety, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Weiyi Chen
- Department of Nutrition and Food Safety, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Dongxue Ren
- Department of Nutrition and Food Safety, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Caiyun Zhong
- Department of Nutrition and Food Safety, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Zili Meng
- Department of Respiratory and Critical Care Medicine, The Affiliated Huai'an No.1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu, P. R. China.
| | - Ye Shi
- Department of Thoracic Surgery, Nanjing Chest Hospital, Affiliated Nanjing Brain Hospital, Nanjing Medical University, Nanjing, China.
| | - Jianyun Zhu
- Department of Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, China.
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4
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Jorud K, Mendoza KM, Kono T, Coulombe RA, Reed KM. Differential Hepatic Expression of miRNA in Response to Aflatoxin B1 Challenge in Domestic and Wild Turkeys. Toxins (Basel) 2024; 16:453. [PMID: 39591208 PMCID: PMC11598555 DOI: 10.3390/toxins16110453] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Revised: 10/08/2024] [Accepted: 10/21/2024] [Indexed: 11/28/2024] Open
Abstract
Aflatoxin B1 (AFB1) is a major foodborne mycotoxin that poses a significant economic risk to poultry due to a greater degree of susceptibility compared to other agricultural species. Domesticated turkeys (Meleagris gallopavo) are especially sensitive to AFB1; however, wild turkeys (M. g. silvestris) are more resistant. A lack of functional isoforms of hepatic glutathione S-transferases (GSTs), an enzyme that plays a role in the detoxification of aflatoxin, is suspected as the reason for the increased sensitivity. Previous studies comparing the gene expression of domesticated and wild turkeys exposed to AFB1 identified hepatic genes responding differentially to AFB1, but could not fully explain the difference in response. The current study examined differences in the expression of microRNAs (miRNAs) in the livers of wild and domesticated turkeys fed dietary AFB1 (320 μg/kg in feed). Short-read RNA sequencing and expression analysis examined both domesticated and wild turkeys exposed to AFB1 compared to controls. A total of 25 miRNAs was identified as being significantly differentially expressed (DEM) in pairwise comparisons. The majority of these have mammalian orthologs with known dysregulation in liver disease. The largest number of DEMs occurred between controls, suggesting an underlying difference in liver potential. Sequences of the DEMs were used to identify potential miRNA binding sites in target genes, resulting in an average of 4302 predicted target sites per DEM. These DEMs and gene targets provide hypotheses for future investigations into the role of miRNAs in AFB1 resistance.
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Affiliation(s)
- Kade Jorud
- College of Veterinary Medicine, University of Minnesota, St Paul, MN 55108, USA
| | - Kristelle M. Mendoza
- Department of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, MN 55108, USA
| | - Thomas Kono
- Minnesota Supercomputing Institute, University of Minnesota, St Paul, MN 55108, USA
| | - Roger A. Coulombe
- Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, UT 84322, USA;
| | - Kent M. Reed
- Department of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, MN 55108, USA
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Xu J, Zhao Y, Chen Z, Wei L. Clinical Application of Different Liquid Biopsy Components in Hepatocellular Carcinoma. J Pers Med 2024; 14:420. [PMID: 38673047 PMCID: PMC11051574 DOI: 10.3390/jpm14040420] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Revised: 03/26/2024] [Accepted: 04/04/2024] [Indexed: 04/28/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer, usually occurring in the background of chronic liver disease. HCC lethality rate is in the third highest place in the world. Patients with HCC have concealed early symptoms and possess a high-level of heterogeneity. Once diagnosed, most of the tumors are in advanced stages and have a poor prognosis. The sensitivity and specificity of existing detection modalities and protocols are suboptimal. HCC calls for more sophisticated and individualized therapeutic regimens. Liquid biopsy is non-invasive, repeatable, unaffected by location, and can be monitored dynamically. It has emerged as a useable aid in achieving precision malignant tumor treatment. Circulating tumor cells (CTCs), circulating nucleic acids, exosomes and tumor-educated platelets are the commonest components of a liquid biopsy. It possesses the theoretical ability to conquer the high heterogeneity and the difficulty of early detection for HCC patients. In this review, we summarize the common enrichment techniques and the clinical applications in HCC for different liquid biopsy components. Tumor recurrence after HCC-related liver transplantation is more insidious and difficult to treat. The clinical use of liquid biopsy in HCC-related liver transplantation is also summarized in this review.
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Affiliation(s)
| | | | | | - Lai Wei
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology; Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan 430030, China; (J.X.); (Y.Z.); (Z.C.)
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6
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Nitta Y, Fujii T, Uchiyama T, Sugimoto A, Nishikawa T, Takeda M, Miyake M, Shimada K, Fujimoto K. Overexpression of MicroRNA-138 Affects the Proliferation and Invasion of Urothelial Carcinoma Cells by Suppressing SOX9 Expression. Biomedicines 2023; 11:3064. [PMID: 38002064 PMCID: PMC10669193 DOI: 10.3390/biomedicines11113064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Revised: 11/10/2023] [Accepted: 11/14/2023] [Indexed: 11/26/2023] Open
Abstract
SRY-box transcription factor 9 (SOX9) is important for sexual differentiation, chondrogenic differentiation, and cell proliferation in cancer. It acts as a target molecule of microRNA (miR)-138 in various tumors and is associated with tumor development and growth. In this study, we analyzed the functions of miR-138 and SOX9 in urothelial carcinoma. SOX9 was highly expressed in invasive urothelial carcinoma tissues. miR-138 precursor transfection of T24 and UMUC2 cells significantly decreased SOX9 expression, indicating that SOX9 is a miR-138 target in urothelial carcinoma. Moreover, miR-138 precursor or SOX9 small interfering RNA (siRNA) transfection decreased the proliferation of urothelial carcinoma cell lines. To further confirm that miR-138-SOX9 signaling is involved in cell proliferation and invasion, urothelial carcinoma cells were transfected with the miR-138 precursor or SOX9 siRNA. This transfection reduced the proliferation and invasion of cells via the promotion of autophagy and apoptosis and G0/G1 cell cycle arrest. These results suggest that miR-138-SOX9 signaling modulates the growth and invasive potential of urothelial carcinoma cells.
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Affiliation(s)
- Yuji Nitta
- Department of Diagnostic Pathology, Nara Medical University School of Medicine, Nara 634-8521, Japan
| | - Tomomi Fujii
- Department of Diagnostic Pathology, Nara Medical University School of Medicine, Nara 634-8521, Japan
- Division of Fostering Required Medical Human Resources, Center for Infectious Disease Education and Research (CiDER), Osaka University, Osaka 565-0871, Japan
| | - Tomoko Uchiyama
- Department of Diagnostic Pathology, Nara Medical University School of Medicine, Nara 634-8521, Japan
| | - Aya Sugimoto
- Department of Diagnostic Pathology, Nara Medical University School of Medicine, Nara 634-8521, Japan
| | - Takeshi Nishikawa
- Department of Diagnostic Pathology, Nara Medical University School of Medicine, Nara 634-8521, Japan
- Department of Central Clinical Laboratory, Nara Medical University Hospital, Nara 634-8521, Japan
| | - Maiko Takeda
- Department of Diagnostic Pathology, Nara Medical University School of Medicine, Nara 634-8521, Japan
| | - Makito Miyake
- Department of Urology, Nara Medical University School of Medicine, Nara 634-8521, Japan
| | - Keiji Shimada
- Department of Diagnostic Pathology, Nara City Hospital, Nara 630-8305, Japan
| | - Kiyohide Fujimoto
- Department of Urology, Nara Medical University School of Medicine, Nara 634-8521, Japan
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7
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Kumar P. miRNA dysregulation in traumatic brain injury and epilepsy: a systematic review to identify putative biomarkers for post-traumatic epilepsy. Metab Brain Dis 2023; 38:749-765. [PMID: 36715879 DOI: 10.1007/s11011-023-01172-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2022] [Accepted: 01/18/2023] [Indexed: 01/31/2023]
Abstract
Traumatic brain injury (TBI) leads to post-traumatic epilepsy (PTE); hence, both TBI and PTE share various similar molecular mechanisms. MicroRNA (miRNA) is a small noncoding RNA that acts as a gene-silencing molecule. Notably, the dysregulation of miRNAs in various neurological diseases, including TBI and epilepsy, has been reported in several studies. However, studies on commonly dysregulated miRNAs and the regulation of shared pathways in both TBI and epilepsy that can identify potential biomarkers of PTE are still lacking. This systematic review covers the peer-review publications of TBI and database studies of epilepsy-dysregulated miRNAs of clinical studies. For TBI, 290 research articles were identified after screening, and 12 provided data for dysregulated miRNAs in humans. The compiled data suggest that 85 and 222 miRNAs are consecutively dysregulated in TBI and epilepsy. In both, 10 miRNAs were found to be commonly dysregulated, implying that they are potentially dysregulated miRNAs for PTE. Furthermore, the targets and involvement of each putative miRNA in different pathways were identified and evaluated. Additionally, clusters of predicted miRNAs were analyzed. Each miRNA's regulatory role was linked with apoptosis, inflammation, and cell cycle regulation pathways. Hence, these findings provide insight for future diagnostic biomarkers.
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Affiliation(s)
- Prince Kumar
- Department of Central Sophisticated Instrumentation Cell, Post Graduate Institute of Medical Education and Research, Chandigarh, India.
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de la Cruz-Ojeda P, Schmid T, Boix L, Moreno M, Sapena V, Praena-Fernández JM, Castell FJ, Falcón-Pérez JM, Reig M, Brüne B, Gómez-Bravo MA, Giráldez Á, Bruix J, Ferrer MT, Muntané J. miR-200c-3p, miR-222-5p, and miR-512-3p Constitute a Biomarker Signature of Sorafenib Effectiveness in Advanced Hepatocellular Carcinoma. Cells 2022; 11:cells11172673. [PMID: 36078082 PMCID: PMC9454520 DOI: 10.3390/cells11172673] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 08/21/2022] [Accepted: 08/26/2022] [Indexed: 11/16/2022] Open
Abstract
Background: Sorafenib constitutes a suitable treatment alternative for patients with advanced hepatocellular carcinoma (HCC) in whom atezolizumab + bevacizumab therapy is contraindicated. The aim of the study was the identification of a miRNA signature in liquid biopsy related to sorafenib response. Methods: miRNAs were profiled in hepatoblastoma HepG2 cells and tested in animal models, extracellular vesicles (EVs), and plasma from HCC patients. Results: Sorafenib altered the expression of 11 miRNAs in HepG2 cells. miR-200c-3p and miR-27a-3p exerted an anti-tumoral activity by decreasing cell migration and invasion, whereas miR-122-5p, miR-148b-3p, miR-194-5p, miR-222-5p, and miR-512-3p exerted pro-tumoral properties by increasing cell proliferation, migration, or invasion, or decreasing apoptosis. Sorafenib induced a change in EVs population with an increased number of larger EVs, and promoted an accumulation of miR-27a-3p, miR-122-5p, miR-148b-3p, miR-193b-3p, miR-194-5p, miR-200c-3p, and miR-375 into exosomes. In HCC patients, circulating miR-200c-3p baseline levels were associated with increased survival, whereas high levels of miR-222-5p and miR-512-3p after 1 month of sorafenib treatment were related to poor prognosis. The RNA sequencing revealed that miR-200c-3p was related to the regulation of cell growth and death, whereas miR-222-5p and miR-512-3p were related to metabolic control. Conclusions: The study showed that Sorafenib regulates a specific miRNA signature in which miR-200c-3p, miR-222-5p, and miR-512-3p bear prognostic value and contribute to treatment response.
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Affiliation(s)
- Patricia de la Cruz-Ojeda
- Institute of Biomedicine of Seville (IBiS), Hospital University “Virgen del Rocío”/CSIC/University of Seville, 41013 Seville, Spain
- Networked Biomedical Research Center Hepatic and Digestive Diseases (CIBEREHD), 28029 Madrid, Spain
- Department of Medical Physiology and Biophysics, University of Seville, 41004 Seville, Spain
| | - Tobias Schmid
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60528 Frankfurt, Germany
| | - Loreto Boix
- Networked Biomedical Research Center Hepatic and Digestive Diseases (CIBEREHD), 28029 Madrid, Spain
- BCLC Group, Liver Unit, Hospital Clinic, University of Barcelona, IDIBAPS, CIBEREHD, 08036 Barcelona, Spain
| | - Manuela Moreno
- Department of General Surgery, Hospital University “Virgen del Rocío”/CSIC/University of Seville/IBIS, 41013 Seville, Spain
| | - Víctor Sapena
- BCLC Group, Liver Unit, Hospital Clinic, University of Barcelona, IDIBAPS, CIBEREHD, 08036 Barcelona, Spain
| | | | - Francisco J. Castell
- Department of Radiology, Hospital University “Virgen del Rocío”/CSIC/University of Seville/IBIS, 41013 Seville, Spain
| | - Juan Manuel Falcón-Pérez
- Networked Biomedical Research Center Hepatic and Digestive Diseases (CIBEREHD), 28029 Madrid, Spain
- Exosomes Lab, CIC bioGUNE, 48160 Derio, Spain
| | - María Reig
- Networked Biomedical Research Center Hepatic and Digestive Diseases (CIBEREHD), 28029 Madrid, Spain
- BCLC Group, Liver Unit, Hospital Clinic, University of Barcelona, IDIBAPS, CIBEREHD, 08036 Barcelona, Spain
| | - Bernhard Brüne
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60528 Frankfurt, Germany
- German Cancer Consortium (DKTK), Partner Site Frankfurt, 60528 Frankfurt, Germany
- Frankfurt Cancer Institute, Goethe-University Frankfurt, 60528 Frankfurt, Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, 60528 Frankfurt, Germany
| | - Miguel A. Gómez-Bravo
- Department of General Surgery, Hospital University “Virgen del Rocío”/CSIC/University of Seville/IBIS, 41013 Seville, Spain
| | - Álvaro Giráldez
- Unit for the Clinical Management of Digestive Diseases, Hospital University “Virgen del Rocío”/CSIC/University of Seville/IBIS, 41013 Seville, Spain
| | - Jordi Bruix
- Networked Biomedical Research Center Hepatic and Digestive Diseases (CIBEREHD), 28029 Madrid, Spain
- BCLC Group, Liver Unit, Hospital Clinic, University of Barcelona, IDIBAPS, CIBEREHD, 08036 Barcelona, Spain
| | - María T. Ferrer
- Unit for the Clinical Management of Digestive Diseases, Hospital University “Virgen del Rocío”/CSIC/University of Seville/IBIS, 41013 Seville, Spain
| | - Jordi Muntané
- Institute of Biomedicine of Seville (IBiS), Hospital University “Virgen del Rocío”/CSIC/University of Seville, 41013 Seville, Spain
- Networked Biomedical Research Center Hepatic and Digestive Diseases (CIBEREHD), 28029 Madrid, Spain
- Department of Medical Physiology and Biophysics, University of Seville, 41004 Seville, Spain
- Correspondence: ; Tel.: +34-955-923-122; Fax: +34-955-923-002
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MicroRNA-138-5p Targets Pro-Apoptotic Factors and Favors Neural Cell Survival: Analysis in the Injured Spinal Cord. Biomedicines 2022; 10:biomedicines10071559. [PMID: 35884864 PMCID: PMC9312482 DOI: 10.3390/biomedicines10071559] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 06/22/2022] [Accepted: 06/28/2022] [Indexed: 11/29/2022] Open
Abstract
The central nervous system microRNA miR-138-5p has attracted much attention in cancer research because it inhibits pro-apoptotic genes including CASP3. We hypothesize that miR-138-5p downregulation after SCI leads to overexpression of pro-apoptotic genes, sensitizing neural cells to noxious stimuli. This study aimed to identify miR-138-5p targets among pro-apoptotic genes overexpressed following SCI and to confirm that miR-138-5p modulates cell death in neural cells. Gene expression and histological analyses revealed that the drop in miR-138-5p expression after SCI is due to the massive loss of neurons and oligodendrocytes and its downregulation in neurons. Computational analyses identified 176 potential targets of miR-138-5p becoming dysregulated after SCI, including apoptotic proteins CASP-3 and CASP-7, and BAK. Reporter, RT-qPCR, and immunoblot assays in neural cell cultures confirmed that miR-138-5p targets their 3′UTRs, reduces their expression and the enzymatic activity of CASP-3 and CASP-7, and protects cells from apoptotic stimuli. Subsequent RT-qPCR and histological analyses in a rat model of SCI revealed that miR-138-5p downregulation correlates with the overexpression of its pro-apoptotic targets. Our results suggest that the downregulation of miR-138-5p after SCI may have deleterious effects on neural cells, particularly on spinal neurons.
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Khare S, Khare T, Ramanathan R, Ibdah JA. Hepatocellular Carcinoma: The Role of MicroRNAs. Biomolecules 2022; 12:biom12050645. [PMID: 35625573 PMCID: PMC9138333 DOI: 10.3390/biom12050645] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2022] [Revised: 04/21/2022] [Accepted: 04/25/2022] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. HCC is diagnosed in its advanced stage when limited treatment options are available. Substantial morphologic, genetic and epigenetic heterogeneity has been reported in HCC, which poses a challenge for the development of a targeted therapy. In this review, we discuss the role and involvement of several microRNAs (miRs) in the heterogeneity and metastasis of hepatocellular carcinoma with a special emphasis on their possible role as a diagnostic and prognostic tool in the risk prediction, early detection, and treatment of hepatocellular carcinoma.
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Affiliation(s)
- Sharad Khare
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Missouri, Columbia, MO 65212, USA; (S.K.); (T.K.); (R.R.)
- Harry S. Truman Veterans Hospital, Columbia, MO 65201, USA
| | - Tripti Khare
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Missouri, Columbia, MO 65212, USA; (S.K.); (T.K.); (R.R.)
| | - Raghu Ramanathan
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Missouri, Columbia, MO 65212, USA; (S.K.); (T.K.); (R.R.)
- Harry S. Truman Veterans Hospital, Columbia, MO 65201, USA
| | - Jamal A. Ibdah
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Missouri, Columbia, MO 65212, USA; (S.K.); (T.K.); (R.R.)
- Harry S. Truman Veterans Hospital, Columbia, MO 65201, USA
- Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO 65212, USA
- Correspondence: ; Tel.: 1-573-882-7349; Fax: 1-573-884-4595
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11
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Piechowska A, Kruszniewska-Rajs C, Kimsa-Dudek M, Kołomańska M, Strzałka-Mrozik B, Gola J, Głuszek S. The role of miR-370 and miR-138 in the regulation of BMP2 suppressor gene expression in colorectal cancer: preliminary studies. J Cancer Res Clin Oncol 2022; 148:1569-1582. [PMID: 35292840 DOI: 10.1007/s00432-022-03977-4] [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: 01/04/2022] [Accepted: 03/06/2022] [Indexed: 12/24/2022]
Abstract
PURPOSE Colorectal cancer (CRC) is the fourth-most common cancer worldwide and the second most common cancer cause of death in the world. The components of the TGFβ-signalling pathway, which are often affected by miRNAs, are involved in the regulation of apoptosis and cell cycle. Therefore, in the current study, the expression of BMP2 gene in CRC tissues at different clinical stages compared to the non-tumour tissues has been assessed. Moreover, the plasma BMP2 protein concentration in the same group of CRC patients has been validated. Due to the constant necessity to conduct further research of the correlation between specific miRNAs and mRNAs in CRC, in silico analysis has been performed to select miRNAs that regulate BMP2 mRNA. METHODS The cDNA samples from tumor and non-tumor tissue were used in a qPCR reaction to determine the mRNA expression of the BMP2 gene and the expression of selected miRNAs. The concentration of BMP2 protein in plasma samples was also measured. RESULTS It was indicated that BMP2 was downregulated in CRC tissue. Moreover, miR-370 and miR-138 expression showed an upward trend. Decreased BMP2 with accompanied increasing miR-370 and miR-138 expression was relevant to the malignant clinicopathological features of CRC and consequently poor patient prognosis. CONCLUSION Our data suggest that miR-370 with its clear expression in plasma samples may be a potential diagnostic marker to determine the severity of the disease in patients at a later stage of colorectal cancer.
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Affiliation(s)
- Agnieszka Piechowska
- Department of Surgical Medicine With the Laboratory of Medical Genetics, Institute of Medical Sciences, Collegium Medicum, Jan Kochanowski University, Kielce, Poland
| | - Celina Kruszniewska-Rajs
- Department of Molecular Biology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, Katowice, Jednosci 8, 41-200, Sosnowiec, Poland
| | - Magdalena Kimsa-Dudek
- Department of Nutrigenomics and Bromatology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, Katowice, Jednosci 8, 41-200, Sosnowiec, Poland
| | - Magdalena Kołomańska
- Department of Anatomy, Institute of Medical Sciences, Collegium Medicum, Jan Kochanowski University, Kielce, Poland
| | - Barbara Strzałka-Mrozik
- Department of Molecular Biology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, Katowice, Jednosci 8, 41-200, Sosnowiec, Poland.
| | - Joanna Gola
- Department of Molecular Biology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, Katowice, Jednosci 8, 41-200, Sosnowiec, Poland
| | - Stanisław Głuszek
- Department of Surgical Medicine With the Laboratory of Medical Genetics, Institute of Medical Sciences, Collegium Medicum, Jan Kochanowski University, Kielce, Poland.,Department of Clinic General Oncological and Endocrinological Surgery, Regional Hospital, Kielce, Poland
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Role of miR-498 Combined with CREB1 in Apoptosis and Invasion of Hepatoma Cell Line. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2022; 2022:9621764. [PMID: 35251300 PMCID: PMC8894061 DOI: 10.1155/2022/9621764] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 01/16/2022] [Accepted: 01/31/2022] [Indexed: 11/17/2022]
Abstract
Objective To detect the expression levels of miR-498 in the hepatoma cells and to clarify the biological roles of miR-498 in hepatoma by investigating CREB1, which is the target of miR-498. This study provides a new biomarker for the early diagnosis and targeted therapies for hepatoma. Methods The expression of miR-498 between hepatoma cells and hepatocytes was detected by qRT-PCR. miR-498 was overexpressed in hepatoma cells, and then, flow cytometry was used to analyze the cell apoptosis rate. Cell migration and invasion ability were evaluated by Transwell migration assay and Matrigel invasion assay. The downstream targets of miR-498 were searched in the biological database or related software, and the result can be verified by luciferase reporter assay. The knockdown of the downstream target using RNA interference detected its biological functions in hepatoma cells and was confirmed by cotransfection experiments. Results miR-498 was downregulated in hepatoma cell lines compared with hepatocytes. The overexpression of miR-498 significantly promoted apoptosis. Luciferase reporter assays showed that miR-498 could target CREB1 3′UTR and CREB1 was one of the targets of miR-498. Knockdown of CREB1 also inhibited hepatoma cells' malignant potential and increased the apoptosis rate of hepatoma cells. CREB1 was able to alleviate the changes caused by miR-498 overexpression. Conclusions miR-498 is downregulated in hepatoma cell lines. Therefore, miR-498 can be one of the potential molecular markers for hepatoma diagnosis. miR-498 plays a role in tumor suppression through regulating CREB1.
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Zhao D, Wang C, Liu X, Liu N, Zhuang S, Zhang Q, Bao X, Xu S, Zhou X, Meng Q, Li S, Tang L. CircN4bp1 Facilitates Sepsis-Induced Acute Respiratory Distress Syndrome through Mediating Macrophage Polarization via the miR-138-5p/EZH2 Axis. Mediators Inflamm 2021; 2021:7858746. [PMID: 35002536 PMCID: PMC8739551 DOI: 10.1155/2021/7858746] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 12/04/2021] [Accepted: 12/13/2021] [Indexed: 12/24/2022] Open
Abstract
We recently reported the differential circRNA expression patterns of the pulmonary macrophages in sepsis-induced acute respiratory distress syndrome (ARDS) mice model by microarray analysis. However, their function and hidden molecular mechanism in regulation of macrophage activation and inflammation remain poorly understood. In this study, we found that circN4bp1was overexpressed in PBMC and monocytes, and its expression levels were correlated with a poor prognosis in sepsis induced ARDS patients induced by sepsis. Knockdown of circN4bp1 inhibited the lung injury and improved the long-time survival through blunting the M1 macrophage activation in cecal ligation and puncture- (CLP-) induced ARDS mice. Moreover, bioinformatics analysis predicated a circN4bp1/miR-138-5p ceRNA network, which was confirmed by luciferase reporter assay and RNA binding protein immunoprecipitation (RIP). CircN4bp1 affected macrophage differentiation by binding to miR-138-5p, thus regulating the expression of EZH2 in vivo and ex vivo. Lastly, the m6A level of circN4bp1was found to be elevated in ARDS mice; inhibition of m6A methyltransferase METTL3 blocked this response in vitro. Therefore, circN4bp1 can function as a miR-138-5p sponge for the modulation of macrophage polarization through regulation the expression of EZH2 and may serve as a potential target and/or prognostic marker for ARDS patients following sepsis.
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Affiliation(s)
- Dongyang Zhao
- Department of Internal Emergency Medicine and Critical Care, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Chunxue Wang
- Department of Internal Emergency Medicine and Critical Care, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Xiandong Liu
- Department of Internal Emergency Medicine and Critical Care, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Na Liu
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Shougang Zhuang
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
- Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, RI, USA
| | - Qianqian Zhang
- Department of Internal Emergency Medicine and Critical Care, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Xiaowei Bao
- Department of Internal Emergency Medicine and Critical Care, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Shumin Xu
- Department of Internal Emergency Medicine and Critical Care, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Xiaohui Zhou
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University, Shanghai 200120, China
| | - Qinshu Meng
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University, Shanghai 200120, China
| | - Shao Li
- Department of VIP Clinic, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Lunxian Tang
- Department of Internal Emergency Medicine and Critical Care, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
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Long Non-coding RNAs: Potential Players in Cardiotoxicity Induced by Chemotherapy Drugs. Cardiovasc Toxicol 2021; 22:191-206. [PMID: 34417760 DOI: 10.1007/s12012-021-09681-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 07/24/2021] [Indexed: 10/20/2022]
Abstract
One of the most important side effects of chemotherapy is cardiovascular complications, such as cardiotoxicity. Many factors are involved in the pathogenesis of cardiotoxicity; one of the most important of which is long non-coding RNAs (lncRNAs). lncRNA has 200-1000 nucleotides. It is involved in important processes such as cell proliferation, regeneration and apoptosis; today it is used as a prognostic and diagnostic factor. A, various drugs by acting on lncRNAs can affect cells. Therefore, by accurately identifying IncRNAs function, we can play an effective role in preventing the development of cardiotoxicity-induced chemotherapy drugs, and use them as a therapeutic strategy to improve clinical symptoms and increase patient survival.
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HCV Proteins Modulate the Host Cell miRNA Expression Contributing to Hepatitis C Pathogenesis and Hepatocellular Carcinoma Development. Cancers (Basel) 2021; 13:cancers13102485. [PMID: 34069740 PMCID: PMC8161081 DOI: 10.3390/cancers13102485] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 05/12/2021] [Accepted: 05/17/2021] [Indexed: 12/13/2022] Open
Abstract
Simple Summary According to the last estimate by the World Health Organization (WHO), more than 71 million individuals have chronic hepatitis C worldwide. The persistence of HCV infection leads to chronic hepatitis, which can evolve into liver cirrhosis and ultimately into hepatocellular carcinoma (HCC). Although the pathogenic mechanisms are not fully understood, it is well established that an interplay between host cell factors, including microRNAs (miRNA), and viral components exist in all the phases of the viral infection and replication. Those interactions establish a complex equilibrium between host cells and HCV and participate in multiple mechanisms characterizing hepatitis C pathogenesis. The present review aims to describe the role of HCV structural and non-structural proteins in the modulation of cellular miRNA during HCV infection and pathogenesis. Abstract Hepatitis C virus (HCV) genome encodes for one long polyprotein that is processed by cellular and viral proteases to generate 10 polypeptides. The viral structural proteins include the core protein, and the envelope glycoproteins E1 and E2, present at the surface of HCV particles. Non-structural (NS) proteins consist of NS1, NS2, NS3, NS4A, NS4B, NS5a, and NS5b and have a variable function in HCV RNA replication and particle assembly. Recent findings evidenced the capacity of HCV virus to modulate host cell factors to create a favorable environment for replication. Indeed, increasing evidence has indicated that the presence of HCV is significantly associated with aberrant miRNA expression in host cells, and HCV structural and non-structural proteins may be responsible for these alterations. In this review, we summarize the recent findings on the role of HCV structural and non-structural proteins in the modulation of host cell miRNAs, with a focus on the molecular mechanisms responsible for the cell re-programming involved in viral replication, immune system escape, as well as the oncogenic process. In this regard, structural and non-structural proteins have been shown to modulate the expression of several onco-miRNAs or tumor suppressor miRNAs.
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Sun B, Yang X, Hou F, Yu X, Wang Q, Oh HS, Raja P, Pesola JM, Vanni EAH, McCarron S, Morris-Love J, Ng AHM, Church GM, Knipe DM, Coen DM, Pan D. Regulation of host and virus genes by neuronal miR-138 favours herpes simplex virus 1 latency. Nat Microbiol 2021; 6:682-696. [PMID: 33558653 PMCID: PMC8221016 DOI: 10.1038/s41564-020-00860-1] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Accepted: 11/20/2020] [Indexed: 01/30/2023]
Abstract
MicroRNA miR-138, which is highly expressed in neurons, represses herpes simplex virus 1 (HSV-1) lytic cycle genes by targeting viral ICP0 messenger RNA, thereby promoting viral latency in mice. We found that overexpressed miR-138 also represses lytic processes independently of ICP0 in murine and human neuronal cells; therefore, we investigated whether miR-138 has targets besides ICP0. Using genome-wide RNA sequencing/photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation followed by short interfering RNA knockdown of candidate targets, we identified the host Oct-1 and Foxc1 messenger mRNAs as miR-138's targets, whose gene products are transcription factors important for HSV-1 replication in neuronal cells. OCT-1 has a known role in the initiation of HSV transcription. Overexpression of FOXC1, which was not known to affect HSV-1, promoted HSV-1 replication in murine neurons and ganglia. CRISPR-Cas9 knockout of FOXC1 reduced viral replication, lytic gene expression and miR-138 repression in murine neuronal cells. FOXC1 also collaborated with ICP0 to decrease heterochromatin on viral genes and compensated for the defect of an ICP0-null virus. In summary, miR-138 targets ICP0, Oct-1 and Foxc1 to repress HSV-1 lytic cycle genes and promote epigenetic gene silencing, which together enable favourable conditions for latent infection.
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Affiliation(s)
- Boqiang Sun
- Department of Medical Microbiology and Parasitology, Zhejiang University School of Medicine, Hangzhou, China
- Department of Infectious Diseases of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Thermo Fisher Scientific, Shanghai, China
| | - Xuewei Yang
- Department of Medical Microbiology and Parasitology, Zhejiang University School of Medicine, Hangzhou, China
- Department of Infectious Diseases of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Innovent Biologics, Inc., Suzhou, China
| | - Fujun Hou
- Department of Medical Microbiology and Parasitology, Zhejiang University School of Medicine, Hangzhou, China
- Department of Infectious Diseases of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiaofeng Yu
- Department of Medical Microbiology and Parasitology, Zhejiang University School of Medicine, Hangzhou, China
- Department of Infectious Diseases of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Zhejiang Chinese Medical University, Hangzhou, China
| | - Qiongyan Wang
- Department of Medical Microbiology and Parasitology, Zhejiang University School of Medicine, Hangzhou, China
- Department of Infectious Diseases of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Hyung Suk Oh
- Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
| | - Priya Raja
- Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
| | - Jean M Pesola
- Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
| | - Emilia A H Vanni
- Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
| | - Seamus McCarron
- Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
| | - Jenna Morris-Love
- Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
- Graduate Program in Pathobiology, Brown University, Providence, RI, USA
| | - Alex H M Ng
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Cambridge, MA, USA
- Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
| | - George M Church
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Cambridge, MA, USA
- Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
| | - David M Knipe
- Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
| | - Donald M Coen
- Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
| | - Dongli Pan
- Department of Medical Microbiology and Parasitology, Zhejiang University School of Medicine, Hangzhou, China.
- Department of Infectious Diseases of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
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Li C, Qin Y, Ouyang T, Yao M, Zhang A, Luo P, Pan X. miR-122-5p Mediates Fluoride-Induced Osteoblast Activation by Targeting CDK4. Biol Trace Elem Res 2021; 199:1215-1227. [PMID: 32572801 DOI: 10.1007/s12011-020-02239-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Accepted: 06/08/2020] [Indexed: 02/07/2023]
Abstract
Chronic intake of fluoride, existing in the environment, may cause endemic fluorosis, which is characterized by the occurrence of skeletal and dental fluorosis. However, the pathogenesis of fluorosis has not yet been elucidated. Abnormal osteoblast proliferation and activation have a pivotal role in bone turnover disorders which are linked to skeletal fluorosis. MicroRNAs are involved in fundamental cellular processes, including cell proliferation. Based on our previous study, population study and in vitro experiments were designed to understand the effect of miR-122-5p on osteoblast activation in skeletal fluorosis through targeting cyclin-dependent kinase 4 (CDK4). In human populations with coal-burning type fluoride exposure, the results showed that miR-122-5p was downregulated but CDK4 expression was upregulated and miR-122-5p was negatively correlated with CDK4 expression. Furthermore, in human osteoblasts treated with sodium fluoride, we demonstrated that miR-122-5p mediated osteoblast activation of skeletal fluorosis via upregulation of the CDK4 protein. In support of this, dual-luciferase reporter assay showed that miR-122-5p modulated CDK4 protein levels by targeting its 3'-untranslated region. These findings show, for the first time, that miR-122-5p may be involved in the cause and development of skeletal fluorosis by targeting CDK4.
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Affiliation(s)
- Chen Li
- School of Public Health, the key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang, 550025, China
| | - Yu Qin
- Guizhou Orthopedics Hospital, Guiyang, 550007, China
| | - Ting Ouyang
- School of Public Health, the key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang, 550025, China
| | - Maolin Yao
- School of Public Health, the key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang, 550025, China
| | - Aihua Zhang
- School of Public Health, the key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang, 550025, China
| | - Peng Luo
- School of Public Health, the key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang, 550025, China
| | - Xueli Pan
- School of Public Health, the key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang, 550025, China.
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Ishikawa M, Iwasaki M, Zhao H, Saito J, Hu C, Sun Q, Sakamoto A, Ma D. Sevoflurane and Desflurane Exposure Enhanced Cell Proliferation and Migration in Ovarian Cancer Cells via miR-210 and miR-138 Downregulation. Int J Mol Sci 2021; 22:ijms22041826. [PMID: 33673181 PMCID: PMC7917656 DOI: 10.3390/ijms22041826] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 02/04/2021] [Accepted: 02/08/2021] [Indexed: 12/24/2022] Open
Abstract
Inhalational anaesthetics were previously reported to promote ovarian cancer malignancy, but underlying mechanisms remain unclear. The present study aims to investigate the role of sevoflurane- or desflurane-induced microRNA (miRNA) changes on ovarian cancer cell behaviour. The cultured SKOV3 cells were exposed to 3.6% sevoflurane or 10.3% desflurane for 2 h. Expression of miR-138, -210 and -335 was determined with qRT-PCR. Cell proliferation and migration were assessed with wound healing assay, Ki67 staining and Cell Counting Kit-8 (CCK8) assay with or without mimic miR-138/-210 transfections. The miRNA downstream effector, hypoxia inducible factor-1α (HIF-1α), was also analysed with immunofluorescent staining. Sevoflurane or desflurane exposure to cancer cells enhanced their proliferation and migration. miR-138 expression was suppressed by both sevoflurane and desflurane, while miR-210 expression was suppressed only by sevoflurane. miR-335 expression was not changed by either sevoflurane or desflurane exposure. The administration of mimic miR-138 or -210 reduced the promoting effects of sevoflurane and desflurane on cancer cell proliferation and migration, in line with the HIF-1α expression changes. These data indicated that inhalational agents sevoflurane and desflurane enhanced ovarian cancer cell malignancy via miRNA deactivation and HIF-1α. The translational value of this work needs further study.
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Affiliation(s)
- Masashi Ishikawa
- Department of Anesthesiology and Pain Medicine, Graduate School of Medicine, Nippon Medical School, Tokyo 113-8603, Japan; (M.I.); (M.I.); (A.S.)
- Division of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea & Westminster Hospital, London SW10 9NH, UK; (H.Z.); (J.S.); (C.H.); (Q.S.)
| | - Masae Iwasaki
- Department of Anesthesiology and Pain Medicine, Graduate School of Medicine, Nippon Medical School, Tokyo 113-8603, Japan; (M.I.); (M.I.); (A.S.)
- Division of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea & Westminster Hospital, London SW10 9NH, UK; (H.Z.); (J.S.); (C.H.); (Q.S.)
| | - Hailin Zhao
- Division of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea & Westminster Hospital, London SW10 9NH, UK; (H.Z.); (J.S.); (C.H.); (Q.S.)
| | - Junichi Saito
- Division of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea & Westminster Hospital, London SW10 9NH, UK; (H.Z.); (J.S.); (C.H.); (Q.S.)
- Department of Anesthesiology, Graduate School of Medicine, Hirosaki University, Hirosaki, Aomori 036-8562, Japan
| | - Cong Hu
- Division of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea & Westminster Hospital, London SW10 9NH, UK; (H.Z.); (J.S.); (C.H.); (Q.S.)
| | - Qizhe Sun
- Division of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea & Westminster Hospital, London SW10 9NH, UK; (H.Z.); (J.S.); (C.H.); (Q.S.)
| | - Atsuhiro Sakamoto
- Department of Anesthesiology and Pain Medicine, Graduate School of Medicine, Nippon Medical School, Tokyo 113-8603, Japan; (M.I.); (M.I.); (A.S.)
| | - Daqing Ma
- Division of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea & Westminster Hospital, London SW10 9NH, UK; (H.Z.); (J.S.); (C.H.); (Q.S.)
- Correspondence:
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Fan S, Zhao S, Gao X, Qin Q, Guo Y, Yuan Z, Zhang M, Liu Q, Li H. Circular RNA circGSE1 Promotes Cervical Cancer Progression Through miR-138-5p/Vimentin. Onco Targets Ther 2021; 13:13371-13386. [PMID: 33408484 PMCID: PMC7781114 DOI: 10.2147/ott.s282425] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Accepted: 12/04/2020] [Indexed: 01/01/2023] Open
Abstract
Background A growing number of studies have identified that circular RNAs (circRNAs) play a vital role in the progression of various tumors. However, the underlying functions and mechanisms of circRNAs in cervical cancer have not been clarified. Methods qRT-PCR was used to detect the level of circGSE1 in cervical cancer tissues and matched normal tissues. In vitro cell wound healing, transwell migration and invasion assays were employed to assess the effects of circGSE1 on cell mobility. The pull-down, luciferase reporter, RIP and rescue assays were performed to evaluate the interaction between circGSE1and miR-138-5p and the regulation of miR-138-5p on Vimentin. Results We found that circGSE1 was significantly higher in cervical cancer tissues than that in matched normal tissues. Further analyses revealed that the level of circGSE1 was positively correlated with tumor differentiation, FIGUREO stage, depth of stromal invasion, lymph node metastasis and infiltration of parauterine organ. Kaplan–Meier survival analysis showed that high circGSE1 predicted worse overall survival and disease-free survival. Down-regulated circGSE1 evidently inhibited cell migration and metastasis of cervical cancer, while up-regulated circGSE1 significantly promoted cell migration and metastasis. The pull-down, luciferase reporter and RIP assays revealed that circGSE1 directly bound to and sponge miR-138-5p. MiR-138-5p inhibited the expression of Vimentin through directly binding to 3ʹUTR of Vimentin mRNA. In addition, miR-138-5p suppressed cell migration and invasion through inhibiting Vimentin expression, and circGSE1 promoted cell migration and invasion through sponging miR-138-5p and enhancing Vimentin expression. Conclusion CircGSE1 promotes the progression and may act as a novel diagnostic biomarker for disease progression of cervical cancer.
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Affiliation(s)
- Suzhen Fan
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, People's Republic of China
| | - Shujun Zhao
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, People's Republic of China
| | - Xiang Gao
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, People's Republic of China
| | - Qiaohong Qin
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, People's Republic of China
| | - Yan Guo
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, People's Republic of China
| | - Zhongfu Yuan
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, People's Republic of China
| | - Min Zhang
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, People's Republic of China
| | - Qing Liu
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, People's Republic of China
| | - Hongyu Li
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, People's Republic of China
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Yu J, Fang C, Zhang Z, Zhang G, Shi L, Qian J, Xiong J. H19 Rises in Gastric Cancer and Exerts a Tumor-Promoting Function via miR-138/ E2F2 Axis. Cancer Manag Res 2020; 12:13033-13042. [PMID: 33376397 PMCID: PMC7762430 DOI: 10.2147/cmar.s267357] [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: 06/11/2020] [Accepted: 08/13/2020] [Indexed: 12/16/2022] Open
Abstract
Purpose The aim of this paper was to investigate H19 expression in gastric cancer (GC) and its effects on the biological behavior of gastric cancer cells (GCCs), and at exploring its potential mechanism. Methods H19 expression in the patients’ tissues and serum was detected, and the correlation of the expression with the patients’ pathological data and survival rate was analyzed. Overexpression or inhibitory vectors of H19, microRNA-138 (miR-138) and E2F2 were constructed and transfected into GCCs to observe their effects on the cells’ proliferation, invasion and apoptosis. Results H19 rose in GC and was higher in GC patients with a tumor size ≥5 cm, high stages (III+IV) and lymph node metastasis. High H19 expression was associated with the poorer survival rate of the patients, so serum H19 had a certain diagnostic value for GC. H19 knockdown could inhibit GCCs to proliferate and invade and induce their apoptosis. miR-138 can be used as the target gene of H19, and E2F2 can be negatively regulated by this miR, so miR-138 knockdown or E2F2 upregulation can weaken GCCs’ biological behavior changes that were caused by H19 knockdown. Conclusion H19 can be used as a biological indicator for diagnosing GC and predicting patients’ poor prognosis. Additionally, it promotes GCCs to proliferate and invade through miR-138/E2F2 axis.
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Affiliation(s)
- Jingrong Yu
- Department of Oncology, The Fourth Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province 330003, People's Republic of China
| | - Cheng Fang
- Department of Oncology, Nanchang 334 Hospital, Nanchang, Jiangxi Province, People's Republic of China
| | - Ziyue Zhang
- Department of Oncology, Nanchang 334 Hospital, Nanchang, Jiangxi Province, People's Republic of China
| | - Guifang Zhang
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, People's Republic of China
| | - Lihong Shi
- Department of Gynecology and Pediatrics, Nanchang 334 Hospital, Nanchang, Jiangxi Province, People's Republic of China
| | - Jiayi Qian
- Department of Ultrasound Electrophysiology, Nanchang 334 Hospital, Nanchang, Jiangxi Province, People's Republic of China
| | - Jianping Xiong
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province 330006, People's Republic of China
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21
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Zhou X, Lu Y, Guo P, Zhou C. Upregulation of microRNA‑140‑3p mediates dachshund family transcription factor 1 expression in immunoglobulin A nephropathy through cell cycle‑dependent mechanisms. Mol Med Rep 2020; 23:134. [PMID: 33313942 PMCID: PMC7751451 DOI: 10.3892/mmr.2020.11773] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Accepted: 11/11/2020] [Indexed: 12/03/2022] Open
Abstract
Immunoglobulin A nephropathy (IgAN) is a kidney disease and one of the commonest forms of glomerulonephritis worldwide. The present study investigated the role of dachshund family transcription factor 1 (DACH1) in IgAN and identified one of its binding microRNAs (miRNAs). The expression of DACH1 in human mesangial cells (HMCs) incubated with polymeric IgA (pIgA) isolated and purified from the serum of patients with IgAN or healthy individuals was evaluated by reverse transcription-quantitative (RT-q) PCR and western blotting. Cell proliferation and cell cycle assays were performed in DACH1-overexpressing HMCs to identify the role of DACH1 in IgAN and enzyme-linked immunosorbent assay was carried out to verify the release of inflammatory factors from HMCs. The target miRNAs of DACH1 were predicted using bioinformatics software and miR-140-3p was identified as a target of DACH1 by luciferase report assay, RT-qPCR and western blotting. The results demonstrated that DACH1 was downregulated in HMCs cultured with pIgA-IgAN at both mRNA and protein levels. Overexpression of DACH1 suppressed HMC growth and inhibited inflammatory cytokine release from HMCs cultured with pIgA-IgAN. The expression of DACH1 was negatively regulated by miR-140-3p in IgAN and miR-140-3p inhibition suppressed HMC growth and inhibited inflammatory cytokine release from HMCs cultured with pIgA-IgAN. The findings of the present study demonstrated that DACH1 decreased HMC growth and the release of inflammatory cytokines from HMCs may be targeted by miR-140-3p. The results suggested that DACH1 could be associated with the progression of IgAN and provide a potential target for further studies related to the mechanism of IgAN.
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Affiliation(s)
- Xiaobin Zhou
- Department of Clinical Laboratory, Taizhou People's Hospital, Taizhou, Jiangsu 225300, P.R. China
| | - Yao Lu
- Department of Teaching Research of Medical Technology, Gannan Medical University, Ganzhou, Jiangxi 341000, P.R. China
| | - Pengfei Guo
- Department of Clinical Laboratory, Shanghai Tenth People's Hospital, Shanghai 200072, P.R. China
| | - Chenglin Zhou
- Department of Clinical Laboratory, Taizhou People's Hospital, Taizhou, Jiangsu 225300, P.R. China
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22
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The Relevance of MicroRNAs in the Pathogenesis and Prognosis of HCV-Disease: The Emergent Role of miR-17-92 in Cryoglobulinemic Vasculitis. Viruses 2020; 12:v12121364. [PMID: 33260407 PMCID: PMC7761224 DOI: 10.3390/v12121364] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 11/18/2020] [Accepted: 11/27/2020] [Indexed: 12/26/2022] Open
Abstract
Hepatitis C virus (HCV) is a major public health problem. HCV is a hepatotropic and lymphotropic virus that leads to hepatocellular carcinoma (HCC) and lymphoproliferative disorders such as cryoglobulinemic vasculitis (CV) and non-Hodgkin's lymphoma (NHL). The molecular mechanisms by which HCV induces these diseases are not fully understood. MicroRNAs (miRNAs) are small non-coding molecules that negatively regulate post-transcriptional gene expression by decreasing their target gene expression. We will attempt to summarize the current knowledge on the role of miRNAs in the HCV life cycle, HCV-related HCC, and lymphoproliferative disorders, focusing on both the functional effects of their deregulation as well as on their putative role as biomarkers, based on association analyses. We will also provide original new data regarding the miR 17-92 cluster in chronically infected HCV patients with and without lymphoproliferative disorders who underwent antiviral therapy. All of the cluster members were significantly upregulated in CV patients compared to patients without CV and significantly decreased in those who achieved vasculitis clinical remission after viral eradication. To conclude, miRNAs play an important role in HCV infection and related oncogenic processes, but their molecular pathways are not completely clear. In some cases, they may be potential therapeutic targets or non-invasive biomarkers of tumor progression.
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23
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Karbasforooshan H, Hayes AW, Mohammadzadeh N, Zirak MR, Karimi G. The possible role of Sirtuins and microRNAs in hepatocellular carcinoma therapy. Cell Cycle 2020; 19:3209-3221. [PMID: 33164623 DOI: 10.1080/15384101.2020.1843813] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer. Sirtuins are NAD+-dependent histone deacetylases that regulate many cellular processes such as proliferation, apoptosis, and metabolism. SIRT (silent information regulator)-1, 5, 6 and 7, members of the mammalian Sirtuin family of proteins (SIRT1-SIRT7), are involved in carcinogenesis, prognosis, metastasis, and chemical resistant of HCC. These proteins act through the deacetylation of tumor suppressor or oncogenic factors. MicroRNAs (miRNAs) are a group of small non-coding RNAs that down regulate gene expression by targeting the 3'-untranslated region of miRNAs. MiRNAs can function as tumor suppressors or as oncogenes and are involved in progression, differentiation, apoptosis and drug resistance of tumor cells. The focus of this review is to delineate the relationship between some microRNAs and their target, Sirtuins, and to present an overview of their function in HCC as currently understood.
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Affiliation(s)
- Hedyieh Karbasforooshan
- Department of Clinical Pharmacy, Faculty of Pharmacy, Mashhad University of Medical Sciences , Mashhad, Iran
| | - A Wallace Hayes
- University of South Florida College of Public Health , Tampa, FL, USA.,Institute for Integrative Toxicology, Michigan State University , East Lansing, MI, USA
| | | | - Mohammad Reza Zirak
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences , Mashhad, Iran
| | - Gholamreza Karimi
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences , Mashhad, Iran.,Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences , Mashhad, Iran
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24
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Huang Y, Liu Z, Zhong L, Wen Y, Ye Q, Cao D, Li P, Liu Y. Construction of an 11-microRNA-based signature and a prognostic nomogram to predict the overall survival of head and neck squamous cell carcinoma patients. BMC Genomics 2020; 21:691. [PMID: 33023466 PMCID: PMC7542341 DOI: 10.1186/s12864-020-07104-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2020] [Accepted: 09/24/2020] [Indexed: 12/16/2022] Open
Abstract
Background Head and neck squamous cell carcinoma (HNSCC) is a fatal malignancy owing to the lack of effective tools to predict overall survival (OS). MicroRNAs (miRNAs) play an important role in HNSCC occurrence, development, invasion and metastasis, significantly affecting the OS of patients. Thus, the construction of miRNA-based risk signatures and nomograms is desirable to predict the OS of patients with HNSCC. Accordingly, in the present study, miRNA sequencing data of 71 HNSCC and 13 normal samples downloaded from The Cancer Genome Atlas (TCGA) were screened to identify differentially expressed miRNAs (DEMs) between HNSCC patients and normal controls. Based on the exclusion criteria, the clinical information and miRNA sequencing data of 67 HNSCC samples were selected and used to establish a miRNA-based signature and a prognostic nomogram. Forty-three HNSCC samples were assigned to an internal validation cohort for verifying the credibility and accuracy of the primary cohort. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to explore the functions of 11 miRNA target genes. Results In total, 11 DEMs were successfully identified. An 11-miRNA risk signature and a prognostic nomogram were constructed based on the expression levels of these 11 DEMs and clinical information. The signature and nomogram were further validated by calculating the C-index, area under the curve (AUC) in receiver-operating characteristic curve analysis, and calibration curves, which revealed their promising performance. The results of the internal validation cohort shown the reliable predictive accuracy both of the miRNA-based signature and the prognostic nomogram. GO and KEGG analyses revealed that a mass of signal pathways participated in HNSCC proliferation and metastasis. Conclusion Overall, we constructed an 11-miRNA-based signature and a prognostic nomogram with excellent accuracy for predicting the OS of patients with HNSCC.
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Affiliation(s)
- Yusheng Huang
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, No. 12 Airport Road, Baiyun District, Guangzhou, 510407, China
| | - Zhiguo Liu
- Department of Oral and Maxillofacial Surgery, Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University, 56 Lingyuanxi Road, Guangzhou, China
| | - Limei Zhong
- Department of Laboratory Medicine, Guangdong Second Provincial General Hospital, Guangzhou, China
| | - Yi Wen
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, No. 12 Airport Road, Baiyun District, Guangzhou, 510407, China
| | - Qixiang Ye
- Department of Pediatrics, Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Shenzhen, China
| | - Donglin Cao
- Department of Laboratory Medicine, Guangdong Second Provincial General Hospital, Guangzhou, China
| | - Peiwu Li
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, No. 12 Airport Road, Baiyun District, Guangzhou, 510407, China.
| | - Yufeng Liu
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, No. 12 Airport Road, Baiyun District, Guangzhou, 510407, China. .,Guangzhou First People's Hospital, Guangzhou, 510000, China.
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25
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Wang N, Hao F, Ren J, Fei X, Chen Y, Xu W, Wang J. Positive feedback loop of AKR1B10P1/miR-138/SOX4 promotes cell growth in hepatocellular carcinoma cells. Am J Transl Res 2020; 12:5465-5480. [PMID: 33042431 PMCID: PMC7540089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Accepted: 07/26/2020] [Indexed: 06/11/2023]
Abstract
Potential functions of pseudogenes on tumorigenesis and development of human malignancies have been gradually revealed recently. However, the specific regulation and intracellular events associated with pseudogenes have not been illustrated clearly in hepatocellular carcinoma (HCC). AKR1B10P1 is an isoform pseudogene of oncogenic AKR1B10, and is barely transcribed in normal hepatocytes. In this study, anomalous transcript of AKR1B10P1 was detected in both HCC tissues and cell lines, and is positively correlated with its parental genes. High level of AKR1B10P1 transcript is correlated with dismal clinicopathologic features, including large tumor dimension, high level of serum Alpha-fetoprotein (AFP), advanced TNM stages, tumor microsatellite formation and venous invasion. Loss-of and gain-of function assays demonstrated the exact impact of AKR1B10P1 on promoting HCC cell proliferation. Furthermore, transcription factor SOX4 was discovered facilitating the activation of AKR1B10P1 transcription, and was validated as a down-stream target degraded by tumor-suppressing miR-138. Meanwhile, we discovered the existence of a positive feedback from AKR1B10P1, by which miR-138 interacts with AKR1B10P1 via a competing endogenous RNA (ceRNA) way. Thus, we suggest a positive feedback loop of AKR1B10P1/miR-138/SOX4, promoting HCC cell proliferation. In summary, the AKR1B10P1/miR-138/SOX4 loop in HCC cells provides us potential and probable targets contributing to HCC prevention and therapeutic treatment.
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Affiliation(s)
- Nan Wang
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine197, Rui Jin Er Road, Shanghai 200025, People’s Republic of China
| | - Fengjie Hao
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine197, Rui Jin Er Road, Shanghai 200025, People’s Republic of China
| | - Jiajun Ren
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine197, Rui Jin Er Road, Shanghai 200025, People’s Republic of China
| | - Xiaochun Fei
- Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine197, Rui Jin Er Road, Shanghai 200025, People’s Republic of China
| | - Yongjun Chen
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine197, Rui Jin Er Road, Shanghai 200025, People’s Republic of China
| | - Wen Xu
- State Key Laboratory of Bioreactor Engineering and Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and TechnologyShanghai 200237, People’s Republic of China
| | - Junqing Wang
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine197, Rui Jin Er Road, Shanghai 200025, People’s Republic of China
- Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine197, Rui Jin Er Road, Shanghai 200025, People’s Republic of China
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26
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Liao Y, Wang Z, Wang L, Lin Y, Ye Z, Zeng X, Wei F. MicroRNA-27a-3p directly targets FosB to regulate cell proliferation, apoptosis, and inflammation responses in immunoglobulin a nephropathy. Biochem Biophys Res Commun 2020; 529:1124-1130. [PMID: 32819575 DOI: 10.1016/j.bbrc.2020.06.115] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Accepted: 06/23/2020] [Indexed: 01/08/2023]
Abstract
Immunoglobulin A nephropathy (IgAN) constitutes the most common primary glomerulonephritis worldwide; however, the exact pathogenesis of IgAN is unknown. Previous genome-wide analysis of microRNA (miRNA) expression in the kidney has confirmed that miRNAs are closely related to the pathological changes of IgAN. Accordingly, in this study we found that miR-27a-3p is upregulated in IgAN kidney tissues in addition to human podocytes and tubule epithelial HK2 but not mesangial cells. Methylthiazolyldiphenyl-tetrazolium bromide (MTT), flow cytometry, real-time polymerase chain reaction, western blot, and enzyme-linked immunosorbent assays were used to verify the regulatory effects of miR-27a-3p and its inhibition on cell proliferation, apoptosis, and release of inflammatory factors in podocytes and HK2 cells. The target genes of miR-27a-3p were predicted using bioinformatics software; the identity of FosB as a target gene of miR-27a-3p was confirmed by luciferase report assay and western blot. Overall, our findings demonstrated that miR-27a-3p regulates cell apoptosis, cell proliferation, and the release of inflammatory cytokines of human podocytes and HK2 cells by directly targeting FosB. Our results therefore suggested that miR-27a-3p might be associated with the pathophysiology of IgAN and may represent a potential target for further studies related to IgAN mechanism or therapeutics.
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Affiliation(s)
- Yu Liao
- 2nd Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou, 510405, China; Guangdong Hospital of Traditional Chinese Medicine, Guangzhou, 510120, China
| | - Ziyan Wang
- 2nd Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou, 510405, China; General Hospital of Guangzhou Military Command of PLA, Guangzhou, 510062, China
| | - Lixin Wang
- Guangdong Hospital of Traditional Chinese Medicine, Guangzhou, 510120, China; 2nd Clinical Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510062, China
| | - Yanzhao Lin
- Guangdong Hospital of Traditional Chinese Medicine, Guangzhou, 510120, China; 2nd Clinical Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510062, China
| | - Ziyi Ye
- Guangdong Hospital of Traditional Chinese Medicine, Guangzhou, 510120, China; 2nd Clinical Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510062, China
| | - Xufang Zeng
- Guangdong Hospital of Traditional Chinese Medicine, Guangzhou, 510120, China; 2nd Clinical Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510062, China
| | - Fangning Wei
- Guangdong Hospital of Traditional Chinese Medicine, Guangzhou, 510120, China; 2nd Clinical Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510062, China.
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27
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Song N, Li P, Song P, Li Y, Zhou S, Su Q, Li X, Yu Y, Li P, Feng M, Zhang M, Lin W. MicroRNA-138-5p Suppresses Non-small Cell Lung Cancer Cells by Targeting PD-L1/PD-1 to Regulate Tumor Microenvironment. Front Cell Dev Biol 2020; 8:540. [PMID: 32754587 PMCID: PMC7365935 DOI: 10.3389/fcell.2020.00540] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Accepted: 06/09/2020] [Indexed: 01/05/2023] Open
Abstract
Non-small cell lung cancer (NSCLC) is still challenging for treatment owing to immune tolerance and evasion. MicroRNA-138 (miR-138) not only acts as a tumor suppressor to inhibit tumor cell proliferation and migration but also regulates immune response. The regulatory mechanism of miR-138 in NSCLC remains not very clear. Herein, we demonstrated that miR-138-5p treatment decreased the growth of tumor cells and increased the number of tumor-infiltrated DCs. miR-138-5p not only down-regulated the expression of cyclin D3 (CCND3), CCD20, Ki67, and MCM in A549/3LL cells, but also regulated the maturation of DCs in A549-bearing nude mice and the 3LL-bearing C57BL/6 mouse model, and DCs’ capability to enhance T cells to kill tumor cells. Furthermore, miR-138-5p was found to target PD-L1 to down-regulate PD-L1 on tumor cells to reduce the expression of Ki67 and MCM in tumor cells and decrease the tolerance effect on DCs. miR-138-5p also directly down-regulates the expression of PD-L1 and PD-1 on DCs and T cells. Similar results were obtained from isolated human non-small cell lung cancer (NSCLC) cells and DCs. Thus, miR-138-5p inhibits tumor growth and activates the immune system by down-regulating PD-1/PD-L1 and it is a promising therapeutic target for NSCLC.
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Affiliation(s)
- Nannan Song
- Institute of Basic Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.,Institute of Basic Medicine, Shandong First Medical University & Shandong Academy of Medical School, Jinan, China
| | - Peng Li
- Institute of Basic Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.,Institute of Basic Medicine, Shandong First Medical University & Shandong Academy of Medical School, Jinan, China
| | - Pingping Song
- Shandong Cancer Hospital and Institute, Shandong First Medical University & Shandong Academy of Medical School, Jinan, China
| | - Yintao Li
- Shandong Cancer Hospital and Institute, Shandong First Medical University & Shandong Academy of Medical School, Jinan, China
| | - Shuping Zhou
- Institute of Basic Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.,Institute of Basic Medicine, Shandong First Medical University & Shandong Academy of Medical School, Jinan, China
| | - Qinghong Su
- Institute of Basic Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.,Institute of Basic Medicine, Shandong First Medical University & Shandong Academy of Medical School, Jinan, China
| | - Xiaofan Li
- Institute of Basic Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.,Institute of Basic Medicine, Shandong First Medical University & Shandong Academy of Medical School, Jinan, China
| | - Yong Yu
- Institute of Basic Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.,Institute of Basic Medicine, Shandong First Medical University & Shandong Academy of Medical School, Jinan, China
| | - Pengfei Li
- Departments of Medicine, Tibet Nationalities University, Xianyang, China
| | - Meng Feng
- Institute of Basic Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.,Institute of Basic Medicine, Shandong First Medical University & Shandong Academy of Medical School, Jinan, China.,School of Medicine and Life Sciences, Shandong Academy of Medical Sciences, Jinan University, Jinan, China
| | - Min Zhang
- Departments of Medicine, Tibet Nationalities University, Xianyang, China
| | - Wei Lin
- Institute of Basic Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.,Institute of Basic Medicine, Shandong First Medical University & Shandong Academy of Medical School, Jinan, China
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28
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Chi Q, Geng X, Xu K, Wang C, Zhao H. Potential targets and molecular mechanism of miR-331-3p in hepatocellular carcinoma identified by weighted gene coexpression network analysis. Biosci Rep 2020; 40:BSR20200124. [PMID: 32537629 PMCID: PMC7317601 DOI: 10.1042/bsr20200124] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Revised: 03/27/2020] [Accepted: 04/01/2020] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignant tumor. miR-331-3p has been reported relevant to the progression of HCC, but the molecular mechanism of its regulation is still unclear. In the study, we comprehensively studied the role of miR-331-3p in HCC through weighted gene coexpression network analysis (WGCNA) based on The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) and Oncomine. WGCNA was applied to build gene co-expression networks to examine the correlation between gene sets and clinical characteristics, and to identify potential biomarkers. Five hundred one target genes of miR-331-3p were obtained by overlapping differentially expressed genes (DEGs) from the TCGA database and target genes predicted by miRWalk. The critical turquoise module and its eight key genes were screened by WGCNA. Enrichment analysis was implemented based on the genes in the turquoise module. Moreover, 48 genes with a high degree of connectivity were obtained by protein-protein interaction (PPI) analysis of the genes in the turquoise module. From overlapping genes analyzed by WGCNA and PPI, two hub genes were obtained, namely coatomer protein complex subunit zeta 1 (COPZ1) and elongation factor Tu GTP binding domain containing 2 (EFTUD2). In addition, the expression of both hub genes was also significantly higher in tumor tissues compared with normal tissues, as confirmed by analysis based on TCGA and Oncomine. Both hub genes were correlated with poor prognosis based on TCGA data. Receiver operating characteristic (ROC) curve validated that both hub genes exhibited excellent diagnostic efficiency for normal and tumor tissues.
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Affiliation(s)
- Qingjia Chi
- Department of Mechanics and Engineering Structure, Wuhan University of Technology, Wuhan 430070, China
| | - Xinge Geng
- Department of Mechanics and Engineering Structure, Wuhan University of Technology, Wuhan 430070, China
| | - Kang Xu
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Chunli Wang
- ‘111’ Project Laboratory of Biomechanics and Tissue Repair, Bioengineering College, Chongqing University, Chongqing 400044, China
| | - Han Zhao
- Institute of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430056, China
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29
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Zhang B, Huang L, Tu J, Wu T. Hypoxia-Induced Placenta-Specific microRNA (miR-512-3p) Promotes Hepatocellular Carcinoma Progression by Targeting Large Tumor Suppressor Kinase 2. Onco Targets Ther 2020; 13:6073-6083. [PMID: 32612368 PMCID: PMC7323795 DOI: 10.2147/ott.s254612] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Accepted: 05/28/2020] [Indexed: 12/24/2022] Open
Abstract
Background Sustained proliferation and active metastasis are hallmarks of cancer, and they pose major challenges to the development of treatments and a cure for hepatocellular carcinoma (HCC). Thus, the mechanisms of proliferation, migration, and invasion of cancer cells need to be investigated. Many studies indicate that dysregulation of microRNA plays important roles in the progression of HCC, but the role of placenta-specific microRNA (miR-512-3p) in HCC has not been systematically investigated. Purpose In the current study, the expression, biological function, and mechanisms of miR-512-3p involvement in HCC were investigated. Methods Real-time quantitative polymerase chain reaction assays were conducted to determine miR-512-3p levels in HCC tissues and cell lines. The StarBase V3.0 online platform was used to compare miR-512-3p levels in HCC tissues with TCGA data and to identify potential miR-512-3p target genes. Associations between miR-512-3p and clinicopathological characteristics were analyzed statistically. MTT, ethynyl deoxyuridine, and transwell assays were performed to assess cell viability, proliferation, migration, and invasion. The luciferase reporter gene assay was used to verify target genes. Recuse assays were performed to confirm whether large tumor suppressor kinase 2 (LATS2) participated in the regulatory effects of miR-512-3p on HCC cell proliferation and motility, and whether miR-512-3p mediated the tumor-promoting effects of hypoxia. Results miR-512-3p was upregulated in HCC and it was associated with worse survival and unfavorable clinicopathological characteristics. Functional assays indicated that miR-512-3p contributed to HCC cell proliferation, migration, and invasion. Mechanistically, LATS2—a downstream target of miR-512-3p—mediated the tumor-promoting effects of miR-512-3p in HCC. Hypoxia could elevate miR-512-3p levels in HCC cells, and miR-512-3p partially mediated the tumor-promoting effects of hypoxia. Conclusion Hypoxia-induced miR-512-3p contributes to HCC cell proliferation, migration, and invasion by targeting LATS2 and inhibiting the Hippo/yes-associated protein 1 pathways.
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Affiliation(s)
- Bohan Zhang
- Department of Clinical Medicine, Queen Mary Institute, Nanchang University, Nanchang, Jiangxi Province 330000, People's Republic of China
| | - Liang Huang
- Emergency Department, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province 330006, People's Republic of China
| | - Jiangbo Tu
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province 330006, People's Republic of China
| | - Tianming Wu
- Emergency Department, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province 330006, People's Republic of China
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Zhang X, Hu Y, Gong C, Zhang C. Overexpression of miR-518b in non-small cell lung cancer serves as a biomarker and facilitates tumor cell proliferation, migration and invasion. Oncol Lett 2020; 20:1213-1220. [PMID: 32724361 PMCID: PMC7377155 DOI: 10.3892/ol.2020.11667] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Accepted: 04/29/2020] [Indexed: 12/28/2022] Open
Abstract
Several microRNAs (miRNA/miR) have been reported to serve critical roles in tumorigenesis. The present study aimed to investigate miR-518b expression in non-small cell lung cancer (NSCLC), and determine its clinical significance and biological function in this malignancy. Reverse transcription-quantitative PCR was performed to assess miR-518b expression in NSCLC. The diagnostic value of miR-518b was determined via a receiver operating characteristic curve, while its prognostic value was assessed using the Kaplan-Meier method. Gain- and loss-of-function experiments were performed to determine the functional role of miR-518b in NSCLC progression. The results demonstrated that miR-518b expression was upregulated in NSCLC serum, tissues and cell lines compared with the corresponding normal controls. Furthermore, high miR-518b expression was significantly associated with larger tumor size, lymph node metastasis and advanced TNM stage, as well as poor overall survival in patients with NSCLC. Serum miR-518b expression was identified as a candidate diagnostic biomarker for NSCLC, with sensitivity of 88.1% and specificity of 81.7%. Furthermore, the cell experiments indicated that NSCLC cell proliferation, migration and invasion were enhanced following overexpression of miR-518b; however, these effects were reversed following miR-518b knockdown. Taken together, the results of the present study suggest that elevated miR-518b expression in NSCLC serves a potential oncogenic role by facilitating tumor cell proliferation, migration and invasion, and thus may serve as a candidate diagnostic and prognostic biomarker.
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Affiliation(s)
- Xinfang Zhang
- Clinical Laboratory, Qilu Hospital Huantai Branch, Zibo, Shandong 256400, P.R. China
| | - Ying Hu
- Department of Blood Transfusion, Qilu Hospital Huantai Branch, Zibo, Shandong 256400, P.R. China
| | - Cuixue Gong
- Outpatient Department, Zibo Central Hospital, Zibo, Shandong 255000, P.R. China
| | - Chunjie Zhang
- Clinical Laboratory, Zibo Central Hospital, Zibo, Shandong 255000, P.R. China
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Knockdown of long non-coding RNA HOTAIR reverses cisplatin resistance of ovarian cancer cells through inhibiting miR-138-5p-regulated EZH2 and SIRT1. Biol Res 2020; 53:18. [PMID: 32349783 PMCID: PMC7191713 DOI: 10.1186/s40659-020-00286-3] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2019] [Accepted: 04/17/2020] [Indexed: 02/08/2023] Open
Abstract
Background Cisplatin resistance (DDP-resistance) remains one of the major causes of poor prognosis in females with ovarian cancer. Long non-coding RNAs (lncRNAs) have been shown to participate in the regulation of cellular processes, including chemoresistance. The aim of this study was to explore the role of HOX transcript antisense RNA (HOTAIR) in DDP-resistant ovarian cancer cells. Methods DDP-resistant ovarian cancer cell lines (SKOV3/DDP and A2780/DDP) were established. Real-time PCR, western blot, dual-luciferase reporter assay, and flow cytometry were then used to evaluate the effect of HOTAIR/miR-138-5p axis on chemoresistance of DDP-resistant ovarian cancer cells to DDP. Results We found that HOTAIR was upregulated in DDP-resistant cells, while miR-138-5p was downregulated. Knockdown of HOTAIR increased the expression of miR-138-5p in DDP-resistant cells and miR-138-5p is directly bound to HOTAIR. Upregulation of miR-138-5p induced by HOTAIR siRNA or by its mimics enhanced the chemosensitivity of DDP-resistant cells and decreased the expression of EZH2 (enhancer of zeste 2 polycomb repressive complex 2 subunit) and SIRT1 (sirtuin 1). Furthermore, the HOTAIR silencing-induced chemosensitivity of DDP-resistant cells was weakened by miR-138-5p inhibitor. Conclusions These data demonstrate that HOTAIR acts as a sponge of miR-138-5p to prevent its binding to EZH2 and SIRT1, thereby promoting DDP-resistance of ovarian cancer cells. Our work will shed light on the development of therapeutic strategies for ovarian cancer treatment.
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Liu Y, Liu H, Li Y, Mao R, Yang H, Zhang Y, Zhang Y, Guo P, Zhan D, Zhang T. Circular RNA SAMD4A controls adipogenesis in obesity through the miR-138-5p/EZH2 axis. Am J Cancer Res 2020; 10:4705-4719. [PMID: 32292524 PMCID: PMC7150479 DOI: 10.7150/thno.42417] [Citation(s) in RCA: 90] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2019] [Accepted: 03/01/2020] [Indexed: 01/03/2023] Open
Abstract
A growing body of evidence has suggested that circular RNAs (circRNAs) are crucial for the regulation of gene expression and their dysregulation is implicated in several diseases. However, the function of circRNAs in obesity remains largely unexplored. Methods: Global changes in the circRNA expression patterns were detected in adipose tissues derived from obese and lean individuals. In particular, circSAMD4A was identified as significantly differentially upregulated and was functionally analyzed, both in vitro and in vivo, using various approaches. Results: CircSAMD4A overexpression was correlated with a poor prognosis in obese patients. By contrast, circSAMD4A knockdown inhibited differentiation in isolated preadipocytes. In high-fat diet (HFD) -induced obese mice, circSAMD4A knockdown reversed the associated weight gain, reduced food intake, lower body fat, and increased energy expenditure. These mice also exhibited increased insulin sensitivity and glucose tolerance. Furthermore, in vitro experiments indicated that circSAMD4A affected differentiation by binding to miR-138-5p and regulating EZH2 expression. Conclusions: CircSAMD4A regulated preadipocyte differentiation by acting as a miR-138-5p sponge, and thus increasing EZH2 expression. These results suggested that circSAMD4A can serve as a potential target for obesity treatments and/or as a potential prognostic marker for obese patients following bariatric surgery.
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Cyclin D degradation by E3 ligases in cancer progression and treatment. Semin Cancer Biol 2020; 67:159-170. [PMID: 32006569 DOI: 10.1016/j.semcancer.2020.01.012] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Revised: 01/20/2020] [Accepted: 01/27/2020] [Indexed: 12/15/2022]
Abstract
D cyclins include three isoforms: D1, D2, and D3. D cyclins heterodimerize with cyclin-dependent kinase 4/6 (CDK4/6) to form kinase complexes that can phosphorylate and inactivate Rb. Inactivation of Rb triggers the activation of E2F transcription factors, which in turn regulate the expression of genes whose products drive cell cycle progression. Because D-type cyclins function as mitogenic sensors that link growth factor signaling directly with G1 phase progression, it is not surprising that D cyclin accumulation is dysregulated in a variety of human tumors. Elevated expression of D cyclins results from gene amplification, increased gene transcription and protein translation, decreased microRNA levels, and inefficiency or loss of ubiquitylation-mediated protein degradation. This review focuses on the clinicopathological importance of D cyclins, how dysregulation of Ubiquitin-Proteasome System (UPS) contributes to the overexpression of D cyclins, and the therapeutic potential through targeting D cyclin-related machinery in human tumors.
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Luo Z, Zhang M, Cui R, Tili E, Kim T, Lee TJ, Peng Y, Croce C. A negative feedback regulatory loop between miR-138 and TP53 is mediated by USP10. Oncotarget 2019; 10:6288-6296. [PMID: 31695837 PMCID: PMC6824876 DOI: 10.18632/oncotarget.27275] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Accepted: 09/10/2019] [Indexed: 02/05/2023] Open
Abstract
TP53 is a critical tumor suppressor. In approximately 50% of human cancers the TP53 gene is either lost or mutated. The expression level of TP53 in the cells is tightly controlled by a fine-tune machinery, mainly through the Mdm2-mediated ubiquitination pathway. On the other side, the ubiquitinated TP53 could be reversed and stabilized by USP7 and USP10, to keep the amount of TP53 in check. MicroRNAs can negatively regulate TP53 expression levels through direct targeting or positively regulate TP53 function through the repression of negative regulators of TP53. Here we report that microRNA-138 controls TP53 expression by directly targeting USP10. Furthermore, TP53 represses microRNA-138 expression, forming a negative feedback regulatory loop. This finding adds another layer of complexity to the TP53 network.
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Affiliation(s)
- Zhenghua Luo
- Department of Cancer Biology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
| | - Manchao Zhang
- Department of Cancer Biology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
| | - Ri Cui
- Department of Cancer Biology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
| | - Esmerina Tili
- Department of Cancer Biology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
| | - Taewan Kim
- Department of Cancer Biology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
| | - Tae Jin Lee
- Department of Cancer Biology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
| | - Yong Peng
- State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Carlo Croce
- Department of Cancer Biology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
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Yang X, Liu L, Zou H, Zheng YW, Wang KP. circZFR promotes cell proliferation and migration by regulating miR-511/AKT1 axis in hepatocellular carcinoma. Dig Liver Dis 2019; 51:1446-1455. [PMID: 31147216 DOI: 10.1016/j.dld.2019.04.012] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2018] [Revised: 04/04/2019] [Accepted: 04/15/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND Emerging data suggest the crucial regulatory roles of circular RNAs (circRNAs) in hepatocellular carcinoma (HCC). However, the pathophysiology role of circZFR in HCC remains largely unknown. AIMS This study aims to disclose the functions of circZFR in HCC progression and its potential molecular mechanism. METHODS circZFR and miR-511 were identified by qRT-PCR. Colony formation assay, wound-healing assay, transwell assay, and flow cytometry assay were performed to determine the cell proliferation, migration, invasion and apoptosis. Western blotting and immunohistochemistry (IHC) were utilized to evaluate the expression level of AKT1, GSK3β, β-catenin and cascades of proliferation-related proteins both in vitro and in vivo. Dual luciferase reporter assay was conducted to evaluate the interactions among circZFR, miR-511 and AKT1. RESULTS The expression of circZFR was enhanced and the expression of miR-511 was down-regulated in HCC tissues and cells. Functionally, circZFR silencing or miR-511 overexpression suppressed cell proliferation, migration and invasion, and induced apoptosis of HCC cells. Mechanistically, circZFR acted as a miR-511 sponge to up-regulate its target gene AKT1, which activated cascades of proliferation-related proteins (c-Myc, cyclin D1, Survivin and Bcl-2). Furthermore, depletion of circZFR inhibited tumorigenesis and decreased the expression level of AKT1 in xenograft models. CONCLUSION circZFR promotes HCC progression by directly down-regulating miR-511 to activate AKT1 signaling, suggesting that circZFR is a potential target in HCC treatment. Targeting circZFR may provide therapeutic benefits for HCC.
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Affiliation(s)
- Xin Yang
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, PR China.
| | - Ling Liu
- Department of Hepatobiliary and Pancreatic Surgery, Xiangya Hospital, Central South University, Changsha, PR China
| | - Heng Zou
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, PR China
| | - Yan-Wen Zheng
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, PR China
| | - Kun-Peng Wang
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, PR China
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Roles of microRNAs and prospective view of competing endogenous RNAs in mycotoxicosis. MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH 2019; 782:108285. [DOI: 10.1016/j.mrrev.2019.108285] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/14/2018] [Revised: 05/07/2019] [Accepted: 07/05/2019] [Indexed: 12/14/2022]
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Farcas M, Gavrea AA, Gulei D, Ionescu C, Irimie A, Catana CS, Berindan-Neagoe I. SIRT1 in the Development and Treatment of Hepatocellular Carcinoma. Front Nutr 2019; 6:148. [PMID: 31608282 PMCID: PMC6773871 DOI: 10.3389/fnut.2019.00148] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Accepted: 08/27/2019] [Indexed: 12/17/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death worldwide. Current treatment options for inoperable HCCs have decreased therapeutic efficacy and are associated with systemic toxicity and chemoresistance. Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide–dependent enzyme that is frequently overexpressed in HCC, where it promotes tumorigenicity, metastasis, and chemoresistance. SIRT1 also maintains the tumorigenic and self-renewal proprieties of liver cancer stem cells. Multiple tumor-suppressive microRNAs (miRNAs) are downregulated in HCC and, as a consequence, permit SIRT1-induced tumorigenicity. However, either directly targeting SIRT1, combining conventional chemotherapy with SIRT1 inhibitors, or upregulating tumor-suppressive miRNAs may improve therapeutic efficacy and patient outcomes. Here, we present the interaction between SIRT1, miRNAs, and liver cancer stem cells and discuss the consequences of their interplay for the development and treatment of HCC.
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Affiliation(s)
- Marius Farcas
- "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania.,Research Center for Functional Genomics, Biomedicine and Translational Medicine, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Andrei-Alexandru Gavrea
- "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania.,Research Center for Functional Genomics, Biomedicine and Translational Medicine, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Diana Gulei
- MEDFUTURE-Research Center for Advanced Medicine, "Iuliu-Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Calin Ionescu
- "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania.,5th Surgical Department, Municipal Hospital, Cluj-Napoca, Romania
| | - Alexandru Irimie
- 11th Department of Oncological Surgery and Gynecological Oncology, University of Medicine and Pharmacy "Iuliu Hatieganu", Cluj-Napoca, Romania.,Department of Surgery, The Oncology Institute "Prof. Dr. Ion Chiricuţǎ", Cluj-Napoca, Romania
| | - Cristina S Catana
- Department of Medical Biochemistry, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Ioana Berindan-Neagoe
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania.,MEDFUTURE-Research Center for Advanced Medicine, "Iuliu-Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania.,Department of Functional Genomics and Experimental Pathology, The Oncology Institute "Prof Dr. Ion Chiricuţǎ", Cluj-Napoca, Romania
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Kang H, Heo S, Shin JJ, Ji E, Tak H, Ahn S, Lee KJ, Lee EK, Kim W. A miR‐194/PTBP1/CCND3 axis regulates tumor growth in human hepatocellular carcinoma. J Pathol 2019; 249:395-408. [DOI: 10.1002/path.5325] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2019] [Revised: 06/16/2019] [Accepted: 07/11/2019] [Indexed: 01/05/2023]
Affiliation(s)
- Hoin Kang
- Department of BiochemistryThe Catholic University of Korea, College of Medicine Seoul South Korea
- Institute of Aging and Metabolic DiseasesThe Catholic University of Korea, College of Medicine Seoul South Korea
| | - Sungeun Heo
- Department of Molecular Science and TechnologyAjou University Suwon South Korea
| | - Jung Jae Shin
- Department of Molecular Science and TechnologyAjou University Suwon South Korea
| | - Eunbyul Ji
- Department of BiochemistryThe Catholic University of Korea, College of Medicine Seoul South Korea
| | - Hyosun Tak
- Department of BiochemistryThe Catholic University of Korea, College of Medicine Seoul South Korea
| | - Sojin Ahn
- Department of BiochemistryThe Catholic University of Korea, College of Medicine Seoul South Korea
| | - Kyung Jin Lee
- Department of Convergence Medicine, Asan Institute for Life SciencesUniversity of Ulsan College of Medicine Seoul South Korea
| | - Eun Kyung Lee
- Department of BiochemistryThe Catholic University of Korea, College of Medicine Seoul South Korea
- Institute of Aging and Metabolic DiseasesThe Catholic University of Korea, College of Medicine Seoul South Korea
| | - Wook Kim
- Department of Molecular Science and TechnologyAjou University Suwon South Korea
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Zeng D, Xu H, Ji N, Li J, Zhou M, Dan H, Zhou Y, Zeng X, Jiang L, Chen Q. In situ measurement of miR-138 expression in oral squamous cell carcinoma tissue supports the role of this microRNA as a tumor suppressor. J Oral Pathol Med 2019; 48:911-918. [PMID: 31323152 DOI: 10.1111/jop.12933] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Accepted: 06/17/2019] [Indexed: 02/05/2023]
Abstract
BACKGROUND Oral squamous cell carcinoma is the eighth most common cancer worldwide with a relatively high rate of metastasis (~40%). Previously, we showed that microRNA-138 serves as a functional tumor suppressor and plays an important role in oral squamous cell carcinoma metastasis. However, to date, microRNA-138 expression has not been examined in this tumor tissue. Herein, we demonstrated that microRNA-138 expression is downregulated in metastatic oral squamous cell carcinoma specimens using tissue microarray technology with in situ hybridization. METHODS The study included 254 oral squamous cell carcinoma patients from two centers (160 from the Chengdu center and 90 from the Guangzhou center) and four healthy volunteers. RESULTS Multivariate analysis showed that microRNA-138 expression was independent of tumor stage, age, gender, smoking, and alcohol consumption in oral squamous cell carcinoma patients. Interestingly, patients that expressed lower levels of microRNA-138 (determined by in situ hybridization) were more prone to regional lymph node metastasis and exhibited poorer outcomes. These findings support the role of microRNA-138 as a tumor suppressor in oral squamous cell carcinoma. CONCLUSION In summary, the expression level of microRNA-138 is negatively correlated with oral squamous cell carcinoma metastasis; the lower the expression of microRNA-138, the higher the rate of metastasis and the poorer the prognosis of the patients. Therefore, our study confirms that microRNA-138 serves as a tumor suppressor and plays a functional role in oral squamous cell carcinoma tumor metastasis; microRNA-138 constitutes a promising prognosis biomarker and therapeutic target for oral squamous cell carcinoma with metastasis potential.
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Affiliation(s)
- Dequan Zeng
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Hao Xu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Ning Ji
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Jing Li
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Min Zhou
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Hongxia Dan
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Yu Zhou
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Xin Zeng
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Lu Jiang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Qianming Chen
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
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MiR-200-3p Is Potentially Involved in Cell Cycle Arrest by Regulating Cyclin A during Aestivation in Apostichopus japonicus. Cells 2019; 8:cells8080843. [PMID: 31390757 PMCID: PMC6721757 DOI: 10.3390/cells8080843] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Revised: 08/02/2019] [Accepted: 08/04/2019] [Indexed: 11/16/2022] Open
Abstract
The sea cucumber (Apostichopus japonicus) has become a good model organism for studying environmentally induced aestivation in marine invertebrates. We hypothesized that mechanisms that arrest energy-expensive cell cycle activity would contribute significantly to establishing the hypometabolic state during aestivation. Cyclin A is a core and particularly interesting cell cycle regulator that functions in both the S phase and in mitosis. In the present study, negative relationships between miR-200-3p and AjCA expressions were detected at both the transcriptional and the translational levels during aestivation in A. japonicus. Dual-luciferase reporter assays confirmed the targeted location of the miR-200-3p binding site within the AjCA gene transcript. Furthermore, gain- and loss-of-function experiments were conducted in vivo with sea cucumbers to verify the interaction between miR-200-3p and AjCA in intestine tissue by qRT-PCR and Western blotting. The results show that the overexpression of miR-200-3p mimics suppressed AjCA transcript levels and translated protein production, whereas transfection with a miR-200-3p inhibitor enhanced both AjCA mRNA and AjCA protein in A. japonicus intestine. Our findings suggested a potential mechanism that reversibly arrests cell cycle progression during aestivation, which may center on miR-200-3p inhibitory control over the translation of cyclin A mRNA transcripts.
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Blanca A, Sanchez‐Gonzalez A, Requena MJ, Carrasco‐Valiente J, Gomez‐Gomez E, Cheng L, Cimadamore A, Montironi R, Lopez‐Beltran A. Expression of miR‐100 and miR‐138 as prognostic biomarkers in non‐muscle‐invasive bladder cancer. APMIS 2019; 127:545-553. [DOI: 10.1111/apm.12973] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2018] [Accepted: 06/11/2019] [Indexed: 01/02/2023]
Affiliation(s)
- Ana Blanca
- Urology Department, Maimonides Institute of Biomedical Research (IMIBIC), Reina Sofía Hospital University of Córdoba Córdoba Spain
| | - Alvaro Sanchez‐Gonzalez
- Urology Department, Maimonides Institute of Biomedical Research (IMIBIC), Reina Sofía Hospital University of Córdoba Córdoba Spain
| | - Maria J. Requena
- Urology Department, Maimonides Institute of Biomedical Research (IMIBIC), Reina Sofía Hospital University of Córdoba Córdoba Spain
| | - Julia Carrasco‐Valiente
- Urology Department, Maimonides Institute of Biomedical Research (IMIBIC), Reina Sofía Hospital University of Córdoba Córdoba Spain
| | - Enrique Gomez‐Gomez
- Urology Department, Maimonides Institute of Biomedical Research (IMIBIC), Reina Sofía Hospital University of Córdoba Córdoba Spain
| | - Liang Cheng
- Departments of Pathology and Laboratory Medicine, and Urology Indiana University School of Medicine Indianapolis IN USA
| | - Alessia Cimadamore
- Institute of Pathological Anatomy and Histopathology Polytechnic University of the Marche Region Ancona Italy
| | - Rodolfo Montironi
- Institute of Pathological Anatomy and Histopathology Polytechnic University of the Marche Region Ancona Italy
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Down-regulation of microRNA-138 improves immunologic function via negatively targeting p53 by regulating liver macrophage in mice with acute liver failure. Biosci Rep 2019; 39:BSR20190763. [PMID: 31152110 PMCID: PMC6639459 DOI: 10.1042/bsr20190763] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Revised: 05/08/2019] [Accepted: 05/21/2019] [Indexed: 12/23/2022] Open
Abstract
MicroRNAs (miRNAs) have been frequently identified as key mediators in almost all developmental and pathological processes, including those in the liver. The present study was conducted with aims of investigating the role of microRNA-138 (miR-138) in acute liver failure (ALF) via a mechanism involving p53 and liver macrophage in a mouse model. The ALF mouse model was established using C57BL/6 male mice via tail vein injection of Concanamycin A (Con A) solution. The relationship between miR-138 and p53 was tested. The mononuclear macrophages were infected with mimic and inhibitor of miR-138 in order to identify roles of miR-138 in p53 and levels of inflammatory factors. Reverse transcription quantitative polymerase chain reaction (RT-qPCR), Western blot analysis and ELISA were conducted in order to determine the levels of miR-138, inflammatory factors, and p53 during ALF. The results showed an increase in the levels of miR-138 and inflammatory factors in ALF mice induced by the ConA as time progressed and reached the peak at 12 h following treatment with ConA, while it was on the contrary when it came to the level of p53. Dual-luciferase reporter gene assay revealed that p53 was a target gene of miR-138. Furthermore, the results from the in vitro transfection experiments in primary macrophages of ALF mouse showed that miR-138 down-regulated p53 and enhanced levels of inflammatory factors; thus, improving immune function in ALF mice. In conclusion, by negatively targeting p53, the decreased miR-138 improves immunologic function by regulating liver macrophage in mouse models of ALF.
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Qian C, Liang S, Wan G, Dong Y, Lu T, Yan P. Salidroside alleviates high-glucose-induced injury in retinal pigment epithelial cell line ARPE-19 by down-regulation of miR-138. RNA Biol 2019; 16:1461-1470. [PMID: 31251107 DOI: 10.1080/15476286.2019.1637696] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Diabetic retinopathy (DR) is a complication of diabetes leading cause of blindness in adults. Salidroside (SAL) is a main ingredient from Rhodiola rosea L., has been reported to have a beneficial protection on vascular function. However, whether SAL is a suitable treatment for DR remains unreported. The study aimed to investigate the effect of SAL on high-glucose (HG)-induced injury in ARPE-19 cells. ARPE-19 cells were managed with diverse concentrations of glucose, and constructed a model of HG-induced ARPE-19 cells injury. Then, SAL was employed to stimulate ARPE-19 cells, and cell viability, apoptosis, apoptosis-associated factors, the pro-inflammatory cytokines, and ROS levels were determined. The correlation between miR-138 and SIRT1 was predicated by bioinformatics software of TargetScan (http://www.targetscan.org/) and Dual luciferase reporter assay. MiR-138 mimic, inhibitor and NCs were transfected into ARPE-19 cells, and the impacts of miR-138 on HG-induced cell injury were investigated. PI3K/AKT and AMPK signalling pathways were examined to explore the underlying mechanism. The results disclosed that HG inhibited cell viability, promoted apoptosis, up-regulated IL-6 and TNF-α, as well as increased ROS level in ARPE-19 cells. But, SAL obviously alleviated HG-induced ARPE-19 cells injury. Repressed miR-138 was triggered by SAL, and SIRT1 was predicated as a direct target of miR-138. Overexpressed miR-138 declined the protective effect of SAL on HG-injured ARPE-19 cells. Besides, SAL activated PI3K/AKT and AMPK pathways by adjusting miR-138. In conclusions, SAL flattened HG-induced injury in ARPE-19 cells by repression of miR-138 and activating PI3K/AKT and AMPK pathways.
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Affiliation(s)
- Cheng Qian
- Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University , Zhengzhou , Henan , China
| | - Shenzhi Liang
- Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University , Zhengzhou , Henan , China
| | - Guangming Wan
- Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University , Zhengzhou , Henan , China
| | - Yi Dong
- Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University , Zhengzhou , Henan , China
| | - Taiying Lu
- Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University , Zhengzhou , Henan , China
| | - Panshi Yan
- Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University , Zhengzhou , Henan , China
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Yeh M, Oh CS, Yoo JY, Kaur B, Lee TJ. Pivotal role of microRNA-138 in human cancers. Am J Cancer Res 2019; 9:1118-1126. [PMID: 31285946 PMCID: PMC6610051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Accepted: 05/03/2019] [Indexed: 06/09/2023] Open
Abstract
Aberrant expression of certain microRNAs (miRNAs) has been implicated in cancers as a promising druggable target due to the fact that a modulation of the deregulated single miRNA seems to revert the therapeutically unfavorable gene expressions in cancer cell by targeting multiple genes. Global miRNA profiling from a number of patient cohorts in various type of human cancers has identified miR-138 as a signature of tumor suppressor that are down-regulated in most types of human cancer. As a tumor suppressor, miR-138 can inhibit oncogenic proteins by directly bind to their mRNAs. However, in rare cases of cancer stem cell population from glioblastoma, miR-138 seems to be down-regulated and plays an oncogenic function. This review will summarize accumulating evidence that has shown the expression and functional role of miR-138 in various human cancers with its target genes and pathways in a hope to find a better therapeutic option to treat human cancers.
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Affiliation(s)
- Margaret Yeh
- Department of Neurosurgery, University of Texas Health Science Center at Houston, McGovern Medical SchoolHouston, TX 77030, USA
| | - Christina S Oh
- Biochemistry and Cell Biology, Department of Biosciences, Rice UniversityHouston, TX 77030, USA
| | - Ji Young Yoo
- Department of Neurosurgery, University of Texas Health Science Center at Houston, McGovern Medical SchoolHouston, TX 77030, USA
| | - Balveen Kaur
- Department of Neurosurgery, University of Texas Health Science Center at Houston, McGovern Medical SchoolHouston, TX 77030, USA
| | - Tae Jin Lee
- Department of Neurosurgery, University of Texas Health Science Center at Houston, McGovern Medical SchoolHouston, TX 77030, USA
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[MicroRNA-138 regulates cell adhesion-mediated drug resistance phenotype by targeting SGTA in non-Hodgkin's lymphoma]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2019; 39:668-673. [PMID: 30180469 PMCID: PMC7342837 DOI: 10.3760/cma.j.issn.0253-2727.2018.08.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
目的 分析microRNA-138（miR-138）靶向调节小谷氨酰胺三角四肽重复区蛋白α（SGTA）对非霍奇金淋巴瘤（NHL）细胞黏附介导的耐药（cell adhesion-mediated drug resistance, CAM-DR）的影响。 方法 以HS-5细胞或纤连蛋白（FN）构建NHL细胞黏附模型；Western blotting与RQ-PCR分析miR-138对SGTA蛋白及mRNA表达的影响；双荧光素酶报告基因活性检测分析miR-138对SGTA mRNA 3′UTR活性的影响；分别用miR-138下调慢病毒载体（Lv-shmiR-138）、miR-138过表达慢病毒载体（Lv-miR-138）、对照慢病毒载体（Lv-Ctrl）感染Daudi及OCI-Ly8细胞，分析miR-138对细胞周期、黏附能力及CAM-DR的影响；收集35例弥漫大B细胞淋巴瘤患者的石蜡组织标本，分析miR-138的表达情况及其与疾病进展和耐药关系。 结果 ①NHL细胞与FN或HS-5细胞黏附培养后miR-138表达水平显著高于悬浮培养组（P值均<0.05）。②下调miR-138的表达可增强SGTA蛋白的表达水平（P值均<0.05），而对SGTA mRNA的表达水平无显著影响（P值均>0.05）。③转染野生型SGTA 3′UTR载体时，过表达miR-138可显著抑制荧光素酶报告基因活性（0.73±0.03对1.00±0.02，t=0.914，P=0.002）；而转染结合位点突变的突变型载体时，过表达miR-138不能显著改变报告基因活性（0.93±0.04对1.00±0.02，t=1.375，P=0.241）。④在悬浮及黏附培养状态下，过表达miR-138可显著诱导Daudi及OCI-Ly8细胞G1期停滞（P值均<0.05）。⑤下调miR-138的表达对Daudi及OCI-Ly8细胞的黏附能力均无显著影响（P值均>0.05）。⑥在悬浮培养状态下调miR-138的表达时，多柔比星诱导细胞死亡的比例显著下降，而在黏附培养状态下调miR-138的表达，多柔比星诱导细胞死亡的比例显著上升（P值均<0.05）。⑦miR-138在进展及稳定患者中的表达水平显著高于完全缓解以及部分缓解患者，差异具有统计学意义（9.72±1.11对3.06±0.22，t=9.144，P<0.001）。 结论 在黏附微环境中miR-138可通过靶向抑制SGTA诱导细胞周期G1期停滞促进CAM-DR进程。
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Verduci L, Strano S, Yarden Y, Blandino G. The circRNA-microRNA code: emerging implications for cancer diagnosis and treatment. Mol Oncol 2019; 13:669-680. [PMID: 30719845 PMCID: PMC6441890 DOI: 10.1002/1878-0261.12468] [Citation(s) in RCA: 321] [Impact Index Per Article: 53.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Revised: 01/16/2019] [Accepted: 01/21/2019] [Indexed: 12/20/2022] Open
Abstract
Circular RNAs (circRNAs) comprise an emerging new class of endogenous RNAs expressed abundantly by the eukaryotic transcriptome. They are characterized by a covalently closed loop structure, resulting in RNA molecules that are more stable than linear RNAs. A growing number of studies indicate that circRNAs play critical roles in human diseases and show great potential as biomarkers and therapeutic targets. The molecular events determined by circRNA activity, the circRNA code, involve other types of noncoding RNA molecules, primarily microRNAs, long noncoding RNAs, and RNA-binding proteins. Herein, we mainly focus on the circRNA-microRNA code, showing how this relationship impacts the regulation of gene expression in cancer. The emerging roles for circRNAs in oncogenic pathways highlight new perspectives for the detailed molecular dissection of cancer pathogenesis and, at the same time, offer new opportunities to design innovative therapeutic strategies. Here, we review recent research advancements in understanding the biogenesis, molecular functions, and significance of circRNAs in cancer diagnosis and treatment.
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Affiliation(s)
- Lorena Verduci
- Unit of Oncogenomic and Epigenetic, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Sabrina Strano
- Unit of Oncogenomic and Epigenetic, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Yosef Yarden
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel
| | - Giovanni Blandino
- Unit of Oncogenomic and Epigenetic, IRCCS Regina Elena National Cancer Institute, Rome, Italy
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Li LX, Li YJ, He JX. Long noncoding RNA PAGBC contributes to nitric oxide (NO) production by sponging miR-511 in airway hyperresponsiveness upon intubation. J Cell Biochem 2019; 120:2058-2069. [PMID: 30246300 DOI: 10.1002/jcb.27513] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2018] [Accepted: 07/26/2018] [Indexed: 01/24/2023]
Abstract
BACKGROUND AND OBJECTIVES In this study, we aimed to study the molecular mechanisms underlying the symptoms of hyperresponsiveness during intubation. METHOD The value of circulating long noncoding RNA (lncRNA)-prognosis-associated gallbladder cancer (PAGBC) in the prediction of hyperresponsiveness upon intubation during general anesthesia was evaluated via the receiver operating characteristic analyses of serum miR-511, serum PAGBC, and serum nitric oxide (NO). In addition, the possible association between lncRNA-PAGBC/NOS1 messenger RNA (mRNA) and miR-511 was further validated via real-time quantitative polymerase chain reaction, immunohistochemistry assay, computational analysis, and luciferase assay. Enzyme-linked immunosorbent assay and Western blot analysis were also conducted to establish the regulatory relationship among PAGBC, miR-511, and NO synthase 1 (NOS1). RESULTS Compared with circulating miR-511 and serum NO, circulating PAGBC was associated with a higher predictive value. In addition, a negative correlation was found between serum miR-511 and serum PAGBC (multicorrelation coefficient: -0.5) as well as between serum miR-511 and serum NO (multicorrelation coefficient: -0.6). In addition, both lncRNA-PAGBC and NO were decreased in patients with hyperresponsiveness, whereas the levels of miR-511 and NOS1 in these patients were similar to those in normal patients. Furthermore, our computational analyses and luciferase assays validated the direct binding between miR-511 and lncRNA-PAGBC, whereas NOS1 mRNA was identified as a virtual target gene of miR-511. Moreover, in the presence of lncRNA-PAGBC, we also observed an evident increase in the levels of NOS1 and NO accompanied by an obvious decrease of miR-511 expression. CONCLUSION LncRNA-PAGBC downregulated the expression of miR-511, which in turn upregulated the expression of NOS1 mRNA and led to the increase in NOS1 expression, thus leading to the inhibited responsiveness (normal-responsiveness rather than hyperresponsiveness) to intubation in patients.
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Affiliation(s)
- Ling-Xia Li
- Anesthesia Department, Yanan University Affiliated Hospital, Yanan, Shaanxi, China
| | - Yuan-Jun Li
- Anesthesia Department, Yanan University Affiliated Hospital, Yanan, Shaanxi, China
| | - Jia-Xuan He
- Respiratory Medicine Department, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
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Zhu D, Gu L, Li Z, Jin W, Lu Q, Ren T. MiR-138-5p suppresses lung adenocarcinoma cell epithelial-mesenchymal transition, proliferation and metastasis by targeting ZEB2. Pathol Res Pract 2019; 215:861-872. [PMID: 30712885 DOI: 10.1016/j.prp.2019.01.029] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Revised: 01/05/2019] [Accepted: 01/25/2019] [Indexed: 12/24/2022]
Abstract
BACKGROUND MiR-138-5p is regarded as a tumour suppressor in many cancers. Transforming growth factor beta (TGF-β) often acts as a tumor promotor at the late stages of human cancers. However, the function of miR-138-5p on lung adenocarcinoma cells induced by TGF-β remains to be further confirmed. METHODS RT-qPCR was used to detect the expression of human lung adenocarcinoma tissues, adjacent normal tissues, and relative cell lines. When the lung adenocarcinoma cells A549 and H1299 were transfected with negative control (NC), miR-138-5p mimics and miR-138-5p inhibitor by lipofectamine3000 and treated with or without TGF-β1, the lung adenocarcinoma cell function was detected by Immunofluorescence, Western blotting (WB), cell counting Kit-8 (CCK8), colony formation, EdU, Wound-healing and Transwell assays. The relation between miR-138-5p and zinc finger E-box-binding homeobox 2 (ZEB2) was detected by RT-qPCR, WB, and Luciferase reporter assays. When ZEB2 was knocked down, the lung adenocarcinoma cell function was detected by WB, CCK8 and Transwell assays. RESULTS The expression of miR-138-5p was decreased in lung adenocarcinoma tissues and cell lines. When treated with or without TGF-β1, overexpression of miR-138-5p suppressed EMT, proliferation and metastasis of A549 and H1299. ZEB2 was verified as the direct target of miR-138-5p. Downregulation of ZEB2 suppressed EMT, proliferation and metastasis of lung adenocarcinoma cell, which could be reversed by miR-138-5p inhibitor. CONCLUSIONS MiR-138-5p inhibits epithelial-mesenchymal transition, growth and metastasis of lung adenocarcinoma cells through targeting ZEB2.
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Affiliation(s)
- Dongyi Zhu
- Department of Respiratory Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Li Gu
- Department of Respiratory Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Zhanxia Li
- Department of Intensive Care Unit, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Wenjing Jin
- Department of Intensive Care Unit, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201399, China
| | - Qingchun Lu
- Department of Respiratory Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
| | - Tao Ren
- Department of Respiratory Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China; Department of Respiratory Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
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Hou X, Yang L, Jiang X, Liu Z, Li X, Xie S, Li G, Liu J. Role of microRNA-141-3p in the progression and metastasis of hepatocellular carcinoma cell. Int J Biol Macromol 2019; 128:331-339. [PMID: 30695725 DOI: 10.1016/j.ijbiomac.2019.01.144] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Revised: 01/24/2019] [Accepted: 01/25/2019] [Indexed: 12/16/2022]
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer related death worldwide. However, the mechanisms underlying HCC progression and metastasis are still in obscure. Here, we used bioinformatic analysis to identify miRNAs that regulate GP73, a specific marker for HCC diagnosis and prognosis. The correlations between miR-141-3p and clinic-pathological factors were analyzed in HCC patient samples; proliferation, migration, invasion, and colony formation were studied using established HCC cell lines. Expression levels of target genes (miR-141-3p, GP73, E-cadherin, N-cadherin, occludin, vimentin, and cytokeratin 18) were detected by either Western blot or qRT-PCR analysis. Xenograft models were established to evaluate tumor growth and metastasis. MiR-141-3p was significantly reduced in HCC tumors and cell lines, highly correlated with tumor progression. In contrast, GP73 was negatively correlated with miR-141-3p in HCC tumors. MiR-141-3p overexpression significantly decreased HCC cell proliferation, migration, and invasion by inhibiting epithelial-mesenchymal transition (EMT). GP73 overexpression partially restored the inhibitory effects of miR-141-3p, while miR-141-3p overexpression markedly inhibited tumor growth and pulmonary metastasis, which were partially reversed by GP73 overexpression. Our findings suggest that miR-141-3p targets GP73 to reverse EMT, subsequently inhibiting HCC progression and metastasis. Thus, overexpression of miR-141-3p could serve as a therapeutic strategy to arrest HCC.
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Affiliation(s)
- Xu Hou
- Department of Hepatobiliary Surgery, Liaocheng People Hospital, Liaocheng, Shandong, China
| | - Le Yang
- Department of Transcranial Doppler, Liaocheng People Hospital, Liaocheng, Shandong, China
| | - Xiaohong Jiang
- Zhong Yuan Academy of Biological Medicine, Liaocheng People's Hospital/Affiliated Liaocheng University, Liaocheng, Shandong, China
| | - Zhiheng Liu
- Department of Hepatobiliary Surgery, Liaocheng People Hospital, Liaocheng, Shandong, China
| | - Xuehua Li
- Department of Hepatobiliary Surgery, Liaocheng People Hospital, Liaocheng, Shandong, China
| | - Shuli Xie
- Department of Hepatobiliary and Pancreatic Surgery, First Hospital of Norman Bethune Medical College, Jilin University, Changchun, Jilin, China
| | - Guangbing Li
- Department of Liver Transplantation and Hepatobiliary Surgery, Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China
| | - Jun Liu
- Department of Liver Transplantation and Hepatobiliary Surgery, Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China.
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Sadri Nahand J, Bokharaei-Salim F, Salmaninejad A, Nesaei A, Mohajeri F, Moshtzan A, Tabibzadeh A, Karimzadeh M, Moghoofei M, Marjani A, Yaghoubi S, Keyvani H. microRNAs: Key players in virus-associated hepatocellular carcinoma. J Cell Physiol 2018; 234:12188-12225. [PMID: 30536673 DOI: 10.1002/jcp.27956] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2018] [Accepted: 11/19/2018] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) is known as one of the major health problems worldwide. Pathological analysis indicated that a variety of risk factors including genetical (i.e., alteration of tumor suppressors and oncogenes) and environmental factors (i.e., viruses) are involved in beginning and development of HCC. The understanding of these risk factors could guide scientists and clinicians to design effective therapeutic options in HCC treatment. Various viruses such as hepatitis B virus (HBV) and hepatitis C virus (HCV) via targeting several cellular and molecular pathways involved in HCC pathogenesis. Among various cellular and molecular targets, microRNAs (miRNAs) have appeared as key players in HCC progression. miRNAs are short noncoding RNAs which could play important roles as oncogenes or tumor suppressors in several malignancies such as HCC. Deregulation of many miRNAs (i.e., miR-222, miR-25, miR-92a, miR-1, let-7f, and miR-21) could be associated with different stages of HCC. Besides miRNAs, exosomes are other particles which are involved in HCC pathogenesis via targeting different cargos, such as DNAs, RNAs, miRNAs, and proteins. In this review, we summarize the current knowledge of the role of miRNAs and exosomes as important players in HCC pathogenesis. Moreover, we highlighted HCV- and HBV-related miRNAs which led to HCC progression.
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Affiliation(s)
- Javid Sadri Nahand
- Department of Virology, Iran University of Medical Sciences, Tehran, Iran
| | | | - Arash Salmaninejad
- Drug Applied Research Center, Student Research Committee, Tabriz University of Medical Science, Tabriz, Iran.,Department of Medical Genetics, Medical Genetics Research Center, Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Abolfazl Nesaei
- Department of Basic Sciences, Faculty of Medicine, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Fatemeh Mohajeri
- Department of Infectious Disease, School of Medicine, Isfahan University of Medical Science, Isfahan, Iran
| | - Azadeh Moshtzan
- Department of Infectious Disease, School of Medicine, Isfahan University of Medical Science, Isfahan, Iran
| | - Alireza Tabibzadeh
- Department of Virology, Iran University of Medical Sciences, Tehran, Iran
| | | | - Mohsen Moghoofei
- Department of Microbiology, Faculty of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Arezo Marjani
- Department of Virology, Iran University of Medical Sciences, Tehran, Iran
| | - Shoeleh Yaghoubi
- Department of Infectious Disease, School of Medicine, Isfahan University of Medical Science, Isfahan, Iran
| | - Hossein Keyvani
- Department of Virology, Iran University of Medical Sciences, Tehran, Iran
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