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Oshins R, Huo Z, Greenberg Z, Clark V, Duarte S, Zhou H, West J, He M, Brantly M, Khodayari N. Plasma Extracellular Vesicle-derived MicroRNA Associated with Human Alpha-1 Antitrypsin Deficiency-mediated Liver Disease. J Clin Transl Hepatol 2025; 13:118-129. [PMID: 39917464 PMCID: PMC11797821 DOI: 10.14218/jcth.2024.00253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Revised: 09/30/2024] [Accepted: 11/04/2024] [Indexed: 02/09/2025] Open
Abstract
Background and Aims Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder associated with liver disease, ranging from fibrosis to hepatocellular carcinoma. The disease remains asymptomatic until its final stages when liver transplantation is the only available therapy. Biomarkers offer an advantage for disease evaluation. The presence of microRNAs (miRNAs) in plasma extracellular vesicles (EVs) presents a noninvasive approach to assess the molecular signatures of the disease. In this study, we aimed to identify miRNA biomarkers to distinguish molecular signatures of the liver disease associated with AATD in AATD individuals. Methods Using small RNA sequencing and qPCR, we examined plasma EV miRNAs in healthy controls (n = 20) and AATD patients (n = 17). We compared the EV miRNAs of AATD individuals with and without liver disease, developing an approach for detecting liver disease. A set of miRNAs identified in the AATD testing cohort was validated in a separate cohort of AATD patients (n = 45). Results We identified differential expression of 178 EV miRNAs in the plasma of the AATD testing cohort compared to controls. We categorized AATD individuals into those with and without liver disease, identifying 39 differentially expressed miRNAs. Six miRNAs were selected to test their ability to discriminate liver disease in AATD. These were validated for their specificity and sensitivity in an independent cohort of 45 AATD individuals. Our logistic model established composite scores with three- and four-miRNA combinations, achieving areas under the curve of 0.737 and 0.751, respectively, for predicting AATD liver disease. Conclusions We introduce plasma EV-derived miRNAs as potential biomarkers for evaluating AATD liver disease. Plasma EV-associated miRNAs may represent a molecular signature of AATD liver disease and could serve as valuable tools for its detection and monitoring.
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Affiliation(s)
- Regina Oshins
- Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Florida, Gainesville, FL, USA
| | - Zhiguang Huo
- Department of Biostatistics, College of Public Health, University of Florida, Gainesville, FL, USA
| | - Zachary Greenberg
- Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, USA
| | - Virginia Clark
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, University of Florida, Gainesville, FL, USA
| | - Sergio Duarte
- Department of Surgery, Division of Transplantation and Hepatobiliary Surgery, University of Florida, Gainesville, FL, USA
| | - Huiping Zhou
- Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond VA Medical Center, Richmond, VA, USA
| | - Jesse West
- Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Florida, Gainesville, FL, USA
| | - Mei He
- Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, USA
| | - Mark Brantly
- Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Florida, Gainesville, FL, USA
| | - Nazli Khodayari
- Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Florida, Gainesville, FL, USA
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Mohamed AA, Nagah Amer N, Osama N, Hafez W, Abdelrahman Ali AE, Shaheen MM, Alhady Alkhalegy AA, Abouahmed EA, Soaida SM, Samy LA, El-Kassas A, Cherrez-Ojeda I, R El-Awady R. Expression of miR-15b-5p and toll-like receptor4 as potential novel diagnostic biomarkers for hepatitis C virus-induced hepatocellular carcinoma. Noncoding RNA Res 2025; 10:262-268. [PMID: 39844891 PMCID: PMC11751402 DOI: 10.1016/j.ncrna.2024.12.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2024] [Revised: 10/08/2024] [Accepted: 12/04/2024] [Indexed: 01/24/2025] Open
Abstract
Objectives Globally, hepatocellular Carcinoma (HCC) ranks seventh in women's cancer and fifth in men's cancer. Early identification can minimize mortality and morbidity. MicroRNAs and Toll-like receptors have been suggested as potential new biomarkers for HCC; Therefore, we explored Toll-like receptor 4 (TLR-4) and miRNA 15b-5p as new non-invasive HCC biomarkers and early detection approaches. Methodology In this case-control study, four primary groups were formed from 400 patients who participated in this study: 100 hepatitis C (HCV) patients without cirrhosis or HCC, 100 HCV with cirrhosis patients, 100 HCC and HCV patients, and 100 healthy controls. The HCC diagnosis was confirmed according to the American Association for the Study of Liver Disease (AASLD) Practice Guidelines. Triphasic computed tomography was used to assess the HCC tumor size. Real-time PCR was used to analyze miRNA 15b-5p and Toll-like receptor 4 (TLR-4) expression profiles. Results Significant diagnostic performance was achieved by miRNA 15b-5p in differentiating the HCC group from the control group, with 90 % sensitivity and 88 % specificity (AUC] 0.935, p < 0.001), while TLR-4 had moderate diagnostic performance with 85 % sensitivity and 86 % specificity (AUC:0.885, p < 0.001). Conclusions The ability of miR-15b-5p to recognize HCC was positive and it outperformed Toll-like receptor4. MiR-15b-5p has the potential to be a more precise and predictive biological marker for HCC than Toll-like receptor4. Future studies exploring different miRNAs and HCC cases from various etiologies are required to better understand the role of miRNAs in this disease and allow for more effective strategies.
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Affiliation(s)
- Amal Ahmed Mohamed
- Department of Biochemistry and Molecular Biology, National Hepatology and Tropical Medicine Research Institute, GOTHI, Cairo, Egypt
| | - Noha Nagah Amer
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt
| | - Noha Osama
- Pediatritic Nutrition, Fitoverfat Nutrition Clinic, Cairo, Egypt
| | - Wael Hafez
- Internal Medicine Department, Medical Research and Clinical Studies Institute, The National Research Centre, Cairo, Egypt
| | - Ali Elsaid Abdelrahman Ali
- Department of Diagnostic and Interventional Radiology, National Hepatology and Tropical Medicine Research Institute, GOTHI, Cairo, Egypt
| | | | | | | | | | - Lamees A. Samy
- Department of Clinical Pathology, Cairo University, Cairo, Egypt
| | - Ahmed El-Kassas
- Department of Radiology, Elsahel Teaching Hospital, GOTHI, Cairo, Egypt
| | - Ivan Cherrez-Ojeda
- Department of Allergy and Immunology, Universidad Espiritu Santo, Samborondon, Ecuador
- Respiralab Research Group, Guayaquil, Ecuador
| | - Rehab R El-Awady
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt
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Asakage M, Usui Y, Komatsu H, Maruyama K, Nezu N, Shimizu H, Tsubota K, Yamakawa N, Umezu T, Takanashi M, Kuroda M, Goto H. Comprehensive microRNA analyses using vitreous humor of ocular sarcoidosis. Graefes Arch Clin Exp Ophthalmol 2025; 263:501-526. [PMID: 39249513 PMCID: PMC11868165 DOI: 10.1007/s00417-024-06619-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Revised: 07/18/2024] [Accepted: 08/15/2024] [Indexed: 09/10/2024] Open
Abstract
PURPOSE MicroRNAs (miRNAs) are non-coding RNAs which have attracted attention as biomarkers in a variety of diseases. However, extensive unbiased analysis of miRNA in vitreous humor of sarcoidosis patients has not been reported. In the present study, we comprehensively analyzed the dysregulated miRNAs in ocular sarcoidosis to search for potential biomarkers. MATERIALS AND METHODS This study included seven patients diagnosed with ocular sarcoidosis (five definite and two presumed). Five patients with unclassified uveitis and 24 with non-inflammatory diseases served as controls. MicroRNA expression levels in vitreous humor samples were measured by microarray, and differentially expressed miRNAs between sarcoidosis and other diseases were explored. Next, pathway enrichment analysis was performed to evaluate the functions of the dysregulated miRNAs, and machine learning was used to search for candidate biomarkers. RESULTS A total of 614 upregulated miRNAs and 8 downregulated miRNAs were detected in vitreous humor of patients with ocular sarcoidosis compared with patients with unclassified uveitis and non-inflammatory diseases. Some dysregulated miRNAs were involved in the TGF-β signaling pathway. Furthermore, we identified miR-764 as the best predictor for ocular sarcoidosis using Boruta selection. CONCLUSIONS In this study, comprehensive miRNA analysis of vitreous humor samples identified dysregulated miRNAs in ocular sarcoidosis. This study suggests new insights into molecular pathogenetic mechanisms of sarcoidosis and may provide useful information toward developing novel diagnostic biomarkers and therapeutic targets for sarcoidosis.
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Affiliation(s)
- Masaki Asakage
- Department of Ophthalmology, Tokyo Medical University, 6-7-1 Nishi-Shinjuku, Shinjuku-Ku, Tokyo, 160-0023, Japan
| | - Yoshihiko Usui
- Department of Ophthalmology, Tokyo Medical University, 6-7-1 Nishi-Shinjuku, Shinjuku-Ku, Tokyo, 160-0023, Japan.
| | - Hiroyuki Komatsu
- Department of Ophthalmology, Tokyo Medical University, 6-7-1 Nishi-Shinjuku, Shinjuku-Ku, Tokyo, 160-0023, Japan
| | - Kazuichi Maruyama
- Department of Vision Informatics, Graduate School of Medicine, Osaka University, 22 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Naoya Nezu
- Department of Ophthalmology, Tokyo Medical University, 6-7-1 Nishi-Shinjuku, Shinjuku-Ku, Tokyo, 160-0023, Japan
| | - Hiroyuki Shimizu
- Department of Ophthalmology, Tokyo Medical University, 6-7-1 Nishi-Shinjuku, Shinjuku-Ku, Tokyo, 160-0023, Japan
| | - Kinya Tsubota
- Department of Ophthalmology, Tokyo Medical University, 6-7-1 Nishi-Shinjuku, Shinjuku-Ku, Tokyo, 160-0023, Japan
| | - Naoyuki Yamakawa
- Department of Ophthalmology, Tokyo Medical University, 6-7-1 Nishi-Shinjuku, Shinjuku-Ku, Tokyo, 160-0023, Japan
| | - Tomohiro Umezu
- Department of Molecular Pathology, Tokyo Medical University, 6-7-1 Nishi-Shinjuku, Shinjuku-Ku, Tokyo, 160-0023, Japan
| | - Masakatsu Takanashi
- Department of Molecular Pathology, Tokyo Medical University, 6-7-1 Nishi-Shinjuku, Shinjuku-Ku, Tokyo, 160-0023, Japan
| | - Masahiko Kuroda
- Department of Molecular Pathology, Tokyo Medical University, 6-7-1 Nishi-Shinjuku, Shinjuku-Ku, Tokyo, 160-0023, Japan
| | - Hiroshi Goto
- Department of Ophthalmology, Tokyo Medical University, 6-7-1 Nishi-Shinjuku, Shinjuku-Ku, Tokyo, 160-0023, Japan
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Chen M, Wang R, Liao L, Li Y, Sun X, Wu H, Lan Q, Deng Z, Liu P, Xu T, Zhou H, Liu M. DanShen Decoction targets miR-93-5p to provide protection against MI/RI by regulating the TXNIP/NLRP3/Caspase-1 signaling pathway. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 135:156225. [PMID: 39547100 DOI: 10.1016/j.phymed.2024.156225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 09/11/2024] [Accepted: 11/05/2024] [Indexed: 11/17/2024]
Abstract
BACKGROUND Bone marrow mesenchymal stem cells (BMSCs) derived exosomes have demonstrated potential therapeutic efficacy on myocardial ischemia/reperfusion injury (MI/RI). This study has explored the underlying mechanisms of Danshen decoction (DSD) pretreated BMSCs-exosomes to treat MI/RI in vivo and in vitro. METHODS Extracellular vesicles extracted from BMSCs were identified, miRNA sequencing was performed to screen the effects of DSD, and verified to target TXNIP in vivo. After MI/RI modeling, rats were treated with BMSCs-exosomes pretreated with DSD or miRNA inhibitor. BMSCs-exosomes, DSD-pretreated BMSCs-exosomes, and miRNA inhibitor/anti-miRNA-pretreated BMSCs-exosomes were used to treat H9c2 cells or MI/RI rats. CCK-8, Tunnel staining, and flow cytometry were performed to measure cell viability. LDH, CK, CK-MB were detected to evaluate cell injury. MDA, SOD, and ROS were used to confirm oxidative stress. Furthermore, IL-1β, IL-18, cleaved-caspase-1, pro-caspase-1, NLRP3, TXNIP, and GSDMD were quantified for the TXNIP/NLRP3/Caspase-1 signaling activation. In addition, echocardiography was used to observe the heart function, and H&E stain was performed to detect pathological injury. RESULTS Following DSD pretreatment, there was a marked elevation in the expression levels of miR-93-5p, miR-16-5p, and miR-15b-5p, with miR-93-5p exhibiting the highest baseMean value. The administration of a miR-93-5p inhibitor yielded effects counteractive to those observed with DSD treatment, leading to reduced cell proliferation, heightened oxidative stress (as indicated by increased levels of SOD and ROS, alongside a decrease in MDA), and enhanced cell apoptosis. Furthermore, DSD effectively mitigated the miR-93-5p-induced upregulation of key inflammatory and apoptotic markers, including IL-1β, IL-18, caspase-1, NLRP3, TXNIP, and GSDMD. Notably, exosomes derived from DSD-pretreated BMSCs demonstrated a capacity to alleviate cardiac damage. CONCLUSION DSD may target miR-93-5p within BMSC-derived exosomes to confer protection against cardiac damage by inhibiting the activation of the TXNIP/NLRP3/Caspase-1 signaling pathway, thereby mitigating cardiomyocyte pyroptosis. This study provides a theoretical foundation for the application of DSD in the treatment of MI/RI.
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Affiliation(s)
- Mingtai Chen
- Department of Cardiovascular Disease, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518000, PR China; Faculty of Chinese Medicine and State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau SAR 999078, PR China
| | - Raoqiong Wang
- Faculty of Chinese Medicine and State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau SAR 999078, PR China; Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou 646000, PR China
| | - Lishang Liao
- Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou 646000, PR China; College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310000, PR China
| | - Yuanyuan Li
- Faculty of Chinese Medicine and State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau SAR 999078, PR China
| | - Xingyu Sun
- Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou 646000, PR China
| | - Hao Wu
- Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou 646000, PR China
| | - Qi Lan
- Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou 646000, PR China
| | - Ziwen Deng
- Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou 646000, PR China
| | - Ping Liu
- Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou 646000, PR China
| | - Tengfei Xu
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310000, PR China.
| | - Hua Zhou
- State Key Laboratory of Traditional Chinese Medicine Syndrome, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510000, China.
| | - Mengnan Liu
- Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou 646000, PR China; College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310000, PR China.
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Guo F, Li H, Wang J, Wang J, Zhang J, Kong F, Zhang Z, Zong J. MicroRNAs in Hepatocellular Carcinoma: Insights into Regulatory Mechanisms, Clinical Significance, and Therapeutic Potential. Cancer Manag Res 2024; 16:1491-1507. [PMID: 39450194 PMCID: PMC11499618 DOI: 10.2147/cmar.s477698] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Accepted: 09/25/2024] [Indexed: 10/26/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. Tumor immune microenvironment (TIME), angiogenesis, epithelial-mesenchymal transformation (EMT), invasion, metastasis, metabolism, and drug resistance are the main factors affecting the development and treatment of tumors. MiRNAs play crucial roles in almost all major cellular biological processes. Studies have been carried out on miRNAs as biomarkers and therapeutic targets. Their dysregulation contributes to the progression and prognosis of HCC. This review aims to explore the molecular cascades and corresponding phenotypic changes caused by aberrant miRNA expression and their regulatory mechanisms, summarize and analyze novel biomarkers from somatic fluids (plasma/serum/urine), and highlight the latent capacity of miRNAs as therapeutic targets.
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Affiliation(s)
- Fenfen Guo
- Departments of Clinical Laboratory, Qingdao Hiser Hospital Affiliated of Qingdao University (Qingdao Traditional Chinese Medicine Hospital), Qingdao, People’s Republic of China
| | - Hong Li
- Departments of Clinical Laboratory, Qingdao Hiser Hospital Affiliated of Qingdao University (Qingdao Traditional Chinese Medicine Hospital), Qingdao, People’s Republic of China
| | - Jingjing Wang
- Departments of Clinical Laboratory, Qingdao Hiser Hospital Affiliated of Qingdao University (Qingdao Traditional Chinese Medicine Hospital), Qingdao, People’s Republic of China
| | - Jiangfeng Wang
- Departments of Clinical Laboratory, Qingdao Hiser Hospital Affiliated of Qingdao University (Qingdao Traditional Chinese Medicine Hospital), Qingdao, People’s Republic of China
| | - Jinling Zhang
- Departments of Clinical Laboratory, Qingdao Hiser Hospital Affiliated of Qingdao University (Qingdao Traditional Chinese Medicine Hospital), Qingdao, People’s Republic of China
| | - Fanfang Kong
- Departments of Clinical Laboratory, Qingdao Hiser Hospital Affiliated of Qingdao University (Qingdao Traditional Chinese Medicine Hospital), Qingdao, People’s Republic of China
| | - Zemin Zhang
- Departments of Infectious Disease, Qingdao Women and Children’s Hospital, Qingdao, People’s Republic of China
| | - Jinbao Zong
- Departments of Clinical Laboratory, Qingdao Hiser Hospital Affiliated of Qingdao University (Qingdao Traditional Chinese Medicine Hospital), Qingdao, People’s Republic of China
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Mikulski D, Kościelny K, Dróżdż I, Mirocha G, Nowicki M, Misiewicz M, Perdas E, Strzałka P, Wierzbowska A, Fendler W. Serum Levels of miR-122-5p and miR-125a-5p Predict Hepatotoxicity Occurrence in Patients Undergoing Autologous Hematopoietic Stem Cell Transplantation. Int J Mol Sci 2024; 25:4355. [PMID: 38673940 PMCID: PMC11050045 DOI: 10.3390/ijms25084355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 04/08/2024] [Accepted: 04/12/2024] [Indexed: 04/28/2024] Open
Abstract
Hepatic complications are an acknowledged cause of mortality and morbidity among patients undergoing hematopoietic stem cell transplantation. In this study, we aimed to evaluate the potential role in the prediction of liver injury of five selected microRNAs (miRNAs)-miR-122-5p, miR-122-3p, miR-15b-5p, miR-99b-5p, and miR-125a-5p-in the setting of autologous hematopoietic stem cell transplantation (ASCT). A total of 66 patients were included in the study: 50 patients (75.8%) with multiple myeloma (MM) and 16 (24.2%) with lymphoma. Blood samples were collected after the administration of the conditioning regimen, on the day of transplant (day 0). The expression levels of selected miRNAs were quantified by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) using the miRCURY LNA miRNA Custom PCR Panels (QIAGEN). In a multivariate logistic regression analysis adjusted for age, sex, and the administered conditioning regimen, two miRNAs, hsa-miR-122-5p (odds ratio, OR 2.10, 95% confidence interval, CI: 1.29-3.42, p = 0.0029) and hsa-miR-125a-5p (OR 0.27, 95% CI: 0.11-0.71, p = 0.0079), were independent for hepatic toxicity occurrence during the 14 days after transplant. Our model in 10-fold cross-validation preserved its diagnostic potential with a receiver operating characteristics area under the curve (ROC AUC) of 0.75, 95% CI: 0.63-0.88 and at optimal cut-off reached 72.0% sensitivity and 74.4% specificity. An elevated serum level of miR-122-5p and decreased level of miR-125a-5p on day 0 are independent risk factors for hepatotoxicity in ASCT recipients, showing promise in accurately predicting post-ASCT complications. Identifying patients susceptible to complications has the potential to reduce procedure costs and optimize the selection of inpatient or outpatient procedures.
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Affiliation(s)
- Damian Mikulski
- Department of Biostatistics and Translational Medicine, Medical University of Lodz, 92-215 Lodz, Poland; (D.M.); (K.K.); (G.M.); (E.P.)
- Department of Hematooncology, Copernicus Memorial Hospital in Lodz, 93-513 Lodz, Poland
| | - Kacper Kościelny
- Department of Biostatistics and Translational Medicine, Medical University of Lodz, 92-215 Lodz, Poland; (D.M.); (K.K.); (G.M.); (E.P.)
| | - Izabela Dróżdż
- Department of Clinical Genetics, Medical University of Lodz, 92-215 Lodz, Poland;
| | - Grzegorz Mirocha
- Department of Biostatistics and Translational Medicine, Medical University of Lodz, 92-215 Lodz, Poland; (D.M.); (K.K.); (G.M.); (E.P.)
| | - Mateusz Nowicki
- Department of Hematology, Medical University of Lodz, 92-215 Lodz, Poland; (M.N.); (M.M.); (P.S.); (A.W.)
- Department of Hematology and Transplantology, Copernicus Memorial Hospital in Lodz, 93-513 Lodz, Poland
| | - Małgorzata Misiewicz
- Department of Hematology, Medical University of Lodz, 92-215 Lodz, Poland; (M.N.); (M.M.); (P.S.); (A.W.)
| | - Ewelina Perdas
- Department of Biostatistics and Translational Medicine, Medical University of Lodz, 92-215 Lodz, Poland; (D.M.); (K.K.); (G.M.); (E.P.)
| | - Piotr Strzałka
- Department of Hematology, Medical University of Lodz, 92-215 Lodz, Poland; (M.N.); (M.M.); (P.S.); (A.W.)
- Department of Hematology and Transplantology, Copernicus Memorial Hospital in Lodz, 93-513 Lodz, Poland
| | - Agnieszka Wierzbowska
- Department of Hematology, Medical University of Lodz, 92-215 Lodz, Poland; (M.N.); (M.M.); (P.S.); (A.W.)
- Department of Hematology and Transplantology, Copernicus Memorial Hospital in Lodz, 93-513 Lodz, Poland
| | - Wojciech Fendler
- Department of Biostatistics and Translational Medicine, Medical University of Lodz, 92-215 Lodz, Poland; (D.M.); (K.K.); (G.M.); (E.P.)
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Qin X, Zhou L, Shen Y, Gu Y, Tang J, Qian J, Cui A, Chen M. CircularRNA Hsa_circ_0093335 promotes hepatocellular carcinoma progression via sponging miR-338-5p. J Cell Mol Med 2023; 27:4080-4092. [PMID: 37837352 PMCID: PMC10746945 DOI: 10.1111/jcmm.17991] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 09/18/2023] [Accepted: 10/05/2023] [Indexed: 10/16/2023] Open
Abstract
Circular RNAs play an important role in the development of various malignancies, including hepatocellular carcinoma (HCC). Nevertheless, the role of Hsa_circ_0093335 (circ0093335) in HCC has not yet been explored. To investigate the biological effects and molecular mechanisms of circ0093335 on HCC. Circ0093335 expression was detected in HCC cells and clinical specimens using qRT-PCR. The association between circ0093335 expression and HCC patients' clinical characteristics was determined using SPSS. The role of circ0093335 in HCC was estimated by overexpression and knockdown experiments in vitro and in vivo. qRT-PCR, nucleoplasma separation assay, FISH assay, RIP, dual luciferase reporter assay and rescue assay were used to validate the regulatory effect of circ0093335 on miR-338-5p. The study findings showed that circ0093335 was upregulated in HCC. High circ0093335 expression was linked with the tumour-node-metastasis stage and microvascular tumour invasion. circ0093335 is greatly involved in HCC cell proliferation, aggressive ability and mouse tumour growth, according to many in vitro and in vivo tests. Mechanistically, circ0093335 downregulated miR-338-5p expression by sponging, consequently promoting HCC progression. Our research indicated that circ0093335 might be a target for HCC therapy since it promotes tumour progression by acting as a miR-338-5p 'sponge'.
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Affiliation(s)
- Xiangyu Qin
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan HospitalFudan UniversityShanghaiChina
| | - Lingyu Zhou
- Department of Emergency Medicine, Huashan HospitalFudan UniversityShanghaiChina
| | - Yaojie Shen
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan HospitalFudan UniversityShanghaiChina
| | - Yuwei Gu
- Department of Rehabilitation MedicineHuashan HospitalShanghaiChina
| | - Jia Tang
- Department of Infectious Diseases, Peking Union Medical College HospitalChinese Academy of Medical SciencesBeijingChina
| | - Junwei Qian
- Department of Emergency Medicine, Huashan HospitalFudan UniversityShanghaiChina
| | - An Cui
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan HospitalFudan UniversityShanghaiChina
| | - Mingquan Chen
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan HospitalFudan UniversityShanghaiChina
- Department of Emergency Medicine, Huashan HospitalFudan UniversityShanghaiChina
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8
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Rana M, Saini M, Das R, Gupta S, Joshi T, Mehta DK. Circulating MicroRNAs: Diagnostic Value as Biomarkers in the Detection of Non-alcoholic Fatty Liver Diseases and Hepatocellular Carcinoma. Microrna 2023; 12:99-113. [PMID: 37005546 DOI: 10.2174/2211536612666230330083146] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 01/09/2023] [Accepted: 01/20/2023] [Indexed: 04/04/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD), a metabolic-related disorder, is the most common cause of chronic liver disease which, if left untreated, can progress from simple steatosis to advanced fibrosis and eventually cirrhosis or hepatocellular carcinoma, which is the leading cause of hepatic damage globally. Currently available diagnostic modalities for NAFLD and hepatocellular carcinoma are mostly invasive and of limited precision. A liver biopsy is the most widely used diagnostic tool for hepatic disease. But due to its invasive procedure, it is not practicable for mass screening. Thus, noninvasive biomarkers are needed to diagnose NAFLD and HCC, monitor disease progression, and determine treatment response. Various studies indicated that serum miRNAs could serve as noninvasive biomarkers for both NAFLD and HCC diagnosis because of their association with different histological features of the disease. Although microRNAs are promising and clinically useful biomarkers for hepatic diseases, larger standardization procedures and studies are still required.
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Affiliation(s)
- Minakshi Rana
- M.M. College of Pharmacy, Maharishi Markandeshwar (Deemed to be) University, Mullana, Ambala, HR, India
| | - Manisha Saini
- M.M. College of Pharmacy, Maharishi Markandeshwar (Deemed to be) University, Mullana, Ambala, HR, India
| | - Rina Das
- M.M. College of Pharmacy, Maharishi Markandeshwar (Deemed to be) University, Mullana, Ambala, HR, India
| | - Sumeet Gupta
- M.M. College of Pharmacy, Maharishi Markandeshwar (Deemed to be) University, Mullana, Ambala, HR, India
| | - Tanishq Joshi
- M.M. College of Pharmacy, Maharishi Markandeshwar (Deemed to be) University, Mullana, Ambala, HR, India
| | - Dinesh Kumar Mehta
- M.M. College of Pharmacy, Maharishi Markandeshwar (Deemed to be) University, Mullana, Ambala, HR, India
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9
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He L, Xu K, Niu L, Lin L. Astragalus polysaccharide (APS) attenuated PD-L1-mediated immunosuppression via the miR-133a-3p/MSN axis in HCC. PHARMACEUTICAL BIOLOGY 2022; 60:1710-1720. [PMID: 36086826 PMCID: PMC9467620 DOI: 10.1080/13880209.2022.2112963] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/17/2023]
Abstract
CONTEXT Astragalus polysaccharide (APS) is a new tumour therapeutic drug, that has an inhibitory effect on a variety of solid tumours. Tumour cell immunosuppression is related to the up-regulation of programmed death ligand 1 (PD-L1). However, whether APS exerts its antitumor effect by regulating PD-L1 remains unclear. OBJECTIVE To explore whether APS exerts its antineoplastic effect via regulating PD-L1-mediated immunosuppression in hepatocellular carcinoma (HCC). MATERIALS AND METHODS SMMC-7721 cells were subcutaneous injected into BALB/C mice for HCC model establishment. Mice were intraperitoneally injected with 100, 200 and 400 mg/kg APS for 12 days. Immunohistochemistry (IHC) was performed to assess CD8+ T cells' rate and PD-L1 level in HCC tissues. HCC cells were pre-treated with 0.1, 0.5 and 1 mg/mL APS for 4 h, then were treated with 10 ng/mL IFN-γ 24 h. PD-L1 level and cell apoptosis was detected by flow cytometry. PD-L1 and Moesin (MSN) proteins were measured by western blot. MiR-133a-3p and MSN mRNA levels were assessed by qRT-PCR. The targets of miR-133a-3p were predicted by starBase, and which was verified by dual-luciferase reporter assay. RESULTS Our findings illustrated that APS dose-dependently inhibited HCC growth tested with IC50 values of 4.2 mg/mL, and IFN-γ-induced PD-L1 expression and attenuated PD-L1-mediated immunosuppression in HCC cells. APS attenuated PD-L1-mediated immunosuppression via miR-133a-3p in HCC cells. Besides, miR-133a-3p targeted to MSN, and MSN inhibited the antitumor effect of APS by maintaining the stability of PD-L1. Moreover, APS attenuated PD-L1-mediated immunosuppression via the miR-133a-3p/MSN axis. CONCLUSIONS APS attenuated PD-L1-mediated immunosuppression via miR-133a-3p/MSN axis to develop an antitumor effect. APS may be an effective drug for HCC treatment.
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Affiliation(s)
- Lihua He
- Department of Oncology, Guangzhou University of Traditional Chinese Medicine, Guangzhou, China
| | - Kecheng Xu
- Department of Oncology, Fuda Cancer Hospital, Guangzhou, China
| | - Lizhi Niu
- Department of Oncology, Fuda Cancer Hospital, Guangzhou, China
| | - Lizhu Lin
- Division of Oncology, First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China
- CONTACT Lizhu Lin Division of Oncology, First Affiliated Hospital, Guangzhou University of Chinese Medicine, No.16, JichangRoad, Guangzhou510504, Guangdong Province, P.R. China
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10
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Rusu I, Pirlog R, Chiroi P, Nutu A, Puia VR, Fetti AC, Rusu DR, Berindan-Neagoe I, Al Hajjar N. The Implications of Noncoding RNAs in the Evolution and Progression of Nonalcoholic Fatty Liver Disease (NAFLD)-Related HCC. Int J Mol Sci 2022; 23:12370. [PMID: 36293225 PMCID: PMC9603983 DOI: 10.3390/ijms232012370] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 10/12/2022] [Accepted: 10/13/2022] [Indexed: 11/07/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver pathology worldwide. Meanwhile, liver cancer represents the sixth most common malignancy, with hepatocellular carcinoma (HCC) as the primary, most prevalent subtype. Due to the rising incidence of metabolic disorders, NAFLD has become one of the main contributing factors to HCC development. However, although NAFLD might account for about a fourth of HCC cases, there is currently a significant gap in HCC surveillance protocols regarding noncirrhotic NAFLD patients, so the majority of NAFLD-related HCC cases were diagnosed in late stages when survival chances are minimal. However, in the past decade, the focus in cancer genomics has shifted towards the noncoding part of the genome, especially on the microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), which have proved to be involved in the regulation of several malignant processes. This review aims to summarize the current knowledge regarding some of the main dysregulated, noncoding RNAs (ncRNAs) and their implications for NAFLD and HCC development. A central focus of the review is on miRNA and lncRNAs that can influence the progression of NAFLD towards HCC and how they can be used as potential screening tools and future therapeutic targets.
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Affiliation(s)
- Ioana Rusu
- Department of Pathology, Regional Institute of Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania
- 3rd Department of General Surgery, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400186 Cluj-Napoca, Romania
| | - Radu Pirlog
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania
| | - Paul Chiroi
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania
| | - Andreea Nutu
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania
| | - Vlad Radu Puia
- 3rd Department of General Surgery, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400186 Cluj-Napoca, Romania
- Department of Surgery, Regional Institute of Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania
| | - Alin Cornel Fetti
- 3rd Department of General Surgery, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400186 Cluj-Napoca, Romania
- Department of Surgery, Regional Institute of Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania
| | - Daniel Radu Rusu
- Department of Pathology, Regional Institute of Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania
| | - Ioana Berindan-Neagoe
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania
| | - Nadim Al Hajjar
- 3rd Department of General Surgery, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400186 Cluj-Napoca, Romania
- Department of Surgery, Regional Institute of Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania
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11
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Han Q, Wang M, Dong X, Wei F, Luo Y, Sun X. Non-coding RNAs in hepatocellular carcinoma: Insights into regulatory mechanisms, clinical significance, and therapeutic potential. Front Immunol 2022; 13:985815. [PMID: 36300115 PMCID: PMC9590653 DOI: 10.3389/fimmu.2022.985815] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Accepted: 09/23/2022] [Indexed: 01/27/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a complex and heterogeneous malignancy with high incidence and poor prognosis. In addition, owing to the lack of diagnostic and prognostic markers, current multimodal treatment options fail to achieve satisfactory outcomes. Tumor immune microenvironment (TIME), angiogenesis, epithelial-mesenchymal transition (EMT), invasion, metastasis, metabolism, and drug resistance are important factors influencing tumor development and therapy. The intercellular communication of these important processes is mediated by a variety of bioactive molecules to regulate pathophysiological processes in recipient cells. Among these bioactive molecules, non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), account for a large part of the human transcriptome, and their dysregulation affects the progression of HCC. The purpose of this review is to evaluate the potential regulatory mechanisms of ncRNAs in HCC, summarize novel biomarkers from somatic fluids (plasma/serum/urine), and explore the potential of some small-molecule modulators as drugs. Thus, through this review, we aim to contribute to a deeper understanding of the regulatory mechanisms, early diagnosis, prognosis, and precise treatment of HCC.
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Affiliation(s)
- Qin Han
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory for Research and Evaluation of Pharmacovigilance, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Mengchen Wang
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory for Research and Evaluation of Pharmacovigilance, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Xi Dong
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory for Research and Evaluation of Pharmacovigilance, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Fei Wei
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory for Research and Evaluation of Pharmacovigilance, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Yun Luo
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory for Research and Evaluation of Pharmacovigilance, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- *Correspondence: Yun Luo, ; Xiaobo Sun,
| | - Xiaobo Sun
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory for Research and Evaluation of Pharmacovigilance, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- *Correspondence: Yun Luo, ; Xiaobo Sun,
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12
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Ding J, Zhao W. The Application of Liquid Biopsy Techniques in High-Risk Population for Hepatocellular Carcinoma. Cancer Manag Res 2022; 14:2735-2748. [PMID: 36133739 PMCID: PMC9484767 DOI: 10.2147/cmar.s373165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Accepted: 08/27/2022] [Indexed: 12/01/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors of the digestive system and has a 5-year overall survival rate of 14.1%. Many HCC patients are diagnosed at an advanced stage, and thus early screening is essential for reducing the mortality of HCC. In addition to commonly used detection indicators such as serum alpha-fetoprotein (AFP), lens culinaris agglutinin-reactive fraction of alpha-fetoprotein (AFP-L3) and abnormal prothrombin (protein induced by vitamin K absence II, PIVKA-II), liquid biopsy techniques have been demonstrated to have diagnostic value in HCC detection. Compared with invasive procedures, liquid biopsy can detect circulatory metabolites of malignant neoplasms. Liquid biopsy techniques can detect circulating tumor cells, circulating tumor DNA, circulating RNA and exosomes and have been used in the early screening, diagnosis and prognostic evaluation of HCC. This paper reviews the molecular biological characteristics and application of different liquid biopsy techniques, and aim to highlight promising biomarkers that may be feasible options for early-stage HCC evaluation to improve early screening in populations at high risk for HCC.
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Affiliation(s)
- Jingnuo Ding
- Department of Infectious Diseases, The First Affiliated Hospital of Soochow University, Suzhou, JiangSu Province, 215000, People’s Republic of China
| | - Weifeng Zhao
- Department of Infectious Diseases, The First Affiliated Hospital of Soochow University, Suzhou, JiangSu Province, 215000, People’s Republic of China
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13
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Dai C, Ma Z, Si J, An G, Zhang W, Li S, Ma Y. Hsa_circ_0007312 Promotes Third-Generation Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor Resistance through Pyroptosis and Apoptosis via the MiR-764/MAPK1 Axis in Lung Adenocarcinoma Cells. J Cancer 2022; 13:2798-2809. [PMID: 35812182 PMCID: PMC9254875 DOI: 10.7150/jca.72066] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Accepted: 06/10/2022] [Indexed: 12/24/2022] Open
Abstract
Purposes: Osimertinib is a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) used for patients with gefitinib (first-generation EGFR-TKI) resistance, but osimertinib resistance inevitably occurs. Therefore, it is necessary to explore the mechanisms of osimertinib resistance. Materials and Methods: We performed quantitative real-time polymerase chain reaction to detect hsa_circ_0007312 (circ7312), miR-764, and MAPK1 expressions in tissues and cells. Western blotting was used to detect protein levels in cells. Cell Counting Kit-8, apoptotic, and Transwell assays were used to explore biological functions. Luciferase assays were used to identify the interactions between circ7312 and miR-764, MAPK1 and miR-764. A xenograft experiment was performed to clarify the role of circ7312 in vivo. Public datasets were used to identify the relation between circ7312 expression and the cell half maximal inhibitory concentration value of osimertinib in 41 lung adenocarcinoma cell lines. The Student t-test, Kaplan-Meier analysis, and Pearson correlation analysis were used in data analysis. Results: We found that circ7312 knockdown increased miR-764 expression and decreased MAPK1 expression, and circ7312 regulated MAPK1 by sponging miR-764. In addition, high circ7312 expression has significant positive correlation with osimertinib IC50 values, circ7312 knockdown decreased the cell half maximal inhibitory concentration value of osimertinib and increased pyroptosis and apoptosis by sponging the miR-764/MAPK1 axis. We also found that circ7312 and MAPK1 were highly expressed in tumor tissues and related to poor prognosis. Xenograft experiments revealed that circ7312 knockdown decreased osimertinib resistance in vivo. Conclusion: We demonstrated that the inhibition of circ7312 decreased osimertinib resistance by promoting pyroptosis and apoptosis via the miR-764/MAPK1 axis, providing a novel target for osimertinib resistance therapy.
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Affiliation(s)
- Chenyue Dai
- Department of Thoracic Surgery II, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Zeming Ma
- Department of Thoracic Surgery II, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Jiahui Si
- Department of Anesthesiology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Guo An
- Department of Laboratory Animals, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Wenlong Zhang
- Department of Laboratory Animals, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Shaolei Li
- Department of Thoracic Surgery II, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Yuanyuan Ma
- Department of Thoracic Surgery II, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
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14
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Ghafouri-Fard S, Khoshbakht T, Hussen BM, Jamal HH, Taheri M, Hajiesmaeili M. A Comprehensive Review on Function of miR-15b-5p in Malignant and Non-Malignant Disorders. Front Oncol 2022; 12:870996. [PMID: 35586497 PMCID: PMC9108330 DOI: 10.3389/fonc.2022.870996] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Accepted: 04/05/2022] [Indexed: 01/01/2023] Open
Abstract
miR-15b-5p is encoded by MIR15B gene. This gene is located on cytogenetic band 3q25.33. This miRNA participates in the pathogenesis of several cancers as well as non-malignant conditions, such as abdominal aortic aneurysm, Alzheimer’s and Parkinson’s diseases, cerebral ischemia reperfusion injury, coronary artery disease, dexamethasone induced steatosis, diabetic complications and doxorubicin-induced cardiotoxicity. In malignant conditions, both oncogenic and tumor suppressor impacts have been described for miR-15b-5p. Dysregulation of miR-15b-5p in clinical samples has been associated with poor outcome in different kinds of cancers. In this review, we discuss the role of miR-15b-5p in malignant and non-malignant conditions.
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Affiliation(s)
- Soudeh Ghafouri-Fard
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Tayyebeh Khoshbakht
- Men’s Health and Reproductive Health Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Bashdar Mahmud Hussen
- Department of Pharmacognosy, College of Pharmacy, Hawler Medical University, Erbil, Iraq
- Center of Research and Strategic Studies, Lebanese French University, Erbil, Iraq
| | - Hazha Hadayat Jamal
- Department of Biology, College of Education, Salahaddin University, Erbil, Iraq
| | - Mohammad Taheri
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Institute of Human Genetics, Jena University Hospital, Jena, Germany
- *Correspondence: Mohammad Taheri, ; Mohammadreza Hajiesmaeili,
| | - Mohammadreza Hajiesmaeili
- Skull Base Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Critical Care Fellowship, Department of Anesthesiology, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- *Correspondence: Mohammad Taheri, ; Mohammadreza Hajiesmaeili,
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Yildiz MT, Tutar L, Giritlioğlu NI, Bayram B, Tutar Y. MicroRNAs and Heat Shock Proteins in Breast Cancer Biology. Methods Mol Biol 2022; 2257:293-310. [PMID: 34432285 DOI: 10.1007/978-1-0716-1170-8_15] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Breast cancer has five major immune types; luminal A, luminal B, HER2, Basal-like, and normal-like. Cells produce a family of protein called heat shock proteins (Hsps) in response to exposure to thermal and other proteotoxic stresses play essential roles in cancer metabolism and this large family shows a diverse set of Hsp involvement in different breast cancer immune types. Recently, Hsp members categorized according to their immune type roles. Hsp family consists of several subtypes formed by molecular weight; Hsp70, Hsp90, Hsp100, Hsp40, Hsp60, and small molecule Hsps. Cancer cells employ Hsps as survival factors since most of these proteins prevent apoptosis. Several studies monitored Hsp roles in breast cancer cells and reported Hsp27 involvement in drug resistance, Hsp70 in tumor cell transformation-progression, and interaction with p53. Furthermore, the association of Hsp90 with steroid receptors and signaling proteins in patients with breast cancer directed research to focus on Hsp-based treatments. miRNAs are known to play key roles in all types of cancer that are upregulated or downregulated in cancer which respectively referred to as oncogenes (oncomirs) or tumor suppressors. Expression profiles of miRNAs may be used to classify, diagnose, and predict different cancer types. It is clear that miRNAs play regulatory roles in gene expression and this work reveals miRNA correlation to Hsp depending on specific breast cancer immune types. Deregulation of specific Hsp genes in breast cancer subtypes allows for identification of new targets for drug design and cancer treatment. Here, we performed miRNA network analysis by recruiting Hsp genes detected in breast cancer subtypes and reviewed some of the miRNAs related to aforementioned Hsp genes.
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Affiliation(s)
- Mehmet Taha Yildiz
- Division of Molecular Medicine, Hamidiye Institute of Health Sciences, University of Health Sciences, Istanbul, Turkey
| | - Lütfi Tutar
- Department of Molecular Biology and Genetics, Faculty of Art and Sciences, Kırşehir Ahi Evran University, Kırşehir, Turkey
| | - Nazlı Irmak Giritlioğlu
- Department of Molecular Medicine, Hamidiye Institute of Health Sciences, University of Health Sciences, Istanbul, Turkey
| | - Banu Bayram
- Department of Nutrition and Dietetics, Hamidiye Faculty of Health Sciences, University of Health Sciences, Istanbul, Turkey
| | - Yusuf Tutar
- Division of Molecular Medicine, Hamidiye Institute of Health Sciences, University of Health Sciences, Istanbul, Turkey.
- Division of Biochemistry, Department of Basic Pharmaceutical Sciences, Hamidiye Faculty of Pharmacy, University of Health Sciences, Istanbul, Turkey.
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16
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Han Z, Li K, Wu J, Wang K, Qiu C, Ye H, Cui C, Song C, Wang K, Shi J, Wang P, Zhang J. Diagnostic value of RNA for hepatocellular carcinoma: a network meta-analysis. Biomark Med 2021; 15:1755-1767. [PMID: 34783583 DOI: 10.2217/bmm-2021-0327] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Accepted: 09/03/2021] [Indexed: 02/07/2023] Open
Abstract
Aim: The aim of this study was to evaluate the capacity of RNA in the diagnosis of hepatocellular carcinoma (HCC). Methods: A systematic review was conducted from PubMed, Cochrane Library, EMBASE and Web of Science databases via well-designed retrieval strategy. Subsequently, the network meta-analysis was performed by the STATA software. Results: Through statistical analysis, the three hypotheses of the network meta-analysis were established. In view of these hypotheses, the diagnostic efficacy of the three markers in HCC (HCC vs healthy people) may be consistent, and the cumulative ranking results showed such a trend: circular RNA >long noncoding RNA >microRNA. Conclusion: Circular RNA may be most effective for diagnosing HCC across the three types of RNA.
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Affiliation(s)
- Zhuo Han
- College of Public Health, Zhengzhou University, 100 Science Avenue, Zhengzhou, 450001, China
- Henan Key Laboratory of Tumor Epidemiology and State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, 450052, Henan Province, PR China
| | - Keming Li
- College of Public Health, Zhengzhou University, 100 Science Avenue, Zhengzhou, 450001, China
- Henan Key Laboratory of Tumor Epidemiology and State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, 450052, Henan Province, PR China
| | - Jinyu Wu
- College of Public Health, Zhengzhou University, 100 Science Avenue, Zhengzhou, 450001, China
- Henan Key Laboratory of Tumor Epidemiology and State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, 450052, Henan Province, PR China
| | - Keyan Wang
- Henan Key Laboratory of Tumor Epidemiology and State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, 450052, Henan Province, PR China
- Henan Institute of Medical & Pharmaceutical Sciences, Zhengzhou University, 40 Daxue Road, Zhengzhou, 450052, China
| | - Cuipeng Qiu
- Henan Key Laboratory of Tumor Epidemiology and State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, 450052, Henan Province, PR China
| | - Hua Ye
- College of Public Health, Zhengzhou University, 100 Science Avenue, Zhengzhou, 450001, China
- Henan Key Laboratory of Tumor Epidemiology and State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, 450052, Henan Province, PR China
| | - Chi Cui
- Henan Key Laboratory of Tumor Epidemiology and State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, 450052, Henan Province, PR China
- Henan Institute of Medical & Pharmaceutical Sciences, Zhengzhou University, 40 Daxue Road, Zhengzhou, 450052, China
| | - Chunhua Song
- College of Public Health, Zhengzhou University, 100 Science Avenue, Zhengzhou, 450001, China
- Henan Key Laboratory of Tumor Epidemiology and State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, 450052, Henan Province, PR China
| | - Kaijuan Wang
- College of Public Health, Zhengzhou University, 100 Science Avenue, Zhengzhou, 450001, China
- Henan Key Laboratory of Tumor Epidemiology and State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, 450052, Henan Province, PR China
| | - Jianxiang Shi
- Henan Key Laboratory of Tumor Epidemiology and State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, 450052, Henan Province, PR China
- Henan Institute of Medical & Pharmaceutical Sciences, Zhengzhou University, 40 Daxue Road, Zhengzhou, 450052, China
| | - Peng Wang
- College of Public Health, Zhengzhou University, 100 Science Avenue, Zhengzhou, 450001, China
- Henan Key Laboratory of Tumor Epidemiology and State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, 450052, Henan Province, PR China
| | - Jianying Zhang
- College of Public Health, Zhengzhou University, 100 Science Avenue, Zhengzhou, 450001, China
- Henan Key Laboratory of Tumor Epidemiology and State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, 450052, Henan Province, PR China
- Henan Institute of Medical & Pharmaceutical Sciences, Zhengzhou University, 40 Daxue Road, Zhengzhou, 450052, China
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Barrera-Saldaña HA, Fernández-Garza LE, Barrera-Barrera SA. Liquid biopsy in chronic liver disease. Ann Hepatol 2021; 20:100197. [PMID: 32444248 DOI: 10.1016/j.aohep.2020.03.008] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Accepted: 03/25/2020] [Indexed: 02/04/2023]
Abstract
Chronic liver diseases account for a considerable toll of incapacities, suffering, deaths, and resources of the nation's health systems. They can be prevented, treated or even cured when the diagnosis is made on time. Traditional liver biopsy remains the gold standard to diagnose liver diseases, but it has several limitations. Liquid biopsy is emerging as a superior alternative to surgical biopsy given that it surpasses the limitations: it is more convenient, readily and repeatedly accessible, safe, cheap, and provides a more detailed molecular and cellular representation of the individual patient's disease. Progress in understanding the molecular and cellular bases of diseased tissues and organs that normally release cells and cellular components into the bloodstream is catapulting liquid biopsy as a source of biomarkers for diagnosis, prognosis, and prediction of therapeutic response, thus supporting the realization of the promises of precision medicine. The review aims to summarize the evidence of the usefulness of liquid biopsy in liver diseases, including the presence of different biomarkers as circulating epithelial cells, cell-free nucleic acids, specific species of DNA and RNA, and the content of extracellular vesicles.
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Affiliation(s)
- Hugo A Barrera-Saldaña
- Innbiogem SC at National Laboratory for Services of Research, Development, and Innovation for the Pharma and Biotech Industries (LANSEDI) of CONACyT Vitaxentrum group, Monterrey, N.L., Mexico; Center for Biotechnological Genomics of National Polytechnical Institute, Reynosa, Tamps., Mexico.
| | - Luis E Fernández-Garza
- Innbiogem SC at National Laboratory for Services of Research, Development, and Innovation for the Pharma and Biotech Industries (LANSEDI) of CONACyT Vitaxentrum group, Monterrey, N.L., Mexico
| | - Silvia A Barrera-Barrera
- Innbiogem SC at National Laboratory for Services of Research, Development, and Innovation for the Pharma and Biotech Industries (LANSEDI) of CONACyT Vitaxentrum group, Monterrey, N.L., Mexico; National Institute of Pediatrics, Mexico City, Mexico
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Extracellular Vesicles as a Novel Liquid Biopsy-Based Diagnosis for the Central Nervous System, Head and Neck, Lung, and Gastrointestinal Cancers: Current and Future Perspectives. Cancers (Basel) 2021; 13:cancers13112792. [PMID: 34205183 PMCID: PMC8200014 DOI: 10.3390/cancers13112792] [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: 04/19/2021] [Revised: 05/28/2021] [Accepted: 06/02/2021] [Indexed: 12/11/2022] Open
Abstract
Simple Summary To improve clinical outcomes, early diagnosis is mandatory in cancer patients. Several diagnostic approaches have been proposed, however, the main drawback relies on the invasive procedures required. Extracellular vesicles (EVs) are bilayer lipid membrane structures released by almost all cells and transferred to remote sites via the bloodstream. The observation that their cargo reflects the cell of origin has opened a new frontier for non-invasive biomarker discovery in oncology. Moreover, since EVs can be recovered from different body fluids, their impact as a Correctdiagnostic tool has gained particular interest. Hence, in the last decade, several studies using different biological fluids have been performed, showing the valuable contributions of EVs as tumour biomarkers, and their improved diagnostic power when combined with currently available tumour markers. In this review, the most relevant data on the diagnostic relevance of EVs, alone or in combination with the well-established tumour markers, are discussed. Abstract Early diagnosis, along with innovative treatment options, are crucial to increase the overall survival of cancer patients. In the last decade, extracellular vesicles (EVs) have gained great interest in biomarker discovery. EVs are bilayer lipid membrane limited structures, released by almost all cell types, including cancer cells. The EV cargo, which consists of RNAs, proteins, DNA, and lipids, directly mirrors the cells of origin. EVs can be recovered from several body fluids, including blood, cerebral spinal fluid (CSF), saliva, and Broncho-Alveolar Lavage Fluid (BALF), by non-invasive or minimally invasive approaches, and are therefore proposed as feasible cancer diagnostic tools. In this review, methodologies for EV isolation and characterization and their impact as diagnostics for the central nervous system, head and neck, lung, and gastrointestinal cancers are outlined. For each of these tumours, recent data on the potential clinical applications of the EV’s unique cargo, alone or in combination with currently available tumour biomarkers, have been deeply discussed.
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Zhang F, Yan Y, Cao X, Zhang J, Li Y, Guo C. Methylation of microRNA-338-5p by EED promotes METTL3-mediated translation of oncogene CDCP1 in gastric cancer. Aging (Albany NY) 2021; 13:12224-12238. [PMID: 33882457 PMCID: PMC8109089 DOI: 10.18632/aging.103822] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Accepted: 07/14/2020] [Indexed: 11/25/2022]
Abstract
Unmasking the complex regulatory pathways that mediate the malignant phenotypes of cancer cells can provide novel targets for therapies that could limit the recurrence and metastasis of gastric cancer (GC). Herein, we intended to clarify the role of embryonic ectoderm development protein (EED), microRNA-228-5p (miR-338-5p), methyltransferase like 3 (METTL3) and CUB domain containing protein 1 (CDCP1) in GC. Differentially expressed miRNAs and their target genes were extracted by in silico analysis. The studies revealed high expression of EED in GC tissues and cell lines and it high expression in GC patients was shown to be associated with poor prognosis. The chromatin immunoprecipitation assay identified that EED methylated miR-338-5p to inhibit its expression. EED knockdown could restrain the proliferative and invasive abilities of GC cells by inducing miR-338-5p. Furthermore, miR-338-5p targeted m6A methylase METTL3, while METTL3 amplified the translation of CDCP1 via m6A activity which led to accelerated proliferation and invasion of GC cells. Moreover, in vivo experiments validated that EED promoted the progression of GC through mediating the miR-338-5p/METTL3/CDCP1 axis. Collectively, EED downregulated miR-338-5p through histone methylation, which in turn impaired miR-338-5p-dependent METTL3 inhibition and enhanced CDCP1 translation, therefore contributing to the development of GC.
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Affiliation(s)
- Fangbin Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, P. R. China
| | - Yan Yan
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, P. R. China
| | - Xinguang Cao
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, P. R. China
| | - Jinping Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, P. R. China
| | - Yingxia Li
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, P. R. China
| | - Changqing Guo
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, P. R. China
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20
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Zhu F, Li Q, Li J, Li B, Li D. Long noncoding Mirt2 reduces apoptosis to alleviate myocardial infarction through regulation of the miR-764/PDK1 axis. J Transl Med 2021; 101:165-176. [PMID: 33199822 DOI: 10.1038/s41374-020-00504-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 10/13/2020] [Accepted: 10/16/2020] [Indexed: 11/08/2022] Open
Abstract
Acute myocardial infarction (AMI) is a common clinical cardiovascular disease, which is the leading cause of death and disability worldwide. Abnormal expression of long noncoding RNAs (lncRNA) is reported to be related to myocardial dysfunctions such as myocardial infarction (MI). In this study, we aimed to investigate the role of lncRNA myocardial infarction-related transcription factors 2 (Mirt2) in AMI and the underlying molecular mechanisms in vivo and in vitro. In vivo AMI model was established by occlusion of the left anterior descending coronary artery. Rats were randomly divided into two groups (five rats per group): the sham group and the AMI group. H9c2 cells were cultured under hypoxia for 4 h and then cultured under normoxia to establish the in vitro hypoxia reoxygenation (H/R) model. Our study shows that the myocardial infarct size and the apoptosis in AMI rats were both significantly increased, indicating that the AMI rat model was successfully established. Additionally, the levels of Mirt2 in AMI rats were increased significantly. Knockdown of Mirt2 by shRNA (shMirt2) had no significant effect on apoptosis and MI in sham rats, but significantly promoted apoptosis and MI in AMI rats. In vitro experiments showed that shMirt2 significantly decreased the level of Mirt2 in H9c2 cells and H9c2 cells treated with H/R. It is worth noting that shMirt2 had no significant effect on H9c2 cells, but significantly increased the levels of oxidative stress markers (malondialdehyde and lactate dehydrogenase), and also increased the number of apoptosis of H/R-treated H9c2 cells. Further mechanistic analysis showed that Mirt2 could protect MI and apoptosis in AMI rats by competitively adsorbing miR-764 and reducing the inhibitory effect of miR-764 on 3-phosphoinositide-dependent kinase 1 (PDK1). More importantly, after overexpression of Mirt2, MI and apoptosis were significantly improved in AMI rats, indicating that Mirt2 showed a protective effect in AMI rats. In summary, these findings suggest that that Mirt2 participated in the regulation of MI through the miR-764/PDK1 axis. Therefore, the current findings provide a theoretical basis for the diagnosis and treatment of clinical MI with changes in Mirt2 levels.
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Affiliation(s)
- Fen Zhu
- Department of Cardiology, Wuhan Third Hospital & Tongren Hospital of Wuhan University, Wuhan, 430060, Hubei, China.
| | - Qing Li
- Department of Cardio-Pulmonary Function, Wuhan Third Hospital & Tongren Hospital of Wuhan University, Wuhan, 430060, Hubei, China
| | - Jun Li
- Department of Cardiology, Wuhan Third Hospital & Tongren Hospital of Wuhan University, Wuhan, 430060, Hubei, China
| | - Benlei Li
- Department of Cardiology, Wuhan Third Hospital & Tongren Hospital of Wuhan University, Wuhan, 430060, Hubei, China
| | - Dongsheng Li
- Department of Cardiology, Wuhan Third Hospital & Tongren Hospital of Wuhan University, Wuhan, 430060, Hubei, China
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21
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LncRNA miR503HG inhibits epithelial-mesenchymal transition and angiogenesis in hepatocellular carcinoma by enhancing PDCD4 via regulation of miR-15b. Dig Liver Dis 2021; 53:107-116. [PMID: 33046427 DOI: 10.1016/j.dld.2020.09.008] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2020] [Revised: 09/02/2020] [Accepted: 09/03/2020] [Indexed: 02/08/2023]
Abstract
OBJECTIVE To reveal the effect of lncRNA miR503HG on epithelial-mesenchymal transition (EMT) and angiogenesis in hepatocellular carcinoma (HCC). METHODS The expressions of miR503HG, miR-15b and PDCD4 in HCC tissues and cell lines were measured. After cell transfection, Transwell assay tested the migration and invasion ability of HCC cells. qRT-PCR and Western blot detected the expressions of EMT markers (E-cad, N-cad, Vim and Snail-1). Matrigel-based tube formation assay assessed the angiogenesis capacity of human umbilical vein endothelial cells (HUVECs) cultured in conditioned medium of treated HCC cells. ELISA detected the level of VEGF in supernatant of HUVECs. RIP, RNA pulldown and dual-luciferase reporter assay were applied to verify the binding of miR-15b to miR503HG or PDCD4. pcDNA3.1-miR503HG-BEL-7404 cells or pcDNA3.1-BEL-7404 cells were implanted into nude mice for construction of HCC model in vivo. RESULTS miR503HG and PDCD4 were under-expressed and miR-15b was over-expressed in HCC cells and tissues. Up-regulation of miR503HG and PDCD4 or inhibition of miR-15b hindered migration, invasion and EMT of HCC cells and angiogenesis of HUVECs. Both miR503HG and PDCD4 could bind to miR-15b. Over-expression of miR503HG suppressed HCC growth and angiogenesis in nude mice. CONCLUSION LncRNA miR503HG suppresses EMT and angiogenesis in HCC via miR-15b/PDCD4 axis.
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22
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Resaz R, Cangelosi D, Morini M, Segalerba D, Mastracci L, Grillo F, Bosco MC, Bottino C, Colombo I, Eva A. Circulating exosomal microRNAs as potential biomarkers of hepatic injury and inflammation in a murine model of glycogen storage disease type 1a. Dis Model Mech 2020; 13:dmm043364. [PMID: 32620541 PMCID: PMC7520457 DOI: 10.1242/dmm.043364] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Accepted: 06/23/2020] [Indexed: 12/17/2022] Open
Abstract
Most patients affected by glycogen storage disease type 1a (GSD1a), an inherited metabolic disorder caused by mutations in the enzyme glucose-6-phosphatase-α (G6Pase-α), develop renal and liver complications, including the development of hepatocellular adenoma/carcinoma. The purpose of this study was to identify potential biomarkers of the pathophysiology of the GSD1a-affected liver. To this end, we used the plasma exosomes of a murine model of GSD1a, the LS-G6pc-/- mouse, to uncover the modulation in microRNA expression associated with the disease. The microRNAs differentially expressed between LS-G6pc-/- and wild-type mice, LS-G6pc-/- mice with hepatocellular adenoma and LS-G6pc-/- mice without adenoma, and LS-G6pc-/- mice with amyloidosis and LS-G6pc-/- mice without amyloidosis were identified. Pathway analysis demonstrated that the target genes of the differentially expressed microRNA were significantly enriched for the insulin signaling pathway, glucose and lipid metabolism, Wnt/β-catenin, telomere maintenance and hepatocellular carcinoma, and chemokine and immune regulation signaling pathways. Although some microRNAs were common to the different pathologic conditions, others were unique to the cancerous or inflammatory status of the animals. Therefore, the altered expression of several microRNAs is correlated with various pathologic liver states and might help to distinguish them during the progression of the disease and the development of late GSD1a-associated complications.
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Affiliation(s)
- Roberta Resaz
- Laboratory of Molecular Biology, IRCCS Istituto Giannina Gaslini, Via G. Gaslini 5, 16147 Genova, Italy
| | - Davide Cangelosi
- Laboratory of Molecular Biology, IRCCS Istituto Giannina Gaslini, Via G. Gaslini 5, 16147 Genova, Italy
| | - Martina Morini
- Laboratory of Molecular Biology, IRCCS Istituto Giannina Gaslini, Via G. Gaslini 5, 16147 Genova, Italy
| | - Daniela Segalerba
- Laboratory of Molecular Biology, IRCCS Istituto Giannina Gaslini, Via G. Gaslini 5, 16147 Genova, Italy
| | - Luca Mastracci
- Department of Surgical and Diagnostic Sciences (DISC), Anatomic Pathology Unit, Università degli Studi di Genova, Viale Benedetto XV 6, 16132 Genova, Italy
- National Cancer Research Institute, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132 Genova, Italy
| | - Federica Grillo
- Department of Surgical and Diagnostic Sciences (DISC), Anatomic Pathology Unit, Università degli Studi di Genova, Viale Benedetto XV 6, 16132 Genova, Italy
- National Cancer Research Institute, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132 Genova, Italy
| | - Maria Carla Bosco
- Laboratory of Molecular Biology, IRCCS Istituto Giannina Gaslini, Via G. Gaslini 5, 16147 Genova, Italy
| | - Cristina Bottino
- Department of Experimental Medicine, School of Medicine, Università degli Studi di Genova, Via L. B. Alberti 2, 16132 Genova, Italy
- Laboratory of Clinical and Experimental Immunology, IRCCS Istituto Giannina Gaslini, Via G. Gaslini 5, 16147 Genova, Italy
| | - Irma Colombo
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, via D. Trentacoste 2, 20134 Milano, Italy
| | - Alessandra Eva
- Laboratory of Molecular Biology, IRCCS Istituto Giannina Gaslini, Via G. Gaslini 5, 16147 Genova, Italy
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Orlov YL, Voropaeva EN, Chen M, Baranova AV. Medical genomics at the Systems Biology and Bioinformatics (SBB-2019) school. BMC Med Genomics 2020; 13:127. [PMID: 32948185 PMCID: PMC7500028 DOI: 10.1186/s12920-020-00786-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Affiliation(s)
- Yuriy L. Orlov
- The Digital Health Institute, I.M.Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia
- Novosibirsk State University, 630090 Novosibirsk, Russia
- Research Institute of Internal and Preventive Medicine - Branch of the Institute of Cytology and Genetics SB RAS, 630089 Novosibirsk, Russia
| | - Elena N. Voropaeva
- Research Institute of Internal and Preventive Medicine - Branch of the Institute of Cytology and Genetics SB RAS, 630089 Novosibirsk, Russia
| | - Ming Chen
- Department of Bioinformatics, College of Life Sciences, First Affiliated Hospital of Medical School, Zhejiang University, Hangzhou, 310058 China
| | - Ancha V. Baranova
- George Mason University, Fairfax, VA 22030 USA
- Research Centre for Medical Genetics, 115522 Moscow, Russia
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Zou J, Qian J, Fu H, Yin F, Zhao W, Xu L. MicroRNA‑15b‑5p exerts its tumor repressive role via targeting GDI2: A novel insight into the pathogenesis of thyroid carcinoma. Mol Med Rep 2020; 22:2723-2732. [PMID: 32945458 PMCID: PMC7453593 DOI: 10.3892/mmr.2020.11343] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Accepted: 06/12/2020] [Indexed: 12/24/2022] Open
Abstract
Thyroid carcinoma (THCA) is a malignant tumor of the endocrine system. Previous studies have revealed the vital roles of microRNAs (miRNAs/miRs) in THCA procession. The present study aimed to explore the effects of miR-15b-5p on the progression of THCA and its targeting mechanism. The data of THCA and healthy samples were firstly collected from starbase2.0 and used to analyze the relationship of miR-15b-5p with THCA. Dual-luciferase assay was performed to detect the direct interaction between miR-15b-5p and the predicted target gene GDP dissociation inhibitor 2 (GDI2). The effects of miR-15b-5p and GDI2 on the overall survival of patients with THCA were analyzed using Kaplan-Meier analysis with log rank test. Cell Counting Kit-8 and Transwell assays were conducted to assess the impacts of miR-15b-5p and GDI2 on the proliferation and invasion of THCA cells. Reverse transcription-quantitative PCR and western blot analyses were performed to analyze the expression levels of the related miRNAs and proteins, respectively. miR-15b-5p was found to be downregulated both in THCA tissues and cells, and the low expression of miR-15b-5p was associated with the short overall survival time of patients. Moreover, the upregulation or downregulation of miR-15b-5p could inhibit or enhance the proliferation and invasion of THCA cells, respectively. miR-15b-5p reduced the protein expression levels of matrix metalloproteinase (MMP)2 and MMP9, which were related to cell invasion. Furthermore, GDI2, which was enhanced in THCA and related to the poor prognosis of patients with THCA, was identified as the target gene of miR-15b-5p and negatively regulated by miR-15b-5p. Additional experiments demonstrated that GDI2 overexpression could significantly reduce the antitumor effect of miR-15b-5p and its inhibitory action on the expression levels of MMP2 and MMP9. Thus, the results indicated a potential tumor suppressive role of miR-15b-5p in THCA, which was mainly exerted by targeting GDI2 and modulating MMP2 and MMP9. These findings will increase the understanding on the pathogenesis of THCA and provide novel candidates for THCA therapy.
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Affiliation(s)
- Jidong Zou
- Thyroid Diseases Department, Shandong Provincial ENT Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250022, P.R. China
| | - Jiantong Qian
- Otolaryngology Department, Traditional Chinese Medicine Hospital of Juxian, Rizhao, Shandong 276599, P.R. China
| | - Haiyan Fu
- Pathology Department, Shandong Provincial ENT Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250022, P.R. China
| | - Fawen Yin
- Thyroid Diseases Department, Shandong Provincial ENT Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250022, P.R. China
| | - Wanjun Zhao
- Thyroid Diseases Department, Shandong Provincial ENT Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250022, P.R. China
| | - Liang Xu
- Thyroid Diseases Department, Shandong Provincial ENT Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250022, P.R. China
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Qi Y, Ma Y, Peng Z, Wang L, Li L, Tang Y, He J, Zheng J. Long noncoding RNA PENG upregulates PDZK1 expression by sponging miR-15b to suppress clear cell renal cell carcinoma cell proliferation. Oncogene 2020; 39:4404-4420. [PMID: 32341409 DOI: 10.1038/s41388-020-1297-1] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2019] [Revised: 04/04/2020] [Accepted: 04/07/2020] [Indexed: 11/09/2022]
Abstract
PDZK1 downregulation was reported to independently predict poor prognosis of clear cell renal cell carcinoma (ccRCC) patients and induce ccRCC development and progression. However, the underlying mechanism of PDZK1 downregulation remains unknown. Competing endogenous RNA (ceRNA) networks are emerging as new players in gene regulation and are associated with cancer development. ceRNAs regulate other RNA transcripts by competing for shared miRNAs. To investigate the role and mechanism of ceRNAs in PDZK1 downregulation and the development of ccRCC, we searched databases for miRNAs and lncRNAs that regulate PDZK1 expression in ccRCC tissues and assessed their effects in ccRCC. We found that miR-15b was expressed at higher levels in ccRCC tissues, and its upregulation was clinically associated with lower PDZK1 level, larger tumor size and shorter survival time of ccRCC patients. Conversely, a novel lncRNA (lncPENG) was expressed at a lower level in ccRCC tissues, and its downregulation was associated with the same effects as upregulation of miR-15b. Downregulation of miR-15b and upregulation of lncPENG resulted in a significant increase in PDZK1 level and inhibition of proliferation in vitro and in vivo. Mechanistically, lncPENG directly bound to miR-15b and effectively functioned as a sponge for miR-15b to modulate the expression of PDZK1. Thus, lncPENG may function as a ceRNA to attenuate miR-15b-dependent PDZK1 downregulation and inhibit cell proliferation, suggesting that it may be clinically valuable as a therapeutic target and a prognostic biomarker of ccRCC.
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Affiliation(s)
- Yijun Qi
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
| | - Yuanzhen Ma
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
| | - Zhiqiang Peng
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
| | - Lei Wang
- Department of Urology, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China
| | - Lanxin Li
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
| | - Yilan Tang
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
| | - Junqi He
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
| | - Junfang Zheng
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China.
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Yang Z, Zhang J, Lu D, Sun Y, Zhao X, Wang X, Zhou W, He Q, Jiang Z. Hsa_circ_0137008 suppresses the malignant phenotype in colorectal cancer by acting as a microRNA-338-5p sponge. Cancer Cell Int 2020; 20:67. [PMID: 32158357 PMCID: PMC7057602 DOI: 10.1186/s12935-020-1150-1] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Accepted: 02/24/2020] [Indexed: 12/17/2022] Open
Abstract
Background Circular RNAs (circRNAs) have been shown to play a crucial role in tumorigenesis. In this study, we investigated the function of hsa_circ_0137008 and its underlying molecular mechanism in colorectal cancer (CRC). Methods Gene expression was conducted by quantitative real-time PCR or western blot. Functional experiments were performed by cell count kit-8, colony formation assay, wound healing, and transwell assays. Luciferase reporter assay and RNA pull-down assay were performed to investigate the molecular mechanism of hsa_circ_0137008 in CRC. In addition, the xenograft tumor model was applied to determine the role of hsa_circ_0137008 in vivo. Results Downregulation of hsa_circ_0137008 was observed in CRC tissues and cell lines. Functionally, overexpression of hsa_circ_0137008 inhibited the proliferation of CRC cells, as indicated by the inhibition of proliferative protein expression (Ki67 and PCNA), reduced cell viability and colony formation ability. Upregulation of hsa_circ_0137008 suppressed the migration, invasion, and epithelial to mesenchymal transition (EMT) of CRC cells. Mechanically, hsa_circ_0137008 negatively regulated the expression of microRNA-338-5p (miR-338-5p). Furthermore, hsa_circ_0137008 abated the miR-338-5p mediated promotion on CRC cell progression. Tumor suppressive function of hsa_circ_0137008 was validated in vivo. Conclusion These findings highlighted the fact that overexpression of hsa_circ_0137008 inhibited the progression of CRC via sponging miR-338-5p, suggesting that hsa_circ_0137008/miR-338-5p axis is a principal regulator of CRC tumorigenesis.
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Affiliation(s)
- Zhanfeng Yang
- 1Department of Medicine, Zhengzhou University of Industry Technology, 16 Xueyuan Road, Xinzheng, 451100 Henan China
| | - Jingjing Zhang
- 1Department of Medicine, Zhengzhou University of Industry Technology, 16 Xueyuan Road, Xinzheng, 451100 Henan China
| | - Danghui Lu
- 2Department of Vascular Surgery, Henan Provincial People's Hospital, 7 Weiwu Road, Zhengzhou, 450000 Henan China
| | - Yan Sun
- 1Department of Medicine, Zhengzhou University of Industry Technology, 16 Xueyuan Road, Xinzheng, 451100 Henan China
| | - Xinyong Zhao
- 1Department of Medicine, Zhengzhou University of Industry Technology, 16 Xueyuan Road, Xinzheng, 451100 Henan China
| | - Xiaoqiong Wang
- 1Department of Medicine, Zhengzhou University of Industry Technology, 16 Xueyuan Road, Xinzheng, 451100 Henan China
| | - Wen Zhou
- 3The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, 111 Dade Road, Guangzhou, 510120 China
| | - Qunli He
- 1Department of Medicine, Zhengzhou University of Industry Technology, 16 Xueyuan Road, Xinzheng, 451100 Henan China
| | - Zhi Jiang
- 3The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, 111 Dade Road, Guangzhou, 510120 China
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Gokulnath P, de Cristofaro T, Manipur I, Di Palma T, Soriano AA, Guarracino MR, Zannini M. Long Non-Coding RNA MAGI2-AS3 is a New Player with a Tumor Suppressive Role in High Grade Serous Ovarian Carcinoma. Cancers (Basel) 2019; 11:cancers11122008. [PMID: 31842477 PMCID: PMC6966615 DOI: 10.3390/cancers11122008] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Revised: 12/03/2019] [Accepted: 12/06/2019] [Indexed: 12/24/2022] Open
Abstract
High-Grade Serous Ovarian Carcinoma (HGSC) is the most incidental and lethal subtype of epithelial ovarian cancer (EOC) with a high mortality rate of nearly 65%. Recent findings aimed at understanding the pathogenesis of HGSC have attributed its principal source as the Fallopian Tube (FT). To further comprehend the exact mechanism of carcinogenesis, which is still less known, we performed a transcriptome analysis comparing FT and HGSC. Our study aims at exploring new players involved in the development of HGSC from FT, along with their signaling network, and we chose to focus on non-coding RNAs. Non-coding RNAs (ncRNAs) are increasingly observed to be the major regulators of several cellular processes and could have key functions as biological markers, as well as even a therapeutic approach. The most physiologically relevant and significantly dysregulated non-coding RNAs were identified bioinformatically. After analyzing the trend in HGSC and other cancers, MAGI2-AS3 was observed to be an important player in EOC. We assessed its tumor-suppressive role in EOC by means of various assays. Further, we mapped its signaling pathway using its role as a miRNA sponge to predict the miRNAs binding to MAGI2AS3 and showed it experimentally. We conclude that MAGI2-AS3 acts as a tumor suppressor in EOC, specifically in HGSC by sponging miR-15-5p, miR-374a-5p and miR-374b-5p, and altering downstream signaling of certain mRNAs through a ceRNA network.
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Affiliation(s)
- Priyanka Gokulnath
- IEOS - Institute of Experimental Endocrinology and Oncology ‘G. Salvatore’, National Research Council, via S. Pansini 5, 80131 Napoli, Italy; (P.G.)
- Dpt. Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania “Luigi Vanvitelli”, 81100 Caserta, Italy
| | - Tiziana de Cristofaro
- IEOS - Institute of Experimental Endocrinology and Oncology ‘G. Salvatore’, National Research Council, via S. Pansini 5, 80131 Napoli, Italy; (P.G.)
| | - Ichcha Manipur
- High Performance Computing and Networking Institute, National Research Council, via P. Castellino 111, 80131 Napoli, Italy
| | - Tina Di Palma
- IEOS - Institute of Experimental Endocrinology and Oncology ‘G. Salvatore’, National Research Council, via S. Pansini 5, 80131 Napoli, Italy; (P.G.)
| | - Amata Amy Soriano
- IEOS - Institute of Experimental Endocrinology and Oncology ‘G. Salvatore’, National Research Council, via S. Pansini 5, 80131 Napoli, Italy; (P.G.)
- Present affiliation: IRCCS Casa Sollievo della Sofferenza, Cancer Stem Cells Unit, ISReMIT, 71013 San Giovanni Rotondo FG, Italy
| | - Mario Rosario Guarracino
- Dpt. Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania “Luigi Vanvitelli”, 81100 Caserta, Italy
| | - Mariastella Zannini
- IEOS - Institute of Experimental Endocrinology and Oncology ‘G. Salvatore’, National Research Council, via S. Pansini 5, 80131 Napoli, Italy; (P.G.)
- Correspondence:
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Jiang Y, He J, Li Y, Guo Y, Tao H. The Diagnostic Value of MicroRNAs as a Biomarker for Hepatocellular Carcinoma: A Meta-Analysis. BIOMED RESEARCH INTERNATIONAL 2019; 2019:5179048. [PMID: 31871941 PMCID: PMC6907051 DOI: 10.1155/2019/5179048] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/10/2019] [Revised: 10/15/2019] [Accepted: 11/05/2019] [Indexed: 12/24/2022]
Abstract
BACKGROUND Recently, the role of microRNAs (miRNAs) in diagnosing cancer has been attracted increasing attention. However, few miRNAs have been applied in clinical practice. The purpose of this study was to evaluate the diagnostic efficacy of miRNAs for hepatocellular carcinoma (HCC) at early stages clinically. METHODS A literature search was carried out using PubMed, Web of Science, and EMBASE databases. We explored the diagnostic value of miRNAs in distinguishing HCC from healthy individuals. The quality assessment was performed in Review Manager 5.3 software. The overall sensitivity and specificity and 95% confidence intervals (CIs) were obtained with random-effects models through Stata 14.0 software. And heterogeneity was assessed using Q test and I 2 statistics. Meta-regression and subgroup analyses were conducted based on the sample, nation, quality of studies, and miRNA profiling. The publication bias was evaluated through Deeks' funnel plot. RESULTS A total of 34 studies, involving in 2747 HCC patients and 2053 healthy individuals, met the inclusion criteria in the 33 included literature studies. In the summary receiver operating characteristic (sROC) curve, AUC was 0.92 (95% CI, 0.90-0.94), with 0.84 (95% CI, 0.79-0.88) sensitivity and 0.87 (95% CI, 0.83-0.90) specificity. There was no publication bias (P=0.48). CONCLUSION miRNAs in vivo can be acted as a potential diagnostic biomarker for HCC, which can facilitate the early diagnosis of HCC in clinical practice.
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Affiliation(s)
- Yao Jiang
- Department of Clinical Laboratory Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Jimin He
- Department of Neurosurgery, Suining Central Hospital, Suining, China
| | - Yiqin Li
- Department of Clinical Laboratory Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Yongcan Guo
- Clinical Laboratory of Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, China
| | - Hualin Tao
- Department of Clinical Laboratory Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, China
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Martinez M, Rossetto IMU, Arantes RMS, Lizarte FSN, Tirapelli LF, Tirapelli DPC, Chuffa LGA, Martinez FE. Serum miRNAs are differentially altered by ethanol and caffeine consumption in rats. Toxicol Res (Camb) 2019; 8:842-849. [PMID: 32055392 PMCID: PMC7003974 DOI: 10.1039/c9tx00069k] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Accepted: 07/15/2019] [Indexed: 12/13/2022] Open
Abstract
Alcoholism is a multifactorial disease with high risk for dependence determined by genetic background, environmental factors and neuroadaptations. The excessive consumption of this substance is related to psychiatric problems, epilepsy, cardiovascular disease, cirrhosis and cancers. Caffeine is one of the most popular psychostimulants currently consumed in the world. The combination of ethanol and caffeine ingested by consuming "energy drinks" is becoming increasingly popular among young people. We analyzed the effect of simultaneous consumption of ethanol and caffeine on the serum profile of miRNAs differentially expressed in the ethanol-drinking rat model (UChB strain). Adult rats were divided into three groups (n = 5 per group): UChB group (rats fed with 1 : 10 (v/v) ethanol ad libitum); UChB + caffeine group (rats fed with 1 : 10 (v/v) ethanol ad libitum + 3 g L-1 of caffeine); control group (rats drinking water used as the control for UChB). The treatment with caffeine occurred from day 95 to 150 days old, totalizing 55 days of ethanol + caffeine ingestion. The expressions of microRNAs (miR) -9-3p, -15b-5p, -16-5p, -21-5p, -200a-3p and -222-3p were detected by Real Time-PCR (RT-PCR). The expressions of miR-9-3p, -15b-5p, -16-5p and -222-3p were upregulated in the UChB group. Conversely, simultaneous ingestion of ethanol and caffeine significantly reversed these expressions to similar levels to control animals, thus emphasizing that caffeine had a protective effect in the presence of ethanol. In addition, miR-21-5p was downregulated with ethanol consumption whereas miR-222-3p was unchanged. Ethanol and caffeine consumption was capable of altering serum miRNAs, which are potential biomarkers for the systemic effects of these addictive substances.
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Affiliation(s)
- M Martinez
- Department of Morphology and Pathology , Federal University of São Carlos (UFSCar) , São Carlos , SP , Brazil
| | - I M U Rossetto
- Department Structural and Functional Biology , University of Campinas (UNICAMP) , Campinas , SP , Brazil
| | - R M S Arantes
- Department of Morphology and Pathology , Federal University of São Carlos (UFSCar) , São Carlos , SP , Brazil
| | - F S N Lizarte
- Department of Surgery and Anatomy , University of São Paulo (USP) , Ribeirão Preto , SP , Brazil
| | - L F Tirapelli
- Department of Surgery and Anatomy , University of São Paulo (USP) , Ribeirão Preto , SP , Brazil
| | - D P C Tirapelli
- Department of Surgery and Anatomy , University of São Paulo (USP) , Ribeirão Preto , SP , Brazil
| | - L G A Chuffa
- Department of Anatomy , State University of São Paulo (UNESP) , Botucatu , SP , Brazil . ; ; Tel: +55 (14) 3880-0024
| | - F E Martinez
- Department of Anatomy , State University of São Paulo (UNESP) , Botucatu , SP , Brazil . ; ; Tel: +55 (14) 3880-0024
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Xu J, Zhang J, Shan F, Wen J, Wang Y. SSTR5‑AS1 functions as a ceRNA to regulate CA2 by sponging miR‑15b‑5p for the development and prognosis of HBV‑related hepatocellular carcinoma. Mol Med Rep 2019; 20:5021-5031. [PMID: 31638225 PMCID: PMC6854603 DOI: 10.3892/mmr.2019.10736] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Accepted: 05/29/2019] [Indexed: 02/06/2023] Open
Abstract
Long non-coding RNAs (lncRNAs) have been implicated in the development and progression of cancer. However, the mechanisms of lncRNAs in hepatitis B virus (HBV) infection-induced hepatocellular carcinoma (HCC) remain unclear. The study aimed to reveal the roles of lncRNAs for HBV-HCC based on the hypothesis of competing endogenous RNA (ceRNA). The lncRNA (GSE27462), miRNA (GSE76903) and mRNA (GSE121248) expression profiles were collected from the Gene Expression Omnibus database. Differentially expressed lncRNAs (DELs), genes (DEGs) and miRNAs (DEMs) were identified using the LIMMA or EdgeR package, respectively. The ceRNA network was constructed based on interaction pairs between miRNAs and mRNAs/lncRNAs. The functions of DEGs in the ceRNA network were predicted using the DAVID database, which was overlapped with the known HCC pathways of Comparative Toxicogenomics Database (CTD) to construct the HCC-related ceRNA network. The prognosis values [overall survival, (OS); recurrence-free survival (RFS)] of genes were validated using the Cancer Genome Atlas (TCGA) data with Cox regression analysis. The present study screened 38 DELs, 127 DEMs and 721 DEGs. A ceRNA network was constructed among 17 DELs, 12 DEMs and 173 DEGs, including the FAM138B-hsa-miR-30c-CCNE2/RRM2 and SSTR5-AS1-hsa-miR-15b-5p-CA2 ceRNA axes. Function enrichment analysis revealed the genes in the ceRNA network that participated in the p53 signaling pathway [cyclin E2 (CCNE2), ribonucleotide reductase M2 subunit (RRM2)] and nitrogen metabolism [carbonic anhydrase 2 (CA2)], which were also included in the pathways of the CTD. Univariate Cox regression analysis revealed that six RNAs (2 DELs: FAM138B, SSTR5-AS1; 2 DEMs: hsa-miR-149, hsa-miR-7; 2 DEGs: CCNE2, RRM2) were significantly associated with OS; while seven RNAs (1 DEL: LINC00284; 3 DEMs: hsa-miR-7, hsa-miR-15b, hsa-miR-30c-2; and 3 DEGs: RRM2, CCNE2, CA2) were significantly associated with RFS. In conclusion, FAM138B-hsa-miR-30c-CCNE2/RRM2 and the SSTR5-AS1-hsa-miR-15b-5p-CA2 ceRNA axes may be important mechanisms for HBV-related HCC.
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Affiliation(s)
- Jing Xu
- Infectious Diseases Division, Affiliated Hospital of Jining Medical University, Jining, Shandong 272029, P.R. China
| | - Jing Zhang
- Department of Gastroenterology, Affiliated Hospital of Jining Medical University, Jining, Shandong 272029, P.R. China
| | - Fenglian Shan
- Infectious Diseases Division, Affiliated Hospital of Jining Medical University, Jining, Shandong 272029, P.R. China
| | - Jie Wen
- Respiratory Medicine, Affiliated Hospital of Jining Medical University, Jining, Shandong 272029, P.R. China
| | - Yue Wang
- Infectious Diseases Division, Affiliated Hospital of Jining Medical University, Jining, Shandong 272029, P.R. China
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An T, Fan T, Zhang XQ, Liu YF, Huang J, Liang C, Lv BH, Wang YQ, Zhao XG, Liu JX, Fu YH, Jiang GJ. Comparison of Alterations in miRNA Expression in Matched Tissue and Blood Samples during Spinal Cord Glioma Progression. Sci Rep 2019; 9:9169. [PMID: 31235820 PMCID: PMC6591379 DOI: 10.1038/s41598-019-42364-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Accepted: 03/28/2019] [Indexed: 02/07/2023] Open
Abstract
Abnormal expression of microRNAs (miRNAs) contributes to glioma initiation. However, the expression of miRNAs in tumour tissue or blood of spinal cord glioma (SCG) patients, particularly in high-grade spinal gliomas (Grade IV) known as glioblastoma (GBM), remains largely unknown. In this study we aimed to determine differentially expressed miRNAs (DEmiRNAs) in the tissue and blood between spinal cord glioblastoma (SC-GBM) patients and low grade SCG (L-SCG) patients. Additionally, we predicted key miRNA targets and pathways that may be critical in glioma development using pathway and gene ontology analysis. A total of 74 miRNAs were determined to be differentially expressed (25 upregulated and 49 downregulated) in blood, while 207 miRNAs (20 up-regulated and 187 down-regulated) were identified in tissue samples. Gene ontology analysis revealed multicellular organism development and positive regulation of macromolecule metabolic process to be primarily involved. Pathway analysis revealed "Glioma", "Signalling pathways regulating pluripotency of stem cells" to be the most relevant pathways. miRNA-mRNA analysis revealed that hsa-miRNA3196, hsa-miR-27a-3p, and hsa-miR-3664-3p and their target genes are involved in cancer progression. Our study provides a molecular basis for SCG pathological grading based on differential miRNA expression.
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Affiliation(s)
- Tian An
- Traditional Chinese Medicine School, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Tao Fan
- Department of Neurosurgery, Sanbo Brain Hospital, Capital Medical University, Beijing, 100093, China.
| | - Xin Qing Zhang
- Department of Neurosurgery, ChuiYangLiu Hospital affiliated to Tsinghua University, Beijing, 100022, China
| | - Yu-Fei Liu
- The Third Affiliated Hospital, Beijing University of Chinese Medicine, Beijing, 100029, China
| | | | - Cong Liang
- Department of Neurosurgery, Sanbo Brain Hospital, Capital Medical University, Beijing, 100093, China
| | - Bo-Han Lv
- Traditional Chinese Medicine School, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Yin-Qian Wang
- Department of Neurosurgery, Sanbo Brain Hospital, Capital Medical University, Beijing, 100093, China
| | - Xin-Gang Zhao
- Department of Neurosurgery, Sanbo Brain Hospital, Capital Medical University, Beijing, 100093, China
| | - Jia-Xian Liu
- University of Southern California, Los Angeles, CA, 90007, USA
| | - Yu- Huan Fu
- Molecular Development and Diagnosis of Tumor Pathology, Department of Basic Medicine, Tangshan Vocational and Technical College, Tangshan, 063000, China
| | - Guang-Jian Jiang
- Traditional Chinese Medicine School, Beijing University of Chinese Medicine, Beijing, 100029, China.
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Peng C, Ye Y, Wang Z, Guan L, Bao S, Li B, Li W. Circulating microRNAs for the diagnosis of hepatocellular carcinoma. Dig Liver Dis 2019; 51:621-631. [PMID: 30744930 DOI: 10.1016/j.dld.2018.12.011] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Revised: 12/16/2018] [Accepted: 12/17/2018] [Indexed: 12/11/2022]
Abstract
AIM There are no existing biomarkers that demonstrate very reliable performance in the diagnosis of hepatocellular carcinoma (HCC), especially in the early stage. Studies have shown that numerous aberrantly expressed circulating microRNAs (miRNAs) can be used as a diagnostic tool for HCC; however, these studies have produced inconsistent results. METHODS We performed a meta-analysis to summarize the diagnostic accuracy of circulating miRNAs, alpha-fetoprotein (AFP), and AFP combined with miRNAs in differentiating HCC patients from non-HCC controls, healthy controls and chronic liver disease controls. We also evaluated the diagnostic accuracy of circulating miRNAs for early-stage HCC. Furthermore, we systematically reviewed the diagnostic effectiveness of single miRNAs and individual miRNA panels. RESULTS Circulating miRNAs showed good diagnostic performance. Compared with single miRNAs, the diagnostic accuracy of miRNA panels was clearly better. The combination of AFP and miRNAs improved the diagnostic accuracy compared with the use of miRNAs or AFP alone. For early-stage HCC patients, circulating miRNAs exhibited relatively satisfactory diagnostic accuracy. CONCLUSIONS Circulating miRNAs can be used as an early diagnostic marker of HCC. The combination of miRNAs and AFP has great potential as a novel strategy for the diagnosis of HCC.
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Affiliation(s)
- Cheng Peng
- Department of Hepatobiliary-Pancreatic Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Yanshuo Ye
- Department of Hepatobiliary-Pancreatic Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Zhanpeng Wang
- Department of Hepatobiliary-Pancreatic Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Lianyue Guan
- Department of Hepatobiliary-Pancreatic Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Suriguga Bao
- Department of Hepatobiliary-Pancreatic Surgery, Inner Mongolia people's Hospital, Hohhot, China
| | - Bo Li
- Department of Epidemiology, School of Public Health of Jilin University, Changchun, China
| | - Wei Li
- Department of Hepatobiliary-Pancreatic Surgery, China-Japan Union Hospital of Jilin University, Changchun, China.
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Fu L, Qi J, Gao X, Zhang N, Zhang H, Wang R, Xu L, Yao Y, Niu M, Xu K. High expression of miR‐338 is associated with poor prognosis in acute myeloid leukemia undergoing chemotherapy. J Cell Physiol 2019; 234:20704-20712. [PMID: 30997674 DOI: 10.1002/jcp.28676] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2019] [Revised: 03/22/2019] [Accepted: 03/25/2019] [Indexed: 12/20/2022]
Affiliation(s)
- Lin Fu
- Blood Diseases Institute Affiliated Hospital of Xuzhou Medical University Xuzhou Medical University Xuzhou Jiangsu China
- Department of Hematology Affiliated Hospital of Xuzhou Medical University Xuzhou Jiangsu China
- Department of Hematology The Second Affiliated Hospital of Guangzhou Medical University Guangzhou China
- Translational Medicine Center The Second Affiliated Hospital of Guangzhou Medical University Guangzhou China
| | - Jialei Qi
- Blood Diseases Institute Affiliated Hospital of Xuzhou Medical University Xuzhou Medical University Xuzhou Jiangsu China
- Department of Hematology Affiliated Hospital of Xuzhou Medical University Xuzhou Jiangsu China
| | - Xiang Gao
- Blood Diseases Institute Affiliated Hospital of Xuzhou Medical University Xuzhou Medical University Xuzhou Jiangsu China
- Department of Hematology Affiliated Hospital of Xuzhou Medical University Xuzhou Jiangsu China
| | - Ninghan Zhang
- Blood Diseases Institute Affiliated Hospital of Xuzhou Medical University Xuzhou Medical University Xuzhou Jiangsu China
| | - Huihui Zhang
- Blood Diseases Institute Affiliated Hospital of Xuzhou Medical University Xuzhou Medical University Xuzhou Jiangsu China
| | - Rong Wang
- Blood Diseases Institute Affiliated Hospital of Xuzhou Medical University Xuzhou Medical University Xuzhou Jiangsu China
| | - Linyan Xu
- Blood Diseases Institute Affiliated Hospital of Xuzhou Medical University Xuzhou Medical University Xuzhou Jiangsu China
- Department of Hematology Affiliated Hospital of Xuzhou Medical University Xuzhou Jiangsu China
| | - Yao Yao
- Blood Diseases Institute Affiliated Hospital of Xuzhou Medical University Xuzhou Medical University Xuzhou Jiangsu China
- Department of Hematology Affiliated Hospital of Xuzhou Medical University Xuzhou Jiangsu China
| | - Mingshan Niu
- Blood Diseases Institute Affiliated Hospital of Xuzhou Medical University Xuzhou Medical University Xuzhou Jiangsu China
- Department of Hematology Affiliated Hospital of Xuzhou Medical University Xuzhou Jiangsu China
| | - Kailin Xu
- Blood Diseases Institute Affiliated Hospital of Xuzhou Medical University Xuzhou Medical University Xuzhou Jiangsu China
- Department of Hematology Affiliated Hospital of Xuzhou Medical University Xuzhou Jiangsu China
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Pan WY, Zeng JH, Wen DY, Wang JY, Wang PP, Chen G, Feng ZB. Oncogenic value of microRNA-15b-5p in hepatocellular carcinoma and a bioinformatics investigation. Oncol Lett 2018; 17:1695-1713. [PMID: 30675229 PMCID: PMC6341845 DOI: 10.3892/ol.2018.9748] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2017] [Accepted: 10/12/2018] [Indexed: 02/07/2023] Open
Abstract
miR-15b-5p has frequently been reported to function as a biomarker in some malignancies; however, the function of miR-15b-5p in hepatocellular carcinoma (HCC) and its molecular mechanism are still not well understood. The present study was designed to confirm the clinical value of miR-15b-5p and further explore its underlying molecular mechanism. A comprehensive investigation of the clinical value of miR-15b-5p in HCC was investigated by data mining The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets as well as literature. In addition, intersected target genes of miR-15b-5p were predicted using the miRWalk database and differentially expressed genes of HCC from TCGA. Furthermore, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were carried out. Then, a protein-protein interaction network (PPI) was constructed to reveal the interactions between some hub target genes of miR-15b-5p. The miR-15b-5p expression level in HCC was predominantly overexpressed compared with non-HCC tissues samples (SMD=0.618, 95% CI: 0.207, 1.029; P<0.0001) based on 991 HCC and 456 adjacent non-HCC tissue samples. The pooled summary receiver operator characteristic (SROC) of miR-15b-5p was 0.81 (Q*=0.74), and the pooled sensitivity and specificity of miR-15b-5p in HCC were 72% (95% CI: 69–75%) and 68% (95% CI: 65–72%), respectively. Bioinformatically, 225 overlapping genes were selected as prospective target genes of miR-15b-5p in HCC, and profoundly enriched GO terms and KEGG pathway investigation in silico demonstrated that the target genes were associated with prostate cancer, proximal tubule bicarbonate reclamation, heart trabecula formation, extracellular space, and interleukin-1 receptor activity. Five genes (ACACB, RIPK4, MAP2K1, TLR4 and IGF1) were defined as hub genes from the PPI network. The high expression of miR-15b-5p could play an essential part in hepatocarcinogenesis through diverse regulation approaches.
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Affiliation(s)
- Wen-Ya Pan
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Jiang-Hui Zeng
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Dong-Yue Wen
- Department of Ultrasonography, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Jie-Yu Wang
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Peng-Peng Wang
- Department of Nursing, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Gang Chen
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Zhen-Bo Feng
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
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Wang F, Zu Y, Zhu S, Yang Y, Huang W, Xie H, Li G. Long noncoding RNA MAGI2-AS3 regulates CCDC19 expression by sponging miR-15b-5p and suppresses bladder cancer progression. Biochem Biophys Res Commun 2018; 507:231-235. [PMID: 30442369 DOI: 10.1016/j.bbrc.2018.11.013] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Accepted: 11/03/2018] [Indexed: 01/09/2023]
Abstract
Bladder cancer (BCa) belongs to a popular urological malignancy and leads to large numbers of deaths worldwide. Recently, emerging evidences indicate that long noncoding RNAs (lncRNAs) are closely related with BC occurrence and progression. However, the function of lncRNA MAGI2-AS3 remains poorly understood in BC. In this present study, we screened out a novel lncRNA MAGI2-AS3 whose expression was downregulated in BCa tissues. We showed that MAGI2-AS3 downregulation in BCa patients indicated a poor prognosis. Functionally, we showed that MAGI2-AS3 overexpression inhibits proliferation, migration and invasion of BCa cells. Moreover, ectopic expression of MAGI2-AS3 suppresses BCa growth in vivo. Bioinformatics analysis revealed that MAGI2-AS3 could serve as a competing endogenous RNA (ceRNA) for miR-15b-5p. In the meantime, miR-15b-5p directly targeted CCDC19, a tumor suppressor in BCa. Rescue assays demonstrated that knockdown of CCDC19 restored the proliferation, migration and invasion of BCa cells suppressed by MAGI2-AS3 overexpression. In conclusion, this study identified a novel mechanism that MAGI2-AS3/miR-15b-5p/CCDC19 signaling pathway regulates BCa progression.
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Affiliation(s)
- Feng Wang
- Department of Urology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China; Department of Urology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Yanwen Zu
- Department of Parasitology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, 325035, China
| | - Shibin Zhu
- Department of Urology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China
| | - Yu Yang
- Department of Urology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Weiping Huang
- Department of Urology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Hui Xie
- Department of Urology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Gonghui Li
- Department of Urology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China.
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Bilegsaikhan E, Liu HN, Shen XZ, Liu TT. Circulating miR-338-5p is a potential diagnostic biomarker in colorectal cancer. J Dig Dis 2018; 19:404-410. [PMID: 29952077 DOI: 10.1111/1751-2980.12643] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2018] [Revised: 04/12/2018] [Accepted: 06/25/2018] [Indexed: 12/11/2022]
Abstract
OBJECTIVE The expression of miR-338-5p has been reported to be upregulated in colorectal cancer (CRC) tissues. Clinicopathological features indicate that miR-338-5p overexpression correlates with the metastatic status of CRC. This study was aimed to investigate the diagnostic value of serum miR-338-5p for CRC. METHODS Peripheral blood samples were collected from 210 participants, including 80 patients with CRC, 50 with colorectal polyps and 80 healthy controls. Serum miR-338-5p was quantified by quantitative reverse-transcription polymerase chain reaction. The area under the receiver operating characteristic curve (AUROC) was used to estimate the diagnostic value of miR-338-5p, carcinoembryonic antigen (CEA) and the combination of these two biomarkers. RESULTS Serum miR-338-5p levels (fold change) in patients with CRC and colorectal polyps, and controls were 4.94 ± 1.13, 4.12 ± 0.75 and 3.07 ± 0.75, respectively. Significant differences were observed between the groups (P < 0.001). The AUROC of miR-338-5p was 0.923 (95% CI 0.882-0.964) and 0.845 (95% CI 0.792-0.898), respectively, for distinguishing CRC from healthy controls or from those without CRC. The AUROC of the combination of miR-338-5p and CEA was 0.932 (95% CI 0.882-0.964), with a sensitivity of 85%, a specificity of 88.8% at a cut-off value of 8.16. CONCLUSIONS Circulating miR-338-5p may serve as a potential noninvasive diagnostic biomarker for detecting CRC. The combination of miR-338-5p and CEA exhibits the highest diagnostic value in our study.
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Affiliation(s)
| | - Hai Ning Liu
- Department of Gastroenterology, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Xi Zhong Shen
- Department of Gastroenterology, Zhongshan Hospital of Fudan University, Shanghai, China.,Shanghai Institute of Liver Diseases, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Tao Tao Liu
- Department of Gastroenterology, Zhongshan Hospital of Fudan University, Shanghai, China
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Lin X, Chen Y. Identification of Potentially Functional CircRNA-miRNA-mRNA Regulatory Network in Hepatocellular Carcinoma by Integrated Microarray Analysis. Med Sci Monit Basic Res 2018; 24:70-78. [PMID: 29706616 PMCID: PMC5949053 DOI: 10.12659/msmbr.909737] [Citation(s) in RCA: 70] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Accepted: 04/05/2018] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the most common malignancy of the liver and recent studies have revealed that circular RNA (circRNA) plays an important role in the pathogenesis of HCC. Some circRNAs may act as a microRNA (miRNA) sponge to affect miRNA activities in the regulation of messenger RNA (mRNA) expression. However, the circRNA-miRNA-mRNA network in HCC remains largely unknown. MATERIAL AND METHODS The circRNA expression profiles (GSE94508 and GSE97332), miRNA and mRNA expression profile (GSE22058) were downloaded from Gene Expression Omnibus microarray data and then a circRNA-miRNA-mRNA regulatory network in HCC was constructed. Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of differentially expressed (DE) genes were performed. The functional circRNA-miRNA-mRNA regulatory modules were constructed using cytoHubba plugin based on Cytoscape and KEGG enrichment analysis. RESULTS The network contained 60 circRNA-miRNA pairs and 4982 miRNA-mRNA pairs, including 29 circRNAs, 16 miRNAs, and 1249 mRNAs. GO and KEGG pathway analysis revealed the network might be involved in the procession of carcinogenesis such as cell proliferation, cell cycle, and p53 signaling pathway. In addition, 3 top ranked circRNAs (hsa_circ_0078279, hsa_circ_0007456, and hsa_circ_0004913) related networks were identified to be highly correlated with the pathogenesis of HCC. Furthermore, the functional circRNA-miRNA-mRNA regulatory modules were constructed based on the 3 top-ranked circRNAs and those DE genes enriched in carcinogenesis related pathways. CONCLUSIONS This study suggests that a specific circRNA-miRNA-mRNA network is associated with the carcinogenesis of HCC, which might aid in the identification of molecular biomarkers and therapeutic targets for HCC.
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Affiliation(s)
- Xiaoming Lin
- Department of Ultrasound, First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, P.R. China
| | - Yuhan Chen
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
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Li Y, Huang Y, Qi Z, Sun T, Zhou Y. MiR-338-5p Promotes Glioma Cell Invasion by Regulating TSHZ3 and MMP2. Cell Mol Neurobiol 2018; 38:669-677. [PMID: 28780604 PMCID: PMC11482023 DOI: 10.1007/s10571-017-0525-x] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2017] [Accepted: 07/19/2017] [Indexed: 01/11/2023]
Abstract
This study was designed to examine differential expression of miR-338-5p in gliomas and the role of miR-338-5p in glioma cell invasion via its potential target gene TSHZ3 encoding Teashirt zinc finger homobox 3, predicted by bioinformatics, and matrix metallopeptidase 2 (MMP2), the key pro-invasive protease overexpressed in gliomas. Quantitative real-time reverse transcription PCR (qRT-PCR) and Spearman correlation analysis were used to determine differential expressions of miR-338-5p and TSHZ3 in astrocytic gliomas of different grades (n = 35) and glioblastoma cell lines (U87 and U251) in comparison to non-neoplastic brain (NNB) tissues (n = 6). Western blotting was used to determine the protein levels of TSHZ3 and MMP2 in glioblastoma cell lines and Matrigel invasion assay to examine the role of miR-338-5p in cell invasiveness. The results showed that the expression of miR-338-5p, normalized to hsnRNA U6, was significantly higher in grade III and IV gliomas and glioblastoma cell lines compared to that in NNB and grade II gliomas, whereas TSHZ3 expression, normalized to GAPDH, was inversely related to miR-338-5p (R = -0.636, P < 0.01). Luciferase assays showed TSHZ3 to be a target gene of miR-338-5p. In both U87 and U251 cells, miR-338-5p mimics increased MMP2 and invasiveness of the cells. Overexpression of ectopic TSHZ3 suppressed the cell invasiveness and attenuated the pro-invasive effect of miR-338-5p mimics. Overall, our results showed that miR-338-5p has a function in promoting glioma cell invasion by targeting TSHZ3 suppression on MMP2. In conclusion, miR-338-5p is a possible potential biomarker for the diagnosis and target for therapy of high-grade glioma.
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Affiliation(s)
- Yanyan Li
- Department of Neurosurgery and Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, China
| | - Yulun Huang
- Department of Neurosurgery and Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, China
| | - Zhenyu Qi
- Department of Neurosurgery and Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, China
| | - Ting Sun
- Department of Neurosurgery and Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, China
| | - Youxin Zhou
- Department of Neurosurgery and Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, China.
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The dual-inhibitory effect of miR-338-5p on the multidrug resistance and cell growth of hepatocellular carcinoma. Signal Transduct Target Ther 2018. [PMID: 29527329 PMCID: PMC5837112 DOI: 10.1038/s41392-017-0003-4] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Chemotherapeutic treatments against hepatocellular carcinoma (HCC) are necessary for both inoperable patients to improve prospects for survival and surgery patients to improve the outcome after surgical resection. However, multidrug resistance (MDR) is a major obstacle to obtaining desirable results. Currently, increasing the chemotherapy sensitivity of tumor cells or discovering novel tumor inhibitors is an effective therapeutic strategy to solve this issue. In the present study, we uncovered the dual-inhibitory effect of miR-338-5p: on the one hand, it could downregulate ABCB1 expression and sensitize HCC cells to doxorubicin and vinblastine by directly targeting the 3′-untranslated region (3′-UTR) of ABCB1, while, on the other hand, it could suppress the proliferation of HCC cells by directly targeting the 3′-UTR of EGFR and reducing EGFR expression. Since EGFR regulates ABCB1 levels, the indirect action of miR-338-5p in ABCB1 modulation was revealed, in which miR-338-5p inhibits ABCB1 expression by targeting the EGFR/ERK1/2 signaling pathway. These data indicate that the miR-338-5p/EGFR/ABCB1 regulatory loop plays a critical role in HCC, and a negative correlation between miR-338-5p and EGFR or ABCB1 was also detected in HCC clinical samples. In conclusion, these findings reveal a critical role for miR-338-5p in the regulation of MDR and proliferation of HCC, suggesting the potential therapeutic implications of miR-338-5p in HCC treatment. A small RNA molecule inhibits the growth of liver cancer cells while also making the cells sensitive to the anti-cancer drugs. These twin effects of the natural microRNA miR-338-5p were discovered by researchers in China, led by Chunzhu Li and Jin Ren at the Center for Drug Safety Evaluation and Research in Shanghai. MicroRNAs control gene activity by interacting with the messenger RNA copies of genes that guide synthesis of the proteins the genes encode. The research identified a gene whose expression miR-338-5p inhibits to restrict the growth of hepatocellular carcinoma – the most common form of liver cancer. This is also one of the most drug-resistant forms of liver cancer. A different gene whose activity miR-338-5p controls to sensitize cells to chemotherapeutic drugs was also identified. Using miR-338-5p to treat liver cancer warrants further investigation.
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Chen R, Sheng L, Zhang HJ, Ji M, Qian WQ. miR-15b-5p facilitates the tumorigenicity by targeting RECK and predicts tumour recurrence in prostate cancer. J Cell Mol Med 2018; 22:1855-1863. [PMID: 29363862 PMCID: PMC5824417 DOI: 10.1111/jcmm.13469] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Accepted: 10/26/2017] [Indexed: 12/11/2022] Open
Abstract
MicroRNAs (miRNAs) have been reported to participate in many biological behaviours of multiple malignancies. Recent studies have shown that miR‐15b‐5p (miR‐15b) exhibits dual roles by accelerating or blocking tumour progression. However, the molecular mechanisms by which miR‐15b contributes to prostate cancer (PCa) are still elusive. Here, miR‐15b expression was found significantly up‐regulated in PCa in comparison with the normal samples and was positively correlated with age and Gleason score in patients with PCa. Notably, PCa patients with miR‐15b high expression displayed a higher recurrence rate than those with miR‐15b low expression (P = 0.0058). Knockdown of miR‐15b suppressed cell growth and invasiveness in 22RV1 and PC3 cells, while overexpression of miR‐15b reversed these effects. Then, we validated that RECK acted as a direct target of miR‐15b by dual‐luciferase assay and revealed the negative correlation of RECK with miR‐15b expression in PCa tissues. Ectopic expression of RECK reduced cell proliferation and invasive potential and partially abrogated the tumour‐promoting effects caused by miR‐15b overexpression. Additionally, miR‐15b knockdown inhibited tumour growth activity in a mouse PCa xenograft model. Taken together, our findings indicate that miR‐15b promotes the progression of PCa cells by targeting RECK and represents a potential marker for patients with PCa.
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Affiliation(s)
- Ran Chen
- Department of Urology, Huadong Hospital Affiliated to Fudan University, Shanghai, China
| | - Lu Sheng
- Department of Urology, Huadong Hospital Affiliated to Fudan University, Shanghai, China
| | - Hao-Jie Zhang
- Department of Urology, Huadong Hospital Affiliated to Fudan University, Shanghai, China
| | - Ming Ji
- Shanghai Dingdian Biotechnology Limited Company, Shanghai, China
| | - Wei-Qing Qian
- Department of Urology, Huadong Hospital Affiliated to Fudan University, Shanghai, China
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Liang L, Gao L, Zou XP, Huang ML, Chen G, Li JJ, Cai XY. Diagnostic significance and potential function of miR-338-5p in hepatocellular carcinoma: A bioinformatics study with microarray and RNA sequencing data. Mol Med Rep 2017; 17:2297-2312. [PMID: 29207053 PMCID: PMC5783480 DOI: 10.3892/mmr.2017.8125] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2017] [Accepted: 11/09/2017] [Indexed: 12/12/2022] Open
Abstract
MicroRNA (miR)-338-5p has been studied in hepatocellular carcinoma (HCC); however, the diagnostic value and molecular mechanism underlying its actions remains to be elucidated. The present study aimed to validate the diagnostic ability of miR-338-5p and further explore the underlying molecular mechanism. Data from eligible studies, Gene Expression Omnibus (GEO) chips and The Cancer Genome Atlas (TCGA) datasets were gathered in the data mining and the integrated meta-analysis, to evaluate the significance of miR-338-5p in diagnosing HCC comprehensively. The potential target genes of miR-338-5p were achieved from the intersection of the deregulated targets of miR-338-5p from GEO and TCGA in addition to the predicted target genes from 12 online software. A protein-protein-interaction (PPI) network was drawn to illustrate the interaction between target genes and to define the hub genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to investigate the function of the target genes. From the results, miR-338-5p exhibited favorable value in diagnosing HCC. Types of sample and experiment were defined as the possible sources of heterogeneity in meta-analysis. A total of 423 genes were selected as the potential target genes of miR-338-5p, and five genes were defined as the hub genes from the PPI network. The GO and KEGG analyses indicated that the target genes were significantly assembled in the pathways of metabolic process and cell cycle. miR-338-5p may function as a novel diagnostic target for HCC through regulating certain target genes and signaling pathways.
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Affiliation(s)
- Liang Liang
- Department of General Surgery, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530007, P.R. China
| | - Li Gao
- Department of General Surgery, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530007, P.R. China
| | - Xiao-Ping Zou
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Meng-Lan Huang
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Gang Chen
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Jian-Jun Li
- Department of General Surgery, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530007, P.R. China
| | - Xiao-Yong Cai
- Department of General Surgery, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530007, P.R. China
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Abstract
Extracellular RNAs consist of coding and non-coding transcripts released from all cell types, which are involved in multiple cellular processes, predominantly through regulation of gene expression. Recent advances have helped us better understand the functions of these molecules, particularly microRNAs (miRNAs). Numerous pre-clinical and human studies have demonstrated that miRNAs are dysregulated in cancer and contribute to tumorigenesis and metastasis. miRNA profiling has extensively been evaluated as a non-invasive method for cancer diagnosis, prognostication, and assessment of response to cancer therapies. Broader applications for miRNAs in these settings are currently under active development. Investigators have also moved miRNAs into the realm of cancer therapy. miRNA antagonists targeting miRNAs that silence tumor suppressor genes have shown promising pre-clinical activity. Alternatively, miRNA mimics that silence oncogenes are also under active investigation. These miRNA-based cancer therapies are in early development, but represent novel strategies for clinical management of human cancer.
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Affiliation(s)
- Jonathan R Thompson
- Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, 53226, USA
| | - Jing Zhu
- Department of Pathology and MCW Cancer Center, TBRC-C4970, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA
| | - Deepak Kilari
- Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, 53226, USA
| | - Liang Wang
- Department of Pathology and MCW Cancer Center, TBRC-C4970, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA.
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Wen H, Chen L, He J, Lin J. MicroRNA expression profiles and networks in placentas complicated with selective intrauterine growth restriction. Mol Med Rep 2017; 16:6650-6673. [PMID: 28901463 PMCID: PMC5865797 DOI: 10.3892/mmr.2017.7462] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2017] [Accepted: 08/24/2017] [Indexed: 12/31/2022] Open
Abstract
The microRNA (miRNA) profiles of placentas complicated with selective intrauterine growth restriction (sIUGR) are unknown. In the present study, the sIUGR‑associated placental miRNA expression was investigated using microarray and confirmatory reverse transcriptase‑quantitative polymerase chain reaction studies. Placenta samples around the individual insertion region for each umbilical cord were collected from monochorionic twins complicated with (n=17) or without sIUGR (control, n=16). miRNA profile analysis was performed on two sIUGR cases and one control using an Affymetrix microRNA 4.0 Array system. A total of 14 miRNAs were identified to be specifically differentially expressed (7 upregulated and 7 downregulated) among larger twins of sIUGR cases compared with smaller twins of sIUGR cases. The target genes of the identified miRNAs participate in organ size, cell differentiation, cell proliferation and migration. In addition, according to the miRNA‑pathway network analysis, key miRNAs and pathways (transforming growth factor‑β, mitogen‑activated protein kinase and Wnt) were identified to be associated with the pathogenesis of sIUGR. To the best of our knowledge, the results of the current study have provided the most complete miRNA profiles and the most detailed miRNA regulatory networks of placental tissues complicated with sIUGR.
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Affiliation(s)
- Hong Wen
- Department of Obstetrics, The Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, P.R. China
| | - Lu Chen
- Department of Obstetrics, The Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, P.R. China
| | - Jing He
- Department of Obstetrics, The Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, P.R. China
| | - Jun Lin
- Department of Obstetrics, The Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, P.R. China
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Pant K, Venugopal SK. Circulating microRNAs: Possible role as non-invasive diagnostic biomarkers in liver disease. Clin Res Hepatol Gastroenterol 2017; 41:370-377. [PMID: 27956256 DOI: 10.1016/j.clinre.2016.11.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2016] [Revised: 09/30/2016] [Accepted: 11/07/2016] [Indexed: 02/08/2023]
Abstract
Liver is the central organ for metabolism and the hepatocytes metabolize several drugs, hepatotoxins, alcohol, etc. Continuous exposure of the hepatocytes to these toxins result in various chronic diseases, such as alcoholic liver disease, non-alcoholic fatty liver disease, viral hepatitis and hepatocellular carcinoma. Although several diagnostic methods, such as serum markers, liver biopsy or imaging studies are currently available, most of these are either invasive or detect the disease at advanced stages. Hence, there is a need for new molecular markers that can be used for early detection of the disease. MicroRNAs (miRNAs) are naturally occurring, 20-22 nucleotide long, non-coding RNA molecules that regulate the gene expression at post-transcriptional levels, thereby modulating various biological functions. Their expression is deregulated under pathological conditions, and recent studies showed that they are secreted and can be detected in various body fluids. Since the cellular changes occur at earlier stages of the disease, detecting miRNAs in the body fluids could make them as potential novel biomarkers. Albeit, the difficulties in standardization procedures, cost and availability should be addressed before using them in the clinical arena. This review highlights the possible role of secreted miRNAs to use as early non-invasive diagnostic markers for liver disease.
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Affiliation(s)
- Kishor Pant
- Faculty of Life Science and Biotechnology, South Asian University, Akbar Bhawan, Chanakyapuri, 110021 New Delhi, India
| | - Senthil K Venugopal
- Faculty of Life Science and Biotechnology, South Asian University, Akbar Bhawan, Chanakyapuri, 110021 New Delhi, India.
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Okajima W, Komatsu S, Ichikawa D, Miyamae M, Ohashi T, Imamura T, Kiuchi J, Nishibeppu K, Arita T, Konishi H, Shiozaki A, Morimura R, Ikoma H, Okamoto K, Otsuji E. Liquid biopsy in patients with hepatocellular carcinoma: Circulating tumor cells and cell-free nucleic acids. World J Gastroenterol 2017; 23:5650-5668. [PMID: 28883691 PMCID: PMC5569280 DOI: 10.3748/wjg.v23.i31.5650] [Citation(s) in RCA: 71] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2017] [Revised: 04/14/2017] [Accepted: 07/04/2017] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC), with its high incidence and mortality rate, is one of the most common malignant tumors. Despite recent development of a diagnostic and treatment method, the prognosis of HCC remains poor. Therefore, to provide optimal treatment for each patient with HCC, more precise and effective biomarkers are urgently needed which could facilitate a more detailed individualized decision-making during HCC treatment, including the following; risk assessment, early cancer detection, prediction of treatment or prognostic outcome. In the blood of cancer patients, accumulating evidence about circulating tumor cells and cell-free nucleic acids has suggested their potent clinical utilities as novel biomarker. This concept, so-called "liquid biopsy" is widely known as an alternative approach to cancer tissue biopsy. This method might facilitate a more sensitive diagnosis and better decision-making by obtaining genetic and epigenetic aberrations that are closely associated with cancer initiation and progression. In this article, we review recent developments based on the available literature on both circulating tumor cells and cell-free nucleic acids in cancer patients, especially focusing on Hepatocellular carcinoma.
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Affiliation(s)
- Wataru Okajima
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Shuhei Komatsu
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Daisuke Ichikawa
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Mahito Miyamae
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Takuma Ohashi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Taisuke Imamura
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Jun Kiuchi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Keiji Nishibeppu
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Tomohiro Arita
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Hirotaka Konishi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Atsushi Shiozaki
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Ryo Morimura
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Hisashi Ikoma
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Kazuma Okamoto
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Eigo Otsuji
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
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Mohamed AA, Ali-Eldin ZA, Elbedewy TA, El-Serafy M, Ali-Eldin FA, AbdelAziz H. MicroRNAs and clinical implications in hepatocellular carcinoma. World J Hepatol 2017; 9:1001-1007. [PMID: 28878865 PMCID: PMC5569275 DOI: 10.4254/wjh.v9.i23.1001] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2017] [Revised: 05/13/2017] [Accepted: 06/20/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To assess the role of some circulating miRNAs (miR-23a, miR-203, miR338, miR-34, and miR-16) as tumor markers for diagnosis of hepatocellular carcinoma (HCC).
METHODS One hundred and seventy-one subjects were enrolled, 57 patients with HCC, 57 patients with liver cirrhosis (LC) and 57 healthy subjects as control group. Severity of liver disease was assessed by Child Pugh score. Tumor staging was done using Okuda staging system. Quantification of Micro RNA (miR-23a, miR-203, miR338, miR-34, and miR-16) was performed.
RESULTS All studied miRNA showed significant difference between HCC and cirrhotic patients in comparison to healthy control. miR-23a showed statistically significant difference between HCC and cirrhotic patients being higher in HCC group than cirrhotic. miR-23a is significantly higher in HCC patients with focal lesion size equal or more than 5 cm, patients with multiple focal lesions and Okuda stage III. At cutoff value ≥ 210, miR-23a showed accuracy 79.3% to diagnose HCC patients with sensitivity 89.47% and specificity about 64.91%. At cut off level ≥ 200 ng/mL, serum alpha fetoprotein had 73.68% sensitivity, 52.63% specificity, 43.75% PPV, 80% NPV for diagnosis of HCC.
CONCLUSION MicroRNA 23a can be used as a screening test for early detection of HCC. Also, it is related to larger size of tumour, late Okuda staging and multiple hepatic focal lesions, so it might be a prognostic biomarker.
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Circulating miRNAs as novel diagnostic biomarkers in hepatocellular carcinoma detection: a meta-analysis based on 24 articles. Oncotarget 2017; 8:66402-66413. [PMID: 29029522 PMCID: PMC5630422 DOI: 10.18632/oncotarget.18949] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2016] [Accepted: 06/27/2017] [Indexed: 02/07/2023] Open
Abstract
The diagnostic value and suitability of circulating miRNAs for the detection of hepatocellular carcinoma have been inconsistent in the literature. A meta-analysis is used to systematically evaluate the diagnostic value of circulating miRNAs. Eligible studies were selected and the heterogeneity was assessed by subgroup analysis, meta-regression, and publication bias. After strictly and comprehensive screening, the source methods, internal reference and the cut-off values of the included miRNAs were first listed. Circulating miRNAs demonstrated a relatively good diagnostic value in hepatocellular carcinoma, In the subgroup analysis, diagnosis odds ratio showed a higher accuracy with multiple miRNAs than with a single miRNA as well as with serum types than plasma types. In addition, although miRNAs have many expression patterns, the high frequency expression miRNAs (miR-21, miR-199 and miR-122) might be more specific for the diagnosis of hepatocellular carcinoma.The sources of heterogeneity might be related to the number of miRNAs and the specimen types in meta-regression. Furthermore, it’s surprised that the pooled studies were first demonstrated publication bias (P < 0.05). In conclusion, multiple miRNAs in serum have a better diagnostic value, and the publication bias was stable. To validate the potential applicability of miRNAs in the diagnosis of hepatocellular carcinoma, more rigorous studies are needed to confirm these conclusions.
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Zhao C, Li Y, Chen G, Wang F, Shen Z, Zhou R. Overexpression of miR-15b-5p promotes gastric cancer metastasis by regulating PAQR3. Oncol Rep 2017; 38:352-358. [PMID: 28560431 DOI: 10.3892/or.2017.5673] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2016] [Accepted: 11/23/2016] [Indexed: 12/14/2022] Open
Abstract
Gastric cancer (GC) is the fifth most common cancer in the world, with 952,000 new cases diagnosed in 2012. Tumor metastasis is the major cause of cancer recurrence and death. miR-15b-5p has been reported to be dysregulated in numerous types of cancers. However, the role of miR-15b-5p in GC metastasis remains unclear. An miRNA microarray was adopted to analyze the miRNA expression profile. By employing quantitative real-time polymerase chain reaction (qRT-PCR), miR-15b-5p expression levels were detected in GC cell lines, tissues and plasma samples. In addition, the effects of miR-15b-5p on cell proliferation, migration and invasion were studied by applying gain-of-function approaches. Moreover, the target of miR-15b-5p was assessed by dual-luciferase assay, and the mechanism underlying the regulation of GC metastasis by miR-15b-5p was assessed by rescue experiments. The results revealed that miR-15b-5p was upregulated in GC cell lines, tissues and plasma samples. A high plasma level of miR-15b-5p was correlated with distant tumor metastasis. In addition, overexpression of miR‑15b-5p in GC cells promoted cell proliferation, migration, invasion and epithelial-mesenchymal transition (EMT). Moreover, progestin and adipoQ receptor family member 3 (PAQR3) was found to be a direct target of miR-15b-5p and re-expression of PAQR3 in miR-15b-5p-overexpressing GC cells partly attenuated the proliferation, migration and invasion. These findings revealed that miR-15b-5p promotes the metastasis of GC cells through PAQR3 and may represent a potential biomarker of GC.
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Affiliation(s)
- Chengcheng Zhao
- Central Laboratory, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, Jiangsu 210000, P.R. China
| | - Yan Li
- Central Laboratory, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, Jiangsu 210000, P.R. China
| | - Gang Chen
- Department of Oncology, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, Jiangsu 210000, P.R. China
| | - Fen Wang
- Department of Oncology, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, Jiangsu 210000, P.R. China
| | - Zhili Shen
- Department of Oncology, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, Jiangsu 210000, P.R. China
| | - Rongping Zhou
- Department of Oncology, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, Jiangsu 210000, P.R. China
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Nishida N, Arizumi T, Hagiwara S, Ida H, Sakurai T, Kudo M. MicroRNAs for the Prediction of Early Response to Sorafenib Treatment in Human Hepatocellular Carcinoma. Liver Cancer 2017; 6:113-125. [PMID: 28275578 PMCID: PMC5340220 DOI: 10.1159/000449475] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Several studies suggest the role of circulating microRNAs (miRNAs) as biomarkers of hepatocellular carcinoma (HCC). However, the serum miRNA profile associated with the response to sorafenib remains to be elucidated. The aim of this study was to clarify the specific miRNAs in serum that could predict the early response of HCC to sorafenib treatment. SUMMARY Analyzing the sera from 16 HCC patients, we selected five miRNAs that showed differences in serum levels between patients with and without tumor responses among 179 known secretory miRNAs by using locked nucleic acid probe-based quantitative PCR. Through further analysis using a validation cohort that included 53 HCC patients who underwent sorafenib treatment and 8 healthy control subjects, we found that miR-181a-5p and miR-339-5p showed significant differences in serum levels among patients with partial response (PR), stable disease (SD), and progressive disease (PD), where PR patients showed the highest and PD the lowest levels. We also analyzed the factors associated with disease control (DC; PR or SD) 3 months after the initiation of sorafenib treatment; patients with DC showed a significantly higher level of serum miR-181a-5p than non-DC patients or healthy control subjects (p = 0.0349 and 0.0180 for DC vs. non-DC and control vs. non-DC by Tukey-Kramer test, respectively). We further conducted multivariate analysis among HCC patients with Barcelona Clinic Liver Cancer stage C using extrahepatic metastasis, serum decarboxyprothrombin, and miR-181a-5p levels as covariables; serum miR-181a-5p was the only independent factor for achieving DC (p = 0.0092, odds ratio 0.139, and 95% confidence interval 0.011-0.658). In addition, miR-181a-5p level was also the only independent factor affecting overall survival (p = 0.0194, hazard ratio 0.267, and 95% confidence interval 0.070-0.818). KEY MESSAGES A high serum level of miR-181a-5p before treatment is associated with DC after the initiation of sorafenib.
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Affiliation(s)
- Naoshi Nishida
- *Naoshi Nishida, MD, Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 337-2 Ohno-higashi, Osaka-sayama, Osaka 589-8511 (Japan), E-Mail
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Integrated analysis of miRNA and mRNA gene expression microarrays: Influence on platelet reactivity, clopidogrel response and drug-induced toxicity. Gene 2016; 593:172-178. [DOI: 10.1016/j.gene.2016.08.028] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2016] [Revised: 07/17/2016] [Accepted: 08/15/2016] [Indexed: 01/01/2023]
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