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Sartorius K, Wang Y, Sartorius B, Antwi SO, Li X, Chuturgoon A, Yu C, Lu Y, Wang Y. The interactive role of microRNA and other non-coding RNA in hepatitis B (HBV) associated fibrogenesis. Funct Integr Genomics 2025; 25:24. [PMID: 39847120 DOI: 10.1007/s10142-024-01519-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Revised: 11/27/2024] [Accepted: 12/27/2024] [Indexed: 01/24/2025]
Abstract
One of the outstanding features of chronic hepatitis B infection (CHB) is its strong association with liver fibrosis. CHB induced inflammation and injury trigger multiple biochemical and physical changes that include the promotion of a wide range of cytokines, chemokines and growth factors that activate hepatic stellate cells (HSCs) CHB induced activation of hepatic stellate cells (HSCs) is regarded as a central event in fibrogenesis to directly promote the synthesis of myofibroblasts and the expression of a range of materials to repair injured liver tissue. Fibrogenesis is modulated by the mainstream epigenetic machinery, as well as by non-coding RNA (ncRNA) that are often referred to as an ancillary epigenetic response to fine tune gene expression. Although extensive research has explained the regulatory role of ncRNA in liver fibrogenesis, most of this research relates to non-CHB etiologies. This review paper outlines the complex interactive regulatory role of microRNA (miRNA) and their interaction with long non-coding RNA (lncRNA), circular RNA (circRNA) and the mainstream epigenetic machinery in CHB induced liver fibrosis. The paper also illustrates some of the difficulties involved in translating candidate ncRNA into approved drugs or diagnostic tools. In conclusion, the important regulatory role of ncRNA in CHB induced liver fibrosis warrants further investigation to exploit their undoubted potential as diagnostic and therapeutic agents.
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Affiliation(s)
- Kurt Sartorius
- Faculty of Commerce, Law and Management, University of the Witwatersrand, Johannesburg, South Africa.
- Africa Hepatobiliarypancreato Cancer Consortium (AHPBCC), Mayo Clinic, Jacksonville, AL, USA.
| | - Yanglong Wang
- Department of General Surgery, Xinyi People's Hospital, Xinyi, Jiangsu, China
| | - Benn Sartorius
- School of Public Health, University of Queensland, Brisbane, Australia
| | - Samuel O Antwi
- Africa Hepatobiliarypancreato Cancer Consortium (AHPBCC), Mayo Clinic, Jacksonville, AL, USA
- Division of Epidemiology Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, AL, USA
| | - Xiaodong Li
- Africa Hepatobiliarypancreato Cancer Consortium (AHPBCC), Mayo Clinic, Jacksonville, AL, USA
| | - Anil Chuturgoon
- School of Laboratory Medicine and Molecular Sciences, UKZN, Durban, South Africa
| | - Chongyuan Yu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yunjie Lu
- Africa Hepatobiliarypancreato Cancer Consortium (AHPBCC), Mayo Clinic, Jacksonville, AL, USA.
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China.
| | - Yu Wang
- Department of Hepatobiliary Surgery, Jintan Affiliated Hospital of Jiangsu University, 213200, Changzhou, Jiangsu, China.
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2
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Hass R, von der Ohe J, Luo T. Human mesenchymal stroma/stem-like cell-derived taxol-loaded EVs/exosomes transfer anti-tumor microRNA signatures and express enhanced SDF-1-mediated tumor tropism. Cell Commun Signal 2024; 22:506. [PMID: 39420354 PMCID: PMC11488203 DOI: 10.1186/s12964-024-01886-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Accepted: 10/08/2024] [Indexed: 10/19/2024] Open
Abstract
BACKGROUND The release of extracellular vesicles (EVs) including exosomes from human mesenchymal stroma/stem-like cells (MSC) represents valuable cell-free carriers for the delivery of regenerative and medicinal compounds. METHODS EVs/exosomes were isolated by differential centrifugation from four individual MSC as controls and after treatment with a sub-lethal concentration of 10 mM taxol for 24 h, respectively. The isolated EVs/exosomes were characterized and quantified by nano-tracking-analysis and by Western blots. MicroRNAs (miRs) were isolated from the different EVs/exosome populations and expression levels were quantified by qPCR using 1246 miR templates. Cytotoxic effects of the different MSC-derived taxol-loaded EVs/exosomes were determined in five different GFP-transduced cancer cell lines and quantified by a fluoroscan assay with a GFP-detecting fluorimeter. The presence of stroma cell-derived factor 1 (SDF-1) in MSC-derived EVs/exosomes and its enhanced expression in the vesicles after taxol treatment of MSC was quantified by a specific ELISA. RESULTS EVs/exosomes isolated from four individual taxol-treated MSC displayed a larger size and higher yields as the control EVs/exosomes and were used as anti-tumor therapeutic vehicles. Application of each of the four MSC-derived taxol-loaded EVs/exosome populations revealed significant cytotoxic effects in cell lines of five different tumor entities (carcinomas of lung, breast, ovar, colon, astrocytoma) in a concentration-dependent manner. Expression analysis of 1246 miRs in these taxol-loaded EVs/exosomes as compared to the corresponding MSC-derived control EVs/exosomes unraveled a taxol-mediated up-regulation of 11 miRs with predominantly anti-tumorigenic properties. Moreover, various constitutively expressed protein levels were unanimously altered in the MSC cultures. Taxol treatment of the different MSC revealed an up-regulation of tetraspanins and a 2.2-fold to 5.4-fold increased expression of SDF-1 among others. Treatment of cancer cells with MSC-derived taxol-loaded EVs/exosomes in the presence of a neutralizing SDF-1 antibody significantly abolished the cytotoxic effects between 20.3% and 27%. CONCLUSIONS These findings suggested a taxol-mediated increase of anti-cancer properties in MSC that enhance the tropism of derived EVs/exosomes to tumors, thereby specifically focusing the therapeutic effects of the delivered products.
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Affiliation(s)
- Ralf Hass
- Department of Obstetrics and Gynecology, Biochemistry and Tumor Biology Laboratory, Hannover Medical School, 30625, Hannover, Germany.
| | - Juliane von der Ohe
- Department of Obstetrics and Gynecology, Biochemistry and Tumor Biology Laboratory, Hannover Medical School, 30625, Hannover, Germany
| | - Tianjiao Luo
- Department of Obstetrics and Gynecology, Biochemistry and Tumor Biology Laboratory, Hannover Medical School, 30625, Hannover, Germany
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Zhang MH, Yuan YF, Liu LJ, Wei YX, Yin WY, Zheng LZY, Tang YY, Lv Z, Zhu F. Dysregulated microRNAs as a biomarker for diagnosis and prognosis of hepatitis B virus-associated hepatocellular carcinoma. World J Gastroenterol 2023; 29:4706-4735. [PMID: 37664153 PMCID: PMC10473924 DOI: 10.3748/wjg.v29.i31.4706] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 06/29/2023] [Accepted: 08/01/2023] [Indexed: 08/18/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a malignancy with a high incidence and fatality rate worldwide. Hepatitis B virus (HBV) infection is one of the most important risk factors for its occurrence and development. Early detection of HBV-associated HCC (HBV-HCC) can improve clinical decision-making and patient outcomes. Biomarkers are extremely helpful, not only for early diagnosis, but also for the development of therapeutics. MicroRNAs (miRNAs), a subset of non-coding RNAs approximately 22 nucleotides in length, have increasingly attracted scientists' attention due to their potential utility as biomarkers for cancer detection and therapy. HBV profoundly impacts the expression of miRNAs potentially involved in the development of hepatocarcinogenesis. In this review, we summarize the current progress on the role of miRNAs in the diagnosis and treatment of HBV-HCC. From a molecular standpoint, we discuss the mechanism by which HBV regulates miRNAs and investigate the exact effect of miRNAs on the promotion of HCC. In the near future, miRNA-based diagnostic, prognostic, and therapeutic applications will make their way into the clinical routine.
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Affiliation(s)
- Ming-He Zhang
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Yu-Feng Yuan
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Li-Juan Liu
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Yu-Xin Wei
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
| | - Wan-Yue Yin
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Lan-Zhuo-Yin Zheng
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
- Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Ying-Ying Tang
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
- Department of Neurology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Zhao Lv
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Fan Zhu
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
- Hubei Province Key Laboratory of Allergy & Immunology, Wuhan University, Wuhan 430071, Hubei Province, China
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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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5
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Ishaq Y, Ikram A, Alzahrani B, Khurshid S. The Role of miRNAs, circRNAs and Their Interactions in Development and Progression of Hepatocellular Carcinoma: An Insilico Approach. Genes (Basel) 2022; 14:genes14010013. [PMID: 36672755 PMCID: PMC9858589 DOI: 10.3390/genes14010013] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 12/06/2022] [Accepted: 12/14/2022] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a type of malignant tumor. miRNAs are noncoding RNAs and their differential expression patterns are observed in HCC-induced by alcoholism, HBV and HCV infections. By acting as a competing endogenous RNA (ceRNA), circRNA regulates the miRNA function, indirectly controlling the gene expression and leading to HCC progression. In the present study, data mining was performed to screen out all miRNAs and circRNA involved in alcohol, HBV or HCV-induced HCC with statistically significant (≤0.05%) expression levels reported in various studies. Further, the interaction of miRNAs and circRNA was also investigated to explore their role in HCC due to various causative agents. Together, these study data provide a deeper understanding of the circRNA-miRNA regulatory mechanisms in HCC. These screened circRNA, miRNA and their interactions can be used as prognostic biomarkers or therapeutic targets for the treatment of HCC.
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Affiliation(s)
- Yasmeen Ishaq
- Institute of Molecular Biology and Biotechnology (IMBB), University of Lahore (UOL), Lahore 54000, Pakistan
| | - Aqsa Ikram
- Institute of Molecular Biology and Biotechnology (IMBB), University of Lahore (UOL), Lahore 54000, Pakistan
- Correspondence:
| | - Badr Alzahrani
- Department of Clinical Laboratory Sciences, Jouf University, Sakaka 42421, Saudi Arabia
| | - Sana Khurshid
- Department of Molecular Biology, Virtual University of Pakistan, 1-Davis Road, Lahore 54000, Pakistan
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Schlosser S, Tümen D, Volz B, Neumeyer K, Egler N, Kunst C, Tews HC, Schmid S, Kandulski A, Müller M, Gülow K. HCC biomarkers - state of the old and outlook to future promising biomarkers and their potential in everyday clinical practice. Front Oncol 2022; 12:1016952. [PMID: 36518320 PMCID: PMC9742592 DOI: 10.3389/fonc.2022.1016952] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Accepted: 11/04/2022] [Indexed: 08/27/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common and deadly tumors worldwide. Management of HCC depends on reliable biomarkers for screening, diagnosis, and monitoring of the disease, as well as predicting response towards therapy and safety. To date, imaging has been the established standard technique in the diagnosis and follow-up of HCC. However, imaging techniques have their limitations, especially in the early detection of HCC. Therefore, there is an urgent need for reliable, non/minimal invasive biomarkers. To date, alpha-fetoprotein (AFP) is the only serum biomarker used in clinical practice for the management of HCC. However, AFP is of relatively rather low quality in terms of specificity and sensitivity. Liquid biopsies as a source for biomarkers have become the focus of clinical research. Our review highlights alternative biomarkers derived from liquid biopsies, including circulating tumor cells, proteins, circulating nucleic acids, and exosomes, and their potential for clinical application. Using defined combinations of different biomarkers will open new perspectives for diagnosing, treating, and monitoring HCC.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Karsten Gülow
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology, and Infectious Diseases, University Hospital Regensburg, Regensburg, Germany
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7
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Lu F, Zhao X, Zhang Z, Xiong M, Wang Y, Sun Y, He B, Zhu J. The diagnostic and prognostic value of the miR-17-92 cluster in hepatocellular carcinoma: A meta-analysis. Front Genet 2022; 13:927079. [PMID: 36118845 PMCID: PMC9480495 DOI: 10.3389/fgene.2022.927079] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2022] [Accepted: 08/02/2022] [Indexed: 11/23/2022] Open
Abstract
Previous studies demonstrated that microRNAs (miRNAs) could serve as biomarkers in various cancers. This meta-analysis aimed to determine the roles of a miR-17-92 cluster in hepatocellular carcinoma (HCC). Here, eligible included studies were searched through PubMed, Embase, and Wan Fang databases up to 1st February 2022. Relevant data were extracted from each eligible study to evaluate the relationship between miRNA-17-92 cluster miRNA expression and the diagnosis and prognosis of HCC. Finally, a total of 21 studies were pooled and included in the meta-analysis, of which four articles were used for diagnostic meta-analysis and eight articles were used for prognostic meta-analysis. The pooled sensitivity, specificity, and diagnostic odds ratios (DOR) of the miR17-92 cluster for diagnosis of HCC were 0.75 [95% confidence interval (CI): 0.64–0.83], 0.73 (95% CI: 0.65–0.79), and 7.87 (95% CI: 5.36–11.54), respectively. Also, the area under the curve (AUC) for the miR-17-92 cluster when diagnosing HCC was 0.79 (95% CI: 0.76–0.83). For prognostic analysis, hazard ratios (HRs) with 95% CIs were extracted from the included studies and pooled HRs were determined to assess the associations. Patients with increased expression of miR17-92 cluster miRNA were associated with poor overall survival (OS) and recurrence-free survival (RFS) (HR=1.86, 95% CI: 1.04–3.33; HR = 4.18, 95% CI: 3.02–5.77, respectively), but not progression-free survival (PFS) (HR = 0.43, 95% CI: 0.25–0.73), while no association of the miR-17-92 cluster high-expression was detected with disease-free survival (DFS) (HR: 0.95, 95% CI: 0.21–4.34). In short, current pieces of evidence suggested that the miR-17-92 cluster may serve as a novel diagnostic and prognostic biomarker for HCC. However, given the limited study number, larger-size, multi-center, and higher-quality studies are indispensable in the future.
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Affiliation(s)
- Fang Lu
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
- Department of Pharmacy, Nanjing First Hospital, China Pharmaceutical University, Nanjing, China
| | - Xianghong Zhao
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
- Department of Pharmacy, Nanjing First Hospital, China Pharmaceutical University, Nanjing, China
| | - Zhongqiu Zhang
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
- Department of Pharmacy, Nanjing First Hospital, China Pharmaceutical University, Nanjing, China
| | - Mengqiu Xiong
- Department of Laboratory Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Ying Wang
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
- Department of Pharmacy, Nanjing First Hospital, China Pharmaceutical University, Nanjing, China
| | - Yalan Sun
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
- Department of Pharmacy, Nanjing First Hospital, China Pharmaceutical University, Nanjing, China
| | - Bangshun He
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
- Department of Laboratory Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
- *Correspondence: Bangshun He, ; Junrong Zhu,
| | - Junrong Zhu
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
- Department of Pharmacy, Nanjing First Hospital, China Pharmaceutical University, Nanjing, China
- *Correspondence: Bangshun He, ; Junrong Zhu,
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Wang J, Wang X, Zhang X, Shao T, Luo Y, Wang W, Han Y. Extracellular Vesicles and Hepatocellular Carcinoma: Opportunities and Challenges. Front Oncol 2022; 12:884369. [PMID: 35692794 PMCID: PMC9175035 DOI: 10.3389/fonc.2022.884369] [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: 02/26/2022] [Accepted: 04/25/2022] [Indexed: 12/05/2022] Open
Abstract
The incidence of hepatocellular carcinoma (HCC) is increasing worldwide. Extracellular vesicles (EVs) contain sufficient bioactive substances and are carriers of intercellular information exchange, as well as delivery vehicles for nucleic acids, proteins and drugs. Although EVs show great potential for the treatment of HCC and their role in HCC progression has been extensively studied, there are still many challenges such as time-consuming extraction, difficult storage, easy contamination, and low drug loading rate. We focus on the biogenesis, morphological characteristics, isolation and extraction of EVs and their significance in the progression of HCC, tumor invasion, immune escape and cancer therapy for a review. EVs may be effective biomarkers for molecular diagnosis of HCC and new targets for tumor-targeted therapy.
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Affiliation(s)
- Juan Wang
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Xiaoya Wang
- Clinical Medicine, Southwest Medical University, Luzhou, China
| | - Xintong Zhang
- Clinical Medicine, Southwest Medical University, Luzhou, China
| | - Tingting Shao
- Clinical Medicine, Southwest Medical University, Luzhou, China
| | - Yanmei Luo
- Clinical Medicine, Southwest Medical University, Luzhou, China
| | - Wei Wang
- Clinical Medicine, Southwest Medical University, Luzhou, China
| | - Yunwei Han
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China.,Department of Oncology, The Affiliated Hospital of Southwest Medical University, Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Academician (Expert) Workstation of Sichuan Province, Luzhou, China.,Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, China.,School of Basic Medical Sciences, Shandong University, Jinan, China
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Zhang Y, Lin W, Jiang W, Wang Z. MicroRNA-18 facilitates the stemness of gastric cancer by downregulating HMGB3 though targeting Meis2. Bioengineered 2022; 13:9959-9972. [PMID: 35416122 PMCID: PMC9161930 DOI: 10.1080/21655979.2022.2062529] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022] Open
Abstract
The recurrence and metastasis of gastric cancer are related to the stemness of gastric cancer cells. Researches have shown that miR-18 level is negatively correlated to the occurrence and development of certain cancer types. However, the effects of miR-18 on the stemness of gastric cancer remain uncertain. In this research, gastric cancer cell lines with stable overexpression of miR-18 were constructed through lentivirus infection. CCK-8 assay, RT-qPCR, Western blot, flow cytometry, and in vivo tumorigenesis assays were performed to evaluate the effects of miR-18 on the stemness of gastric cancer cells. Moreover, luciferase reporter assays found that Meis2 was the target of miR-18. Furthermore, we also found that the low-expressed oncogene HMGB3 is involved in this miR-18/Meis2 axis to further promote the stemness of gastric cancer cells. These findings suggest that the miR-18/Meis2/HMGB3 axis may be potential prognostic indicators for patients with gastric cancer.
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Affiliation(s)
- Yingjun Zhang
- Oncology Department of Radiotherapy, Zhongshan Hospital of Xiamen University, Xiamen, Fujian China
| | - Weijian Lin
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, Xiamen, Fujian, China
| | - Weiping Jiang
- Oncology Department of Radiotherapy, Zhongshan Hospital of Xiamen University, Xiamen, Fujian China
| | - Zhenfa Wang
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, Xiamen, Fujian, China
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10
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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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11
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Cui M, Qu F, Wang L, Cheng D, Liu X. MiR-18a-5p Facilitates Progression of Hepatocellular Carcinoma by Targeting CPEB3. Technol Cancer Res Treat 2021; 20:15330338211043976. [PMID: 34738854 PMCID: PMC8573499 DOI: 10.1177/15330338211043976] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Objective: To explore the function of the miR-18a-5p/CPEB3 axis in regulating the occurrence of hepatocellular carcinoma (HCC). Methods: Differentially expressed miRNAs and mRNAs were acquired by bioinformatics analysis. qRT-PCR was used for miR-18a-5p and CPEB3 mRNA expression detection. Cell functional assays were implemented to examine the biological functions of HCC cells. The binding relationship between miR-18a-5p and CPEB3 was verified by a dual luciferase assay. Results: In HCC, miR-18a-5p was remarkably highly expressed, while CPEB3 was markedly lowly expressed. HCC cell progression was facilitated after cells transfecting miR-18a-5p mimic, whereas silencing miR-18a-5p caused the opposite result. Overexpressing CPEB3 could restore promoting effect of miR-18a-5p on the growth of HCC cells. Conclusion: Oncogene miR-18a-5p accelerates malignant phenotype by suppressing CPEB3. MiR-18a-5p/CPEB3 axis in HCC identified in this study provides a new target for HCC treatment.
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Affiliation(s)
- Mingxin Cui
- 159363Tangshan Gongren Hospital, Tangshan, China
| | - Fengzhi Qu
- 159363Tangshan Gongren Hospital, Tangshan, China
| | - Libing Wang
- 159363Tangshan Gongren Hospital, Tangshan, China
| | - Daming Cheng
- 159363Tangshan Gongren Hospital, Tangshan, China
| | - Xiaogang Liu
- 159363Tangshan Gongren Hospital, Tangshan, China
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12
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Zhang WT, Gil-Gómez A, Liu CH, Gao SS, Romero-Gómez M. Diagnostic accuracy of circulating microRNA in hepatitis B virus-related hepatocellular carcinoma: a meta-analysis based on Asian data. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2021; 114:280-288. [PMID: 34423645 DOI: 10.17235/reed.2021.8139/2021] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND AND AIM Hepatitis B virus (HBV) is the main risk factor for hepatocellular carcinoma (HCC). We performed a meta-analysis based on Asian data to evaluate the diagnostic accuracy of circulating microRNA as a non-invasive biomarker in the diagnosis of HBV-related HCC. METHODS A comprehensive literature search (updated to May 12, 2021) in PubMed, Embase, Web of Science, Wanfang Database, and China National Knowledge Infrastructure (CNKI) was performed to identify eligible studies. The sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR) and area under the curve (AUC) for diagnosing HBV-related HCC were pooled in this meta-analysis. Subgroup analysis was performed to explore heterogeneity, and Deeks' funnel plot was used to assess publication bias. RESULTS 19 articles including 32 studies were included in the current meta-analysis. The overall sensitivity, specificity, PLR, NLR, DOR and AUC were 0.83 (95% CI: 0.79 - 0.87), 0.78 (95% CI: 0.73 - 0.83), 3.9 (95% CI: 3.0 - 4.9), 0.21 (95% CI: 0.16 - 0.27), 18 (95% CI: 12 - 27) and 0.88 (95% CI: 0.85 - 0.91), respectively. Subgroup analysis shows that miRNA clusters with a large sample size showed better diagnostic accuracy. Although there is no publication bias, it still has some limitations. CONCLUSIONS Circulating miRNAs could serve as a potential non-invasive biomarker in diagnosing of HBV-related HCC in Asian populations.
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Affiliation(s)
- Wen-Ting Zhang
- Digestive Diseases, Hospital Universitario Virgen de Rocío, España
| | | | - Chang-Hai Liu
- Infectious Diseases, West China Hospital of Sichuan University
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13
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Gupta M, Akhtar J, Sarwat M. MicroRNAs: Regulators of immunological reactions in hepatocellular carcinoma. Semin Cell Dev Biol 2021; 124:127-133. [PMID: 34049801 DOI: 10.1016/j.semcdb.2021.05.025] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 04/29/2021] [Accepted: 05/20/2021] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) is the third prominent cause of cancer mortality, with increasing prevalence and poor survival worldwide. Being diagnosed at an advanced stage, HCC frequently results in poor prognosis, treatment failure, and recurrence. Post-treatment reactivation and recurrence often amplify the immunosuppressed state induced by HCC pathogenesis. Therefore, stimulating the immune system may be a potential therapy measure for the treatment of HCC. Immune responses of the body may be potentiated by modulation of various effector cells such as B-cells, T-cells, Treg cells, natural killer cells, dendritic cells, cytotoxic T-lymphocytes, and other antigen-presenting cells. microRNAs (small non-coding RNAs) are the regulators of gene expression via translational inhibition or mRNA degradation. Various activities and developmental stages of the immune system are governed by miRNAs and they have a regulative impact on innate and adaptive immune cells in both, healthy and diseased conditions. Their misexpression has been associated with the initiation, development, and metastasis of various cancer types, including HCC. This review summarizes the functional impact of these immuno-miRNAs in the improvement of tumor conditions.
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Affiliation(s)
- Meenakshi Gupta
- Amity Institute of Pharmacy, Amity University, Noida 201313, Uttar Pradesh, India
| | - Jamal Akhtar
- Central Council for Research in Unani Medicine (CCRUM), Janakpuri, New Delhi 110058, Delhi, India
| | - Maryam Sarwat
- Amity Institute of Pharmacy, Amity University, Noida 201313, Uttar Pradesh, India.
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14
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Song T, Li L, Wu S, Liu Y, Guo C, Wang W, Dai L, Zhang T, Wu H, Su B. Peripheral Blood Genetic Biomarkers for the Early Diagnosis of Hepatocellular Carcinoma. Front Oncol 2021; 11:583714. [PMID: 33777736 PMCID: PMC7991745 DOI: 10.3389/fonc.2021.583714] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Accepted: 02/18/2021] [Indexed: 12/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and has high mortality. Biomarkers related to HCC, such as alpha-fetoprotein, and imaging technology, such as ultrasound and computed tomography, have been used to screen and monitor HCC, but HCC is still difficult to diagnose effectively in the early stage due to the low sensitivity of the above mentioned traditional methods. There is an urgent need for noninvasive biomarkers to facilitate the screening and early diagnosis of HCC. With the advancement of next-generation sequencing, genetic biomarkers are becoming the core of cancer diagnosis. Genetic biomarkers such as peripheral blood circulating tumor DNA, microRNAs, long noncoding RNAs, circular RNAs, and exosomes have become the focus of early HCC diagnostics. HCC genetic biomarkers have been implemented in clinical practice. In this review, we describe the available literature on peripheral blood genetic biomarkers in the diagnosis of early HCC.
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Affiliation(s)
- Ting Song
- Department of Infectious Diseases and Medical Immunology, Beijing Youan Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory for HIV/AIDS Research, Beijing, China.,Department of Hepatology, The Sixth People's Hospital of Qingdao, Qingdao, China
| | - Li Li
- Department of Infectious Diseases and Medical Immunology, Beijing Youan Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory for HIV/AIDS Research, Beijing, China
| | - Shaobo Wu
- Center of Transfusion-Transmitted Infectious Diseases, Institute of Blood Transfusion, Chinese Academy of Medical Sciences (CAMS), Chengdu, China
| | - Yan Liu
- Department of Infectious Diseases and Medical Immunology, Beijing Youan Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory for HIV/AIDS Research, Beijing, China
| | - Caiping Guo
- Department of Infectious Diseases and Medical Immunology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Wen Wang
- Department of Infectious Diseases and Medical Immunology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Lili Dai
- Department of Infectious Diseases and Medical Immunology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Tong Zhang
- Department of Infectious Diseases and Medical Immunology, Beijing Youan Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory for HIV/AIDS Research, Beijing, China
| | - Hao Wu
- Department of Infectious Diseases and Medical Immunology, Beijing Youan Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory for HIV/AIDS Research, Beijing, China
| | - Bin Su
- Department of Infectious Diseases and Medical Immunology, Beijing Youan Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory for HIV/AIDS Research, Beijing, China
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15
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Qian F, Wang J, Wang Y, Gao Q, Yan W, Lin Y, Shen L, Xie Y, Jiang X, Shen B. MiR-378a-3p as a putative biomarker for hepatocellular carcinoma diagnosis and prognosis: Computational screening with experimental validation. Clin Transl Med 2021; 11:e307. [PMID: 33634974 PMCID: PMC7882078 DOI: 10.1002/ctm2.307] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 01/14/2021] [Accepted: 01/18/2021] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a malignant disease with high morbidity and mortality, and the molecular mechanism for the genesis and progression is complex and heterogeneous. Biomarker discovery is crucial for the personalized and precision treatment of HCC. The accumulation of reported microRNA biomarkers makes it possible to combine computational identification with experimental validation to accelerate the discovery of novel biomarker. RESULTS In the present work, we applied a rational computer-aided biomarker discovery model to screen for the HCC diagnosis biomarker. Two HCC-associated networks were constructed based on the microRNA and mRNA expression profiles, and the potential microRNA biomarkers were identified based on their unique regulatory and influential power in the network. These putative biomarkers were then experimentally validated. One prominent example among these identified biomarkers is MiR-378a-3p: It was shown to independently regulate several important transcription factors such as PLAGL2 and β-catenin, affecting the β-catenin signaling. Such mechanism may indicate a potential tumor suppressor role of MiR-378a-3p and the impact of its abnormal expression on the cell growth and invasion of HCC. CONCLUSIONS A bioinformatics model with network topological and functional characterization was successfully applied to the identification of HCC biomarkers. The predicted microRNA biomarkers were than validated with experiments using human HCC cell lines, model animal, and clinical specimens. The results confirmed the prediction by our proposed model that miR-378a-3p was a putative biomarker for diagnosis and prognosis of HCC.
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Affiliation(s)
- Fuliang Qian
- Center for Systems BiologySoochow UniversitySuzhouChina
| | - Jinghan Wang
- Department of the First Biliary Surgery, Shanghai Eastern Hepatobiliary Surgery HospitalNavy Military Medical UniversityShanghaiChina
| | - Ying Wang
- Department of the First Biliary Surgery, Shanghai Eastern Hepatobiliary Surgery HospitalNavy Military Medical UniversityShanghaiChina
| | - Qian Gao
- Department of OncologyThe First Affiliated Hospital of Soochow UniversitySuzhouChina
| | - Wenying Yan
- Center for Systems BiologySoochow UniversitySuzhouChina
| | - Yuxin Lin
- Department of OncologyThe First Affiliated Hospital of Soochow UniversitySuzhouChina
| | - Li Shen
- Institutes for Systems Genetics, Frontiers Science Center for Disease‐related Molecular Network, West China HospitalSichuan UniversityChengduChina
| | - Yufeng Xie
- Center for Systems BiologySoochow UniversitySuzhouChina
- Department of OncologyThe First Affiliated Hospital of Soochow UniversitySuzhouChina
| | - Xiaoqing Jiang
- Department of the First Biliary Surgery, Shanghai Eastern Hepatobiliary Surgery HospitalNavy Military Medical UniversityShanghaiChina
| | - Bairong Shen
- Institutes for Systems Genetics, Frontiers Science Center for Disease‐related Molecular Network, West China HospitalSichuan UniversityChengduChina
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16
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Cao X, Yang Q, Yu Q. Increased Expression of miR-487b Is Associated With Poor Prognosis and Tumor Progression of HBV-Related Hepatocellular Carcinoma. Open Forum Infect Dis 2020; 7:ofaa498. [PMID: 33364257 PMCID: PMC7749721 DOI: 10.1093/ofid/ofaa498] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Accepted: 11/23/2020] [Indexed: 02/06/2023] Open
Abstract
Background Increasing evidence has demonstrated the involvement of microRNAs in the pathogenesis of hepatitis B virus (HBV)–related hepatocellular carcinoma (HCC). The aims of this study were to analyze whether miR-487b can be used as a diagnostic and prognostic biomarker for HBV-related HCC and to explore its effect on the biological function of HCC. Methods The expression levels of miR-487b in the serum of all subjects were measured by real-time quantitative fluorescence polymerase chain reaction. The diagnostic value of miR-487b in serum was assessed using the receiver operating characteristic (ROC) curve. The relationship between miR-487b and the clinical data of patients was analyzed using the chi-square test. The prognostic value of miR-487b in HCC was assessed by Cox regression analysis and Kaplan-Meier survival. Moreover, CCK-8 and Transwell assays were performed to investigate the effect of miR-487b on HBV-related HCC function. Results Our data indicated that miR-487b in HCC patients was significantly higher than in chronic hepatitis B (CHB) patients and healthy controls. Meanwhile, the ROC curve showed that miR-487b had high specificity and sensitivity in the diagnosis of HBV-related HCC. MiR-487b can significantly distinguish between HCC patients and healthy controls and can differentiate HCC patients from CHB patients. Cox regression analysis showed that miR-487b was an independent risk factor. Overexpression of miR-487b was associated with Tumor Node Metastasis stage stage and Barcelona Clinic Liver Cancer stage in HCC patients. Cell function experiments demonstrated that upregulated miR-487b promoted cell proliferation, migration, and invasion. Conclusions Combined the results of the current study demonstrate that the upregulation of serum miR-487b may serve as a promising noninvasive diagnostic biomarker for HBV-related HCC.
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Affiliation(s)
- Xiangang Cao
- Department of Infectious Diseases, Weifang Yidu Central Hospital, Weifang, Shandong, China
| | - Qian Yang
- Department of Infectious Diseases, Weifang Yidu Central Hospital, Weifang, Shandong, China
| | - Qing Yu
- Jinan Infectious Disease Hospital, Jinan, Shandong, China
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17
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Xu J, An P, Winkler CA, Yu Y. Dysregulated microRNAs in Hepatitis B Virus-Related Hepatocellular Carcinoma: Potential as Biomarkers and Therapeutic Targets. Front Oncol 2020; 10:1271. [PMID: 32850386 PMCID: PMC7399632 DOI: 10.3389/fonc.2020.01271] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Accepted: 06/19/2020] [Indexed: 12/12/2022] Open
Abstract
MicroRNAs (miRNAs) are non-coding small RNAs that can function as gene regulators and are involved in tumorigenesis. We review the commonly dysregulated miRNAs in liver tumor tissues and plasma/serum of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) patients. The frequently reported up-regulated miRNAs in liver tumor tissues include miR-18a, miR-21, miR-221, miR-222, and miR-224, whereas down-regulated miRNAs include miR-26a, miR-101, miR-122, miR-125b, miR-145, miR-199a, miR-199b, miR-200a, and miR-223. For a subset of these miRNAs (up-regulated miR-222 and miR-224, down-regulated miR-26a and miR-125b), the pattern of dysregulated circulating miRNAs in plasma/serum is mirrored in tumor tissue based on multiple independent studies. Dysregulated miRNAs target oncogenes or tumor suppressor genes involved in hepatocarcinogenesis. Normalization of dysregulated miRNAs by up- or down-regulation has been shown to inhibit HCC cell proliferation or sensitize liver cancer cells to chemotherapeutic treatment. miRNAs hold as yet unrealized potential as biomarkers for early detection of HCC and as precision therapeutic targets, but further studies in diverse populations and across all stages of HCC are needed.
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Affiliation(s)
- Jinghang Xu
- Department of Infectious Diseases, Center for Liver Diseases, Peking University First Hospital, Peking University, Beijing, China
- Basic Research Laboratory, Molecular Genetic Epidemiology Section, Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD, United States
| | - Ping An
- Basic Research Laboratory, Molecular Genetic Epidemiology Section, Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD, United States
| | - Cheryl A. Winkler
- Basic Research Laboratory, Molecular Genetic Epidemiology Section, Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD, United States
| | - Yanyan Yu
- Department of Infectious Diseases, Center for Liver Diseases, Peking University First Hospital, Peking University, Beijing, China
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Noor MT, Seehra N, Rajput J, Sharma R, Thakur BS. Evaluation of Roles of MicroRNA-21 and MicroRNA-18a in Esophageal Squamous Cell Carcinoma and Comparison of Their Changes in Expression Post-Chemoradiotherapy. Gastroenterology Res 2020; 13:107-113. [PMID: 32655727 PMCID: PMC7331858 DOI: 10.14740/gr1261] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Accepted: 04/28/2020] [Indexed: 11/11/2022] Open
Abstract
Background A number of circulating microRNAs (miRNAs) have been reported to be highly expressed in several cancers; whether their expression is associated with clinicopathological factors and prognosis in patients of esophageal squamous cell carcinoma (ESCC) is still under investigation. Although studies have demonstrated their overexpression in tissues of ESCC, there are limited data for circulating miRNAs. Aim of this study was to evaluate the expressions of miRNA-21 and miRNA-18a in patients of ESCC and the effect of chemoradiotherapy (CRT) on expression of these miRNAs. Methods This was a case-control study conducted from September 2014 to December 2015 at Sri Aurobindo Medical College and Postgraduate Institute, Indore, India. We compared the expression of miRNA-21 and miRNA-18a in 30 ESCC patients and 30 healthy controls using TaqMan probe-based quantitative real-time polymerase chain reaction (qRT-PCR) and changes in the expression in 16 patients of ESCC, who completed CRT. Results Both miRNA-21 and miRNA-18a had significantly higher levels of expression in ESCC patients than healthy controls (95% confidence interval (CI): 5.73 - 34.79; P < 0.002 and 95% CI: 3,361.36 - 6,744.23; P < 0.001), respectively. Receiver operating characteristic (ROC) curve analysis showed that combination of serum miRNA-18a and miRNA-21 overexpression could efficiently distinguish patients of ESCC from healthy controls. The miRNA-21 expression positively correlated with tumor invasion (P < 0.004), lymphatic metastasis (P < 0.011), distant metastasis (P < 0.038), and tumor stage (P < 0.001); however, there was no such association observed with miRNA-18a. In the treatment phase (post-CRT), a significant reduction (P < 0.001) was observed in both miRNAs (73.4% in miRNA-18a and 81.02% in miRNA-21). Conclusions Both miRNA-21 and miRNA-18a were highly overexpressed in patients of ESCC and their expressions changed significantly with CRT. These miRNAs may be useful tools for the diagnosis and assessment of treatment response in ESCC patients. Further studies will be needed to validate these findings using large number of patients.
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Affiliation(s)
- Mohd Talha Noor
- Department of Gastroenterology, Sri Aurobindo Medical College and Postgraduate Institute, Indore-Ujjain State Highway, Indore, Madhya Pradesh 453555, India
| | - Nivesh Seehra
- Department of Gastroenterology, Sri Aurobindo Medical College and Postgraduate Institute, Indore-Ujjain State Highway, Indore, Madhya Pradesh 453555, India
| | - Jitendra Rajput
- Department of Gastroenterology, Sri Aurobindo Medical College and Postgraduate Institute, Indore-Ujjain State Highway, Indore, Madhya Pradesh 453555, India
| | - Rajeev Sharma
- Department of Gastroenterology, Sri Aurobindo Medical College and Postgraduate Institute, Indore-Ujjain State Highway, Indore, Madhya Pradesh 453555, India
| | - Bhagwan Singh Thakur
- Department of Gastroenterology, Sri Aurobindo Medical College and Postgraduate Institute, Indore-Ujjain State Highway, Indore, Madhya Pradesh 453555, India
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Wahyuniari IAI, Arijana IGKN, Sriwidyani NP, Suwito H, Widyarini S, Ghufron M, Mustofa M, Haryana SM. The Effect of (E)-1-(4'-aminophenyl)-3-phenylprop-2-en-1-one on MicroRNA-18a, Dicer1, and MMP-9 Expressions against DMBA-Induced Breast Cancer. Asian Pac J Cancer Prev 2020; 21:1213-1219. [PMID: 32458624 PMCID: PMC7541864 DOI: 10.31557/apjcp.2020.21.5.1213] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Most of breast cancer patients are estrogen receptor alpha-positive and have high resistance and side effect of chemotherapeutic drug. Therefore, discovering an effective anticancer agent is needed. This research explored the effect of (E)-1-(4'-aminophenyl)-3-phenylprop-2-en-1-one (APE) on miR-18a, Dicer1, and MMP-9 expressions. METHODS Twenty four female Sprague-Dawley rats were invetigated in this study. The rats were divided into 6 groups of 4. G1 was considered as normal rat. G2, G3, T1, T2, and T3 were given DMBA 20 mg/kgBW twice a week for 5 weeks to induce mammary cancer. After being affiliated with cancer, G2 was given vehicle and G3 was treated with tamoxifen. T1, T2, and T3 were treated with APE intraperitoneally everyday for 21 days at doses of 5, 15, and 45 mg/kgBW/day, respectively. Blood plasma was collected to measure miR-18a expression using qRT-PCR. Mammary tissues were also collected to determine Dicer1 and MMP-9 expressions by using immunohistochemistry. RESULTS The results showed significant down-regulation of miR-18a relative expression and up-regulation of Dicer1 expression in G3 and T1 compared to G2 (P<0.05). MMP-9 expression has significant decrease in T1 compared to G2 (P<0.05). CONCLUSION APE can decrease miR-18a and MMP-9 expressions and increase Dicer1 expression in rat mammary cancer. Therefore, this compound could be a candidate of novel anticancer.
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Affiliation(s)
| | | | - Ni Putu Sriwidyani
- Department of Anatomical Pathology, Faculty of Medicine, Udayana University, Bali, Indonesia
| | - Hery Suwito
- Department of Chemistry, Faculty of Science and Technology, Universitas Airlangga, Surabaya, Indonesia
| | - Sitarina Widyarini
- Department of Pathology, Faculty of Veterinary Medicine, Universitas Gadjah Mada, Yogyakarta, Indonesia
| | - Muhammad Ghufron
- Department of Histology and Cell Biology,Universitas Gadjah Mada, Yogyakarta, Indonesia
| | - Mustofa Mustofa
- Department of Pharmacology and Therapy, Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta, Indonesia
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20
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Lu Y, Min Z, Qin A, Wu J, Jiang X, Qiao Z. Role of miR-18a and miR-25 disruption and its mechanistic pattern in progression of liver cancer. 3 Biotech 2020; 10:74. [PMID: 32051807 DOI: 10.1007/s13205-020-2064-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2019] [Accepted: 01/08/2020] [Indexed: 12/14/2022] Open
Abstract
This study examined the molecular mechanisms underlying the roles of the microRNAs miR-18a and miR-25 in the progression of human liver cancer. Liver cancer biopsies obtained from early-stage liver cancer patients were examined by qRT-PCR and Northern blotting to examine the expression of miR-18a and miR-25. Both microRNAs were overexpressed in mouse primary hepatocytes following transfection of the cells with vectors encoding the microRNAs. An analysis of biopsy samples from liver cancer patients indicated that both miR-18a and miR-25 were overexpressed during the early stages of liver cancer. Further, qRT-PCR and Northern blotting confirmed that both of these microRNAs play crucial roles in the progression of liver cancer. Our findings clearly indicate that miR-18a and miR-25 can be used as prognostic biomarkers for early-stage liver cancer. Hence, miR-18a and miR-25 may have value as prognostic indicators and may facilitate the development of novel therapeutics for liver cancer.
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Affiliation(s)
- Yijie Lu
- Department of General Surgery, Nanjing Medical University, Affiliated Suzhou Hospital, Suzhou Municipal Hospital, 26 Daoqian Street, Gusu, Suzhou, 215000 Jiangsu People's Republic of China
| | - Zhai Min
- Department of General Surgery, Nanjing Medical University, Affiliated Suzhou Hospital, Suzhou Municipal Hospital, 26 Daoqian Street, Gusu, Suzhou, 215000 Jiangsu People's Republic of China
| | - Ancheng Qin
- Department of General Surgery, Nanjing Medical University, Affiliated Suzhou Hospital, Suzhou Municipal Hospital, 26 Daoqian Street, Gusu, Suzhou, 215000 Jiangsu People's Republic of China
| | - Jianwu Wu
- Department of General Surgery, Nanjing Medical University, Affiliated Suzhou Hospital, Suzhou Municipal Hospital, 26 Daoqian Street, Gusu, Suzhou, 215000 Jiangsu People's Republic of China
| | - Xinwei Jiang
- Department of General Surgery, Nanjing Medical University, Affiliated Suzhou Hospital, Suzhou Municipal Hospital, 26 Daoqian Street, Gusu, Suzhou, 215000 Jiangsu People's Republic of China
| | - Zhiming Qiao
- Department of General Surgery, Nanjing Medical University, Affiliated Suzhou Hospital, Suzhou Municipal Hospital, 26 Daoqian Street, Gusu, Suzhou, 215000 Jiangsu People's Republic of China
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Ziogas IA, Sioutas G, Mylonas KS, Tsoulfas G. Role of MicroRNA in the Diagnosis and Management of Hepatocellular Carcinoma. Microrna 2020; 9:25-40. [PMID: 31218966 DOI: 10.2174/2211536608666190619155406] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Revised: 03/11/2019] [Accepted: 05/06/2019] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Hepatocellular Carcinoma (HCC) is one of the most common malignant tumors in the world and comes third in cancer-induced mortality. The need for improved and more specific diagnostic methods that can detect early-stage disease is immense, as it is amenable to curative modalities, while advanced HCC is associated with low survival rates. microRNA (miRNA) expression is deregulated in HCC and this can be implemented both diagnostically and therapeutically. OBJECTIVE To provide a concise review on the role of miRNA in diagnosis, prognosis, and treatment of HCC. METHODS We conducted a comprehensive review of the PubMed bibliographic database. RESULTS Multiple miRNAs are involved in the pathogenesis of HCC. Measurement of the levels of these miRNAs either in tumor tissue or in the blood constitutes a promising diagnostic, as well as prognostic tool. OncomiRs are miRNAs that promote tumorigenesis, thus inhibiting them by administering antagomiRs is a promising treatment option. Moreover, replacement of the depleted miRNAs is another potential therapeutic approach for HCC. Modification of miRNA levels may also regulate sensitivity to chemotherapeutic agents. CONCLUSION miRNA play a pivotal role in HCC pathogenesis and once the underlying mechanisms are elucidated, they will become part of everyday clinical practice against HCC.
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Affiliation(s)
- Ioannis A Ziogas
- Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece
- Surgery Working Group, Society of Junior Doctors, Athens, Greece
| | - Georgios Sioutas
- Surgery Working Group, Society of Junior Doctors, Athens, Greece
- Medical School, Democritus University of Thrace, Alexandroupolis, Greece
| | - Konstantinos S Mylonas
- Surgery Working Group, Society of Junior Doctors, Athens, Greece
- Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Georgios Tsoulfas
- 1st Department of Surgery, Aristotle University of Thessaloniki, Thessaloniki, Greece
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Shajari E, Mollasalehi H. Ribonucleic-acid-biomarker candidates for early-phase group detection of common cancers. Genomics 2020; 112:163-168. [DOI: 10.1016/j.ygeno.2018.08.011] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Revised: 08/06/2018] [Accepted: 08/31/2018] [Indexed: 02/08/2023]
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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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Jin X, Cai C, Qiu Y. Diagnostic Value of Circulating microRNAs in Hepatitis B Virus-Related Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis. J Cancer 2019; 10:4754-4764. [PMID: 31598147 PMCID: PMC6775527 DOI: 10.7150/jca.32833] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2019] [Accepted: 06/06/2019] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis B virus (CHB) infection is the leading cause of hepatocellular carcinoma (HCC). As it is difficult to diagnose the early-stage hepatocellular carcinoma using the existing approaches, better biomarkers are urgently needed and may improve the patients' prognoses. MicroRNAs are the most studied liquid biopsy biomarkers and multiple studies have demonstrated the significant diagnostic value of miRNA in HBV-related hepatocellular carcinoma. In this meta-analysis, we collected 25 studies from 15 researches that included a total of 2290 HBV-related HCC patients and 1551 HBV patients without HCC. The pooled sensitivity, specificity, PLR, NLR, DOR and AUC were 0.84 (95% CI: 0.79-0.88), 0.75 (95% CI: 0.69-0.81), 3.42 (95% CI: 2.68-4.35), 0.21 (95% CI: 0.16-0.29), 15.99 (95% CI: 9.89-25.83) and 0.87 (95% CI: 0.83-0.89), respectively. Subgroup analysis indicated that multiple microRNAs, downregulated miRNAs assays, serum type and big sample size had much better accuracy and miR-125b especially, showed a significant diagnostic value. In addition, there is no obvious dignostic difference for HCC from both chronic hepatitis B and liver cirrhosis (LC). Publication bias was not found and Fagan's Nomogram showed valuable clinical utility. In conclusion, circulating microRNAs, particularly the miR-125b, may serve as promising biomarkers for the early diagnosis of HBV-related HCC. However, larger and more rigorous studies are needed to confirm our conclusions.
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Affiliation(s)
- Xuehang Jin
- State Key Laboratory for Diagnosis and Treatment of Infectious Disease, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang Provincial Key Laboratory for Drug Clinical Research and Evaluation, The First Affiliated Hospital, Zhejiang University, 79 QingChun Road, Hangzhou, Zhejiang 310000, People's Republic of China
| | - Changzhou Cai
- Department of Gastroenterogy, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Yunqing Qiu
- State Key Laboratory for Diagnosis and Treatment of Infectious Disease, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang Provincial Key Laboratory for Drug Clinical Research and Evaluation, The First Affiliated Hospital, Zhejiang University, 79 QingChun Road, Hangzhou, Zhejiang 310000, People's Republic of 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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Molecular Mechanisms Driving Progression of Liver Cirrhosis towards Hepatocellular Carcinoma in Chronic Hepatitis B and C Infections: A Review. Int J Mol Sci 2019. [PMID: 30889843 DOI: 10.3390/ijms] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Almost all patients with hepatocellular carcinoma (HCC), a major type of primary liver cancer, also have liver cirrhosis, the severity of which hampers effective treatment for HCC despite recent progress in the efficacy of anticancer drugs for advanced stages of HCC. Here, we review recent knowledge concerning the molecular mechanisms of liver cirrhosis and its progression to HCC from genetic and epigenomic points of view. Because ~70% of patients with HCC have hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infection, we focused on HBV- and HCV-associated HCC. The literature suggests that genetic and epigenetic factors, such as microRNAs, play a role in liver cirrhosis and its progression to HCC, and that HBV- and HCV-encoded proteins appear to be involved in hepatocarcinogenesis. Further studies are needed to elucidate the mechanisms, including immune checkpoints and molecular targets of kinase inhibitors, associated with liver cirrhosis and its progression to HCC.
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27
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Molecular Mechanisms Driving Progression of Liver Cirrhosis towards Hepatocellular Carcinoma in Chronic Hepatitis B and C Infections: A Review. Int J Mol Sci 2019; 20:ijms20061358. [PMID: 30889843 PMCID: PMC6470669 DOI: 10.3390/ijms20061358] [Citation(s) in RCA: 190] [Impact Index Per Article: 31.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2019] [Revised: 02/23/2019] [Accepted: 03/14/2019] [Indexed: 02/07/2023] Open
Abstract
Almost all patients with hepatocellular carcinoma (HCC), a major type of primary liver cancer, also have liver cirrhosis, the severity of which hampers effective treatment for HCC despite recent progress in the efficacy of anticancer drugs for advanced stages of HCC. Here, we review recent knowledge concerning the molecular mechanisms of liver cirrhosis and its progression to HCC from genetic and epigenomic points of view. Because ~70% of patients with HCC have hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infection, we focused on HBV- and HCV-associated HCC. The literature suggests that genetic and epigenetic factors, such as microRNAs, play a role in liver cirrhosis and its progression to HCC, and that HBV- and HCV-encoded proteins appear to be involved in hepatocarcinogenesis. Further studies are needed to elucidate the mechanisms, including immune checkpoints and molecular targets of kinase inhibitors, associated with liver cirrhosis and its progression to HCC.
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Wang X, Lu J, Cao J, Ma B, Gao C, Qi F. MicroRNA-18a promotes hepatocellular carcinoma proliferation, migration, and invasion by targeting Bcl2L10. Onco Targets Ther 2018; 11:7919-7934. [PMID: 30519035 PMCID: PMC6235330 DOI: 10.2147/ott.s180971] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is known to feature several microRNA dysregulations. This study aimed to determine and investigate the prognostic value of microRNA (miRNA/miR)-18a and its role in regulating the progression of HCC. METHODS miR-18a expressions in human HCC tissues, pair-matched adjacent normal liver tissues as well as in HCC cell lines were determined by quantitative real-time PCR. The prognostic value of miR-18a was determined using Kaplan-Meier survival analysis and multivariable Cox regression assay. The ability of miR-18a in promoting HCC progression was verified in vitro. RESULTS miR-18a expressions in HCC tissues and cells were more than twice those of the normal control group (P<0.05). miR-18a expression was associated with the alpha-fetoprotein (AFP) level, TNM stage, tumor size, and intrahepatic vascular invasion (P<0.05). Kaplan- Meier survival analysis revealed that HCC patients with high expression of miR-18a possessed a more unfavorable prognosis (log-rank P<0.001). Overexpression of miR-18a promoted cell apoptosis and proliferation, induced S phase transition, as well as enhanced the migration and invasion ability of HCC cells. miR-18a was found to directly target the downstream molecule Bcl2L10. Furthermore, overexpressing Bcl2L10 was able to partly reverse the promoting effects of miR-18a on HCC cell progression. CONCLUSION miR-18a may serve as a prognostic biomarker of HCC as it is demonstrated to carry out a decisive role in HCC progression by promoting HCC cell invasion, migration, and proliferation through targeting Bcl2L10.
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Affiliation(s)
- Xiaodong Wang
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China,
| | - Jian Lu
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China,
| | - Jisen Cao
- Department of Hepatobiliary Surgery, Tianjin Third Center Hospital, Tianjin, China
| | - Bozhao Ma
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China,
| | - Chao Gao
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China,
| | - Feng Qi
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China,
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Yongyu Z, Lewei Y, Jian L, Yuqin S. [ARTICLE WITHDRAWN] MicroRNA-18a Targets IRF2 and CBX7 to Promote Cell Proliferation in Hepatocellular Carcinoma. Oncol Res 2018; 26:1327-1334. [PMID: 29386090 PMCID: PMC7844746 DOI: 10.3727/096504018x15165493852990] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
THIS ARTICLE WAS WITHDRAWN BY THE PUBLISHER IN NOVEMBER 2020.
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Affiliation(s)
- Zhang Yongyu
- *Department of Interventional Radiology, the Fifth Affiliated Hospital of Sun Yat-sen University, Xiangzhou District, Zhuhai, P.R. China
| | - Yang Lewei
- †Department of Radiation Oncology, the Fifth Affiliated Hospital of Sun Yat-sen University, Xiangzhou District, Zhuhai, P.R. China
| | - Liu Jian
- ‡Department of Infectious Diseases, the Fifth Affiliated Hospital of Sun Yat-sen University, Xiangzhou District, Zhuhai, P.R. China
| | - Sun Yuqin
- §Department of Nursing, the Fifth Affiliated Hospital of Sun Yat-sen University, Xiangzhou District, Zhuhai, P.R. China
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30
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Zhou L, Li Z, Pan X, Lai Y, Quan J, Zhao L, Xu J, Xu W, Guan X, Li H, Yang S, Gui Y, Lai Y. Identification of miR-18a-5p as an oncogene and prognostic biomarker in RCC. Am J Transl Res 2018; 10:1874-1886. [PMID: 30018727 PMCID: PMC6038077 DOI: pmid/30018727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2018] [Accepted: 05/07/2018] [Indexed: 02/05/2023]
Abstract
BACKGROUND RCC is a malignant tumor that originates from renal tubular epithelial cells, accounting for nearly 90% of renal malignancies and 3% of adult malignancies. It was reported that more than 30-40% of patients with early localized RCC still have recurrence and metastasis after receiving radical surgery. miRNAs are an endogenous non-coding small RNAs that play an important role in the regulation of tumor cell proliferation, differentiation and apoptosis. METHODS In our study, RT-qPCR, CCK-8 assay, wound scratch assay, transwell assay and flow cytometry assay were designed to identify the expression and functions of miR-18a-5p in RCC. Moreover, we collected the survival data from The Cancer Genome Atlas to predict and clarify the prognostic functions of miR-18a-5p in RCC. The correlation between miR-18a-5p expression and clinicopathological variables or overall survival was analyzed by 42 formalin-fixed paraffin-embedded (FFPE) renal cancer samples. RESULTS The expression of miR-18a-5p in RCC tissues and cell lines was elevated. Further researches suggested that upregulation of miR-18a-5p had a positive effect on RCC cell proliferation, migration, invasion and inhibition of apoptosis, while down-regulation of miR-18a-5p neutralized the effect. In addition, Data of TCGA and prognostic analysis of FFPE RCC samples revealed that high miR-18a-5p expression patients had significantly poorer survival. CONCLUSIONS These results demonstrated that miR-18a-5p functioned as an oncogene and prognostic biomarker in RCC.
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Affiliation(s)
- Liang Zhou
- Department of Urology, Peking University Shenzhen HospitalShenzhen 518036, Guangdong, China
- Department of Urology, Guangzhou Medical UniversityGuangzhou 511436, Guangdong, China
- The Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Peking University Shenzhen Hospital, Institute of Urology of Shenzhen PKU-HKUST Medical CenterShenzhen 518036, Guangdong, China
| | - Zuwei Li
- Department of Urology, Peking University Shenzhen HospitalShenzhen 518036, Guangdong, China
- Department of Urology, Shantou University Medical CollegeShantou 515041, Guangdong, China
- The Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Peking University Shenzhen Hospital, Institute of Urology of Shenzhen PKU-HKUST Medical CenterShenzhen 518036, Guangdong, China
| | - Xiang Pan
- Department of Urology, Peking University Shenzhen HospitalShenzhen 518036, Guangdong, China
- The Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Peking University Shenzhen Hospital, Institute of Urology of Shenzhen PKU-HKUST Medical CenterShenzhen 518036, Guangdong, China
- Department of Urology, Anhui Medical UniversityHefei 230032, Anhui, China
| | - Yulin Lai
- Department of Urology, Peking University Shenzhen HospitalShenzhen 518036, Guangdong, China
- Department of Urology, Guangzhou Medical UniversityGuangzhou 511436, Guangdong, China
- Department of Urology, Anhui Medical UniversityHefei 230032, Anhui, China
| | - Jing Quan
- Department of Urology, Peking University Shenzhen HospitalShenzhen 518036, Guangdong, China
- The Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Peking University Shenzhen Hospital, Institute of Urology of Shenzhen PKU-HKUST Medical CenterShenzhen 518036, Guangdong, China
- Department of Urology, Anhui Medical UniversityHefei 230032, Anhui, China
| | - Liwen Zhao
- Department of Urology, Peking University Shenzhen HospitalShenzhen 518036, Guangdong, China
- The Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Peking University Shenzhen Hospital, Institute of Urology of Shenzhen PKU-HKUST Medical CenterShenzhen 518036, Guangdong, China
- Department of Urology, Anhui Medical UniversityHefei 230032, Anhui, China
| | - Jinling Xu
- Department of Urology, Peking University Shenzhen HospitalShenzhen 518036, Guangdong, China
| | - Weijie Xu
- Department of Urology, Peking University Shenzhen HospitalShenzhen 518036, Guangdong, China
| | - Xin Guan
- Department of Urology, Peking University Shenzhen HospitalShenzhen 518036, Guangdong, China
| | - Hang Li
- Department of Urology, Peking University Shenzhen HospitalShenzhen 518036, Guangdong, China
| | - Shangqi Yang
- Department of Urology, Peking University Shenzhen HospitalShenzhen 518036, Guangdong, China
| | - Yaoting Gui
- The Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Peking University Shenzhen Hospital, Institute of Urology of Shenzhen PKU-HKUST Medical CenterShenzhen 518036, Guangdong, China
| | - Yongqing Lai
- Department of Urology, Peking University Shenzhen HospitalShenzhen 518036, Guangdong, China
- The Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Peking University Shenzhen Hospital, Institute of Urology of Shenzhen PKU-HKUST Medical CenterShenzhen 518036, Guangdong, China
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Du H, Yu H, Yang Y, Song Y, Wang F, Li S, Jiang Y. Computational identification of microRNAs and their targets in liver cirrhosis. Oncol Lett 2017; 14:7691-7698. [PMID: 29250171 PMCID: PMC5727606 DOI: 10.3892/ol.2017.7252] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2015] [Accepted: 04/21/2017] [Indexed: 02/07/2023] Open
Abstract
Previous studies have revealed that the deregulation of circulating miRNAs is associated with liver cirrhosis. The present study aimed to identify reliable candidate biomarkers to improve the early detection of liver cirrhosis. An integrated analysis of expression profiles of microRNAs (miRNAs/miRs) and mRNAs in liver cirrhosis tissues from the GEO database was performed. Next, the regulatory targets of the differentially expressed miRNAs in liver cirrhosis tissues were predicted. In addition, a regulatory network of miRNA-target genes was constructed. A total of 4 eligible mRNA expression profiling studies and 2 miRNA expression profiling studies met the inclusion criteria, and were thus included. A total of 48 differentially expressed miRNAs and 1,773 differentially expressed genes were identified in liver cirrhosis tissues compared with normal tissues. There were 240 miRNA-target pairs whose expression was negatively correlated. In the miRNA-target regulatory network, overexpression of miR-21 and miR-199a-3p was suggested to be closely associated with the progression of liver cirrhosis. In addition, functional enrichment analysis of the target genes indicated that cell cycle was the most significantly enriched pathway, and the dysregulation of leukemia inhibitory factor, cancerous inhibitor of protein phosphatase 2A and retinoblastoma-associated protein 1 clearly suggested their importance in the development of liver cirrhosis. We hypothesized that miR-21 and miR-199a-3p may be promising non-invasive diagnostic biomarkers for the early diagnosis of liver cirrhosis. The miRNA-target regulatory network may provide additional insight into the current data regarding the role of miRNAs in liver cirrhosis.
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Affiliation(s)
- Hongbo Du
- Department of Gastroenterology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100007, P.R. China
| | - Hao Yu
- Department of Integrated Traditional and Western Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, P.R. China
| | - Yuying Yang
- Department of Integrated Traditional and Western Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, P.R. China
| | - Yuanyuan Song
- Department of Integrated Traditional and Western Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, P.R. China
| | - Fei Wang
- Department of Integrated Traditional and Western Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, P.R. China
| | - Shangheng Li
- Department of Integrated Traditional and Western Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, P.R. China
| | - Yuyong Jiang
- Department of Integrated Traditional and Western Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, P.R. China
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Tan W, Liu B, Qu S, Liang G, Luo W, Gong C. MicroRNAs and cancer: Key paradigms in molecular therapy. Oncol Lett 2017; 15:2735-2742. [PMID: 29434998 DOI: 10.3892/ol.2017.7638] [Citation(s) in RCA: 104] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2015] [Accepted: 02/07/2017] [Indexed: 02/06/2023] Open
Abstract
MicroRNAs (miRNAs) are a type of small non-coding RNA molecule that performs an important role in post-transcriptional gene regulation. Since miRNAs were first identified in 1993, a number of studies have demonstrated that they act as tumor suppressors or oncogenes in human cancer, including colorectal, lung, brain, breast and liver cancer, and leukemia. Large high-throughput studies have previously revealed that miRNA profiling is critical for the diagnosis and prognosis of patients with cancer, while certain miRNAs possess the potential to be used as diagnostic and prognostic biomarkers or therapeutic targets in cancer. The present study reviews the studies and examines the roles of miRNAs in cancer diagnosis, prognosis and treatment, and discusses the potential therapeutic modality of exploiting miRNAs.
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Affiliation(s)
- Weige Tan
- Breast Tumor Center and Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510120, P.R. China.,Department of Breast Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 51000, P.R. China
| | - Bodu Liu
- Breast Tumor Center and Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510120, P.R. China
| | - Shaohua Qu
- Breast Tumor Center and Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510120, P.R. China
| | - Gehao Liang
- Breast Tumor Center and Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510120, P.R. China
| | - Wei Luo
- Breast Tumor Center and Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510120, P.R. China
| | - Chang Gong
- Breast Tumor Center and Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510120, P.R. China
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Wu XM, Xi ZF, Liao P, Huang HD, Huang XY, Wang C, Ma Y, Xia Q, Yao JG, Long XD. Diagnostic and prognostic potential of serum microRNA-4651 for patients with hepatocellular carcinoma related to aflatoxin B1. Oncotarget 2017; 8:81235-81249. [PMID: 29113383 PMCID: PMC5655278 DOI: 10.18632/oncotarget.16027] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2016] [Accepted: 02/18/2017] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND The serum microRNAs have been reported as potential biomarkers for hepatitis virus-related hepatocellular carcinoma (HCC); however, their role in aflatoxin B1 (AFB1)-related HCC to has not yet been evaluated. MATERIALS AND METHODS We conducted a case-control study, including 366 HCC cases and 662 controls without any evidence of tumors, to identify and assess diagnostic and prognostic potential of serum microRNAs for AFB1-related HCC. The sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) were used to elucidate diagnostic performance, and to compare the microRNAs with α-fetoprotein (AFP) at a cutoff of 20 ng/mL (AFP20) and 400 ng/mL (AFP400). RESULTS We found 8 differentially expressed microRNAs via the microRNA array analysis; however, only microRNA-4651 was further identified to detect AFB1-positive HCC but not AFB1-negative HCC. For AFB1-positive HCC, microRNA-4651 showed higher accuracy and sensitivity than AFP400 (AUC, 0.85 vs. 0.72; Sensitivity, 78.1% vs. 43.0%). Compared to AFP20, microRNA-4651 exhibited higher potential in identifying small-size (0.68 vs. 0.84 for AUC and 36.7% vs. 75.5% for sensitivity, respectively) and early-stage HCC (0.69 vs. 0.84 for AUC and 38.7% vs. 75.7% for sensitivity, respectively). Additionally, miR-4651 was also associated with HCC prognosis (hazard risk value, 2.67 for overall survival and 3.62 for tumor recurrence analysis). CONCLUSIONS These data suggest that serum microRNA-4651 may be a useful marker for HCC diagnosis and prognosis, especially AFB1-positive cases.
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Affiliation(s)
- Xue-Min Wu
- Department of Pathology, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China
| | - Zhi-Feng Xi
- Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Pinhu Liao
- Department of Medicine, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China
| | - Hong-Dong Huang
- Division of Medicine, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Xiao-Ying Huang
- Department of Pathology, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China
| | - Chao Wang
- Department of Medicine, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China
| | - Yun Ma
- Department of Pathology, The Affiliated Tumor Hospital, Guangxi Medical University, Nanning, China
| | - Qiang Xia
- Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jin-Guang Yao
- Department of Pathology, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China
| | - Xi-Dai Long
- Department of Pathology, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China
- Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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Liu L, Cai X, Liu E, Tian X, Tian C. MicroRNA-18a promotes proliferation and metastasis in hepatocellular carcinoma via targeting KLF4. Oncotarget 2017; 8:68263-68269. [PMID: 28978114 PMCID: PMC5620254 DOI: 10.18632/oncotarget.19293] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2017] [Accepted: 06/19/2017] [Indexed: 01/02/2023] Open
Abstract
MicroRNAs (miRNAs) are short, non-coding and endogenous RNAs that played as important roles in the proliferation and metastasis of tumors. In this study, we determined the role of miR-18a in the regulation of HCC cell motility. We showed that miR-18a expression was upregulated in human HCC tissues and cell lines. Moreover, Elevated expression of miR-18a promoted the HCC cell proliferation and migration. KLF4 was identified as a direct target of miR-18a in HCC cells. Furthermore, overexpression of KLF4 attenuated the effects of miR-18a on the regulation of HCC cell motility. The expression of KLF4 was negatively associated with the expression of miR-18a expression in HCC tissues. We also showed that the cell cycle inhibitor p21 was aberrantly downregulated in HCC cells, whereas this inhibition was reversed by miR-18a inhibitor. These data indicated that miR-18a may play a positive role in hepatocellular carcinoma by promoting the proliferation and migration of HCC cells through targeting KLF4 as well as downstream p21.
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Affiliation(s)
- Li Liu
- Department of Medicine & Appliance, Yunyan District Market Supervision and Administration Bureau, Guizhou 550001, China
| | - Xun Cai
- Department of Oncology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200080, China
| | - Enqiang Liu
- Department of Oncology, Qianjiang Central Hospital of Chongqing Municipality, Chongqing 409000, China
| | - Xia Tian
- Department of Nuclear Medicine, Guizhou Provincial People’s Hospital, Guizhou 550000, China
| | - Chuan Tian
- Department of Nuclear Medicine, Guizhou Provincial People’s Hospital, Guizhou 550000, 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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Klingenberg M, Matsuda A, Diederichs S, Patel T. Non-coding RNA in hepatocellular carcinoma: Mechanisms, biomarkers and therapeutic targets. J Hepatol 2017; 67:603-618. [PMID: 28438689 DOI: 10.1016/j.jhep.2017.04.009] [Citation(s) in RCA: 273] [Impact Index Per Article: 34.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2017] [Revised: 04/10/2017] [Accepted: 04/11/2017] [Indexed: 02/06/2023]
Abstract
The majority of the human genome is not translated into proteins but can be transcribed into RNA. Even though the resulting non-coding RNAs (ncRNAs) do not encode for proteins, they contribute to diseases such as cancer. Here, we review examples of the functions of ncRNAs in liver cancer and their potential use for the detection and treatment of liver cancer.
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Affiliation(s)
- Marcel Klingenberg
- Division of RNA Biology & Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany; Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany; Hartmut Hoffmann-Berling International Graduate School of Molecular and Cellular Biology (HBIGS), University of Heidelberg, Heidelberg, Germany
| | - Akiko Matsuda
- Department of Transplantation, Mayo Clinic, Jacksonville, FL, USA; Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA
| | - Sven Diederichs
- Division of RNA Biology & Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany; Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany; Hartmut Hoffmann-Berling International Graduate School of Molecular and Cellular Biology (HBIGS), University of Heidelberg, Heidelberg, Germany; German Cancer Consortium (DKTK), Freiburg, Germany; Division of Cancer Research, Dept. of Thoracic Surgery, Medical Center - University of Freiburg, Freiburg, Germany; Faculty of Medicine, University of Freiburg, Freiburg, Germany.
| | - Tushar Patel
- Department of Transplantation, Mayo Clinic, Jacksonville, FL, USA; Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.
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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: 73] [Impact Index Per Article: 9.1] [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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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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MicroRNA-18a-5p functions as an oncogene by directly targeting IRF2 in lung cancer. Cell Death Dis 2017; 8:e2764. [PMID: 28471447 PMCID: PMC5520692 DOI: 10.1038/cddis.2017.145] [Citation(s) in RCA: 100] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2016] [Revised: 03/01/2017] [Accepted: 03/02/2017] [Indexed: 02/06/2023]
Abstract
Lung cancer is the major form of cancer resulting in cancer-related mortality around the world. MicroRNAs are endogenous small non-coding single-stranded RNAs, which can engage in the regulation of gene expression. In this study, miR-18a-5p significantly upregulated in non-small cell lung cancer (NSCLC) tissues and NSCLC cell lines, suggesting an oncogenic function in lung cancer. Additionally, miR-18a-5p can promote carcinogenesis by directly targeting interferon regulatory factor 2 (IRF2). Further experiments indicated that IRF2 can increase cell apoptosis, inhibit cell proliferation and migration ability. Our study demonstrates that miR-18a-5p promotes autophagy in NSCLC. Collectively, these results indicate that miR-18a-5p can not only promote NSCLC by suppressing IRF2, but also will be a promising target in the near future.
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Anderton B, Camarda R, Balakrishnan S, Balakrishnan A, Kohnz RA, Lim L, Evason KJ, Momcilovic O, Kruttwig K, Huang Q, Xu G, Nomura DK, Goga A. MYC-driven inhibition of the glutamate-cysteine ligase promotes glutathione depletion in liver cancer. EMBO Rep 2017; 18:569-585. [PMID: 28219903 PMCID: PMC5376764 DOI: 10.15252/embr.201643068] [Citation(s) in RCA: 61] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2016] [Revised: 01/08/2017] [Accepted: 01/13/2017] [Indexed: 12/19/2022] Open
Abstract
How MYC reprograms metabolism in primary tumors remains poorly understood. Using integrated gene expression and metabolite profiling, we identify six pathways that are coordinately deregulated in primary MYC-driven liver tumors: glutathione metabolism; glycine, serine, and threonine metabolism; aminoacyl-tRNA biosynthesis; cysteine and methionine metabolism; ABC transporters; and mineral absorption. We then focus our attention on glutathione (GSH) and glutathione disulfide (GSSG), as they are markedly decreased in MYC-driven tumors. We find that fewer glutamine-derived carbons are incorporated into GSH in tumor tissue relative to non-tumor tissue. Expression of GCLC, the rate-limiting enzyme of GSH synthesis, is attenuated by the MYC-induced microRNA miR-18a. Inhibition of miR-18a in vivo leads to increased GCLC protein expression and GSH abundance in tumor tissue. Finally, MYC-driven liver tumors exhibit increased sensitivity to acute oxidative stress. In summary, MYC-dependent attenuation of GCLC by miR-18a contributes to GSH depletion in vivo, and low GSH corresponds with increased sensitivity to oxidative stress in tumors. Our results identify new metabolic pathways deregulated in primary MYC tumors and implicate a role for MYC in regulating a major antioxidant pathway downstream of glutamine.
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Affiliation(s)
- Brittany Anderton
- Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA, USA
- Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
| | - Roman Camarda
- Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA, USA
- Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
| | - Sanjeev Balakrishnan
- Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA, USA
- Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
| | - Asha Balakrishnan
- Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA, USA
- Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
- Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, TWINCORE, Center for Experimental and Clinical Infection Research, Hannover, Germany
| | - Rebecca A Kohnz
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA, USA
| | - Lionel Lim
- Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA, USA
- Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
| | - Kimberley J Evason
- Department of Pathology and Huntsman Cancer Institute, University of Utah, Salt Lake, UT, USA
| | - Olga Momcilovic
- Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA, USA
- Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
| | - Klaus Kruttwig
- Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA, USA
- Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
| | - Qiang Huang
- Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China
| | - Guowang Xu
- Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China
| | - Daniel K Nomura
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA, USA
| | - Andrei Goga
- Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA, USA
- Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
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Correia CN, Nalpas NC, McLoughlin KE, Browne JA, Gordon SV, MacHugh DE, Shaughnessy RG. Circulating microRNAs as Potential Biomarkers of Infectious Disease. Front Immunol 2017; 8:118. [PMID: 28261201 PMCID: PMC5311051 DOI: 10.3389/fimmu.2017.00118] [Citation(s) in RCA: 160] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2016] [Accepted: 01/25/2017] [Indexed: 12/12/2022] Open
Abstract
microRNAs (miRNAs) are a class of small non-coding endogenous RNA molecules that regulate a wide range of biological processes by post-transcriptionally regulating gene expression. Thousands of these molecules have been discovered to date, and multiple miRNAs have been shown to coordinately fine-tune cellular processes key to organismal development, homeostasis, neurobiology, immunobiology, and control of infection. The fundamental regulatory role of miRNAs in a variety of biological processes suggests that differential expression of these transcripts may be exploited as a novel source of molecular biomarkers for many different disease pathologies or abnormalities. This has been emphasized by the recent discovery of remarkably stable miRNAs in mammalian biofluids, which may originate from intracellular processes elsewhere in the body. The potential of circulating miRNAs as biomarkers of disease has mainly been demonstrated for various types of cancer. More recently, however, attention has focused on the use of circulating miRNAs as diagnostic/prognostic biomarkers of infectious disease; for example, human tuberculosis caused by infection with Mycobacterium tuberculosis, sepsis caused by multiple infectious agents, and viral hepatitis. Here, we review these developments and discuss prospects and challenges for translating circulating miRNA into novel diagnostics for infectious disease.
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Affiliation(s)
- Carolina N Correia
- Animal Genomics Laboratory, UCD School of Agriculture and Food Science, University College Dublin , Dublin , Ireland
| | - Nicolas C Nalpas
- Animal Genomics Laboratory, UCD School of Agriculture and Food Science, University College Dublin , Dublin , Ireland
| | - Kirsten E McLoughlin
- Animal Genomics Laboratory, UCD School of Agriculture and Food Science, University College Dublin , Dublin , Ireland
| | - John A Browne
- Animal Genomics Laboratory, UCD School of Agriculture and Food Science, University College Dublin , Dublin , Ireland
| | - Stephen V Gordon
- UCD School of Veterinary Medicine, University College Dublin, Dublin, Ireland; University College Dublin, UCD Conway Institute of Biomolecular and Biomedical Research, Dublin, Ireland
| | - David E MacHugh
- Animal Genomics Laboratory, UCD School of Agriculture and Food Science, University College Dublin, Dublin, Ireland; University College Dublin, UCD Conway Institute of Biomolecular and Biomedical Research, Dublin, Ireland
| | - Ronan G Shaughnessy
- UCD School of Veterinary Medicine, University College Dublin , Dublin , Ireland
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Shigeyasu K, Toden S, Zumwalt TJ, Okugawa Y, Goel A. Emerging Role of MicroRNAs as Liquid Biopsy Biomarkers in Gastrointestinal Cancers. Clin Cancer Res 2017; 23:2391-2399. [PMID: 28143873 DOI: 10.1158/1078-0432.ccr-16-1676] [Citation(s) in RCA: 104] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Revised: 12/27/2016] [Accepted: 12/27/2016] [Indexed: 12/17/2022]
Abstract
Cancer has emerged as a leading cause of mortality worldwide, claiming more than 8 million lives annually. Gastrointestinal cancers account for about 35% of these mortalities. Recent advances in diagnostic and treatment strategies have reduced mortality among patients with gastrointestinal cancer, yet a significant number of patients still develop late-stage cancer, where treatment options are inadequate. Emerging interests in "liquid biopsies" have encouraged investigators to identify and develop clinically relevant noninvasive genomic and epigenomic signatures that can be exploited as biomarkers capable of detecting premalignant and early-stage cancers. In this context, microRNAs (miRNA), which are small, noncoding RNAs that are frequently dysregulated in cancers, have emerged as promising entities for such diagnostic purposes. Even though the future looks promising, current approaches for detecting miRNAs in blood and other biofluids remain inadequate. This review summarizes existing efforts to exploit circulating miRNAs as cancer biomarkers and evaluates their potential and challenges as liquid biopsy-based biomarkers for gastrointestinal cancers. Clin Cancer Res; 23(10); 2391-9. ©2017 AACR.
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Affiliation(s)
- Kunitoshi Shigeyasu
- Center for Gastrointestinal Research; Center for Translational Genomics and Oncology, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor Research Institute and Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas
| | - Shusuke Toden
- Center for Gastrointestinal Research; Center for Translational Genomics and Oncology, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor Research Institute and Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas
| | - Timothy J Zumwalt
- Center for Gastrointestinal Research; Center for Translational Genomics and Oncology, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor Research Institute and Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas
| | - Yoshinaga Okugawa
- Center for Gastrointestinal Research; Center for Translational Genomics and Oncology, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor Research Institute and Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas
| | - Ajay Goel
- Center for Gastrointestinal Research; Center for Translational Genomics and Oncology, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor Research Institute and Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas.
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Khosla R, Rastogi A, Ramakrishna G, Pamecha V, Mukhopadhyay A, Vasudevan M, Sarin SK, Trehanpati N. EpCAM+ Liver Cancer Stem-Like Cells Exhibiting Autocrine Wnt Signaling Potentially Originate in Cirrhotic Patients. Stem Cells Transl Med 2017; 6:807-818. [PMID: 28176469 PMCID: PMC5442787 DOI: 10.1002/sctm.16-0248] [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: 05/20/2016] [Revised: 08/18/2016] [Accepted: 09/30/2016] [Indexed: 12/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is believed to originate from cancer stem cells (CSCs). While epithelial cell adhesion molecule (EpCAM) is a marker of normal hepatic stem cells (HSCs), EpCAM+ cells from HCC behave like CSCs. Since HCC mostly develops on a cirrhotic background, we sought to determine whether CSC‐like EpCAM+ cells exist in patients with advanced cirrhosis. Both flow cytometry and immunohistochemistry showed that frequency of EpCAM+ cells in advanced cirrhosis was increased as compared to control. To determine whether increased EpCAM population in advanced cirrhosis harbors any CSC‐like cells, we compared molecular and functional features of EpCAM+ cells from advanced cirrhosis (Ep+CIR; n = 20) with EpCAM+ cells from both HCC (Ep+HCC; n = 20) and noncancerous/noncirrhotic (control) (Ep+NSC; n = 7) liver tissues. Ep+CIRs displayed similarity with Ep+HCC cells including upregulated expression of stemness and Notch pathway genes, enhanced self‐renewal in serial spheroid assay and generation of subcutaneous tumors in nonobese diabetic/severe combined immunodeficiency mice. Moreover, transcriptome and miRNome of Ep+CIRs appeared closer to that of Ep+HCC cells than Ep+NSCs. Interestingly, more than 50% micro RNAs (miRNAs) and transcripts specifically expressed in Ep+HCCs were also expressed in Ep+CIRs. However, none of Ep+NSC specific miRNAs and only 7% Ep+NSC specific transcripts were expressed in Ep+CIRs. Further, according to gene expression and in vitro Wnt inhibition analysis, autocrine Wnt signaling appeared to be a distinct feature of Ep+CIR and Ep+HCC cells, which was absent from Ep+NSCs. EpCAM+ cells in advanced cirrhosis possibly include a population of CSC‐like cells which can be explored for early diagnosis of HCC development. Stem Cells Translational Medicine2017;6:807–818
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Affiliation(s)
- Ritu Khosla
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Archana Rastogi
- Department of Pathology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Gayatri Ramakrishna
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Viniyendra Pamecha
- Department of Liver Transplant and Hepato Pancreato Biliary Surgery, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Ashok Mukhopadhyay
- Stem Cell Biology Laboratory, National Institute of Immunology, New Delhi, India
| | | | - Shiv Kumar Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Nirupma Trehanpati
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
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Biomarker MicroRNAs for Diagnosis, Prognosis and Treatment of Hepatocellular Carcinoma: A Functional Survey and Comparison. Sci Rep 2016; 6:38311. [PMID: 27917899 PMCID: PMC5137156 DOI: 10.1038/srep38311] [Citation(s) in RCA: 73] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2016] [Accepted: 11/07/2016] [Indexed: 12/17/2022] Open
Abstract
Hepatocellular Carcinoma (HCC) is one of the most common malignant tumors with high incidence and mortality rate. Precision and effective biomarkers are therefore urgently needed for the early diagnosis and prognostic estimation. MicroRNAs (miRNAs) are important regulators which play functions in various cellular processes and biological activities. Accumulating evidence indicated that the abnormal expression of miRNAs are closely associated with HCC initiation and progression. Recently, many biomarker miRNAs for HCC have been identified from blood or tissues samples, however, the universality and specificity on clinicopathological features of them are less investigated. In this review, we comprehensively surveyed and compared the diagnostic, prognostic, and therapeutic roles of HCC biomarker miRNAs in blood and tissues based on the cancer hallmarks, etiological factors as well as ethnic groups, which will be helpful to the understanding of the pathogenesis of biomarker miRNAs in HCC development and further provide accurate clinical decisions for HCC diagnosis and treatment.
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He S, Hu XW, Wang D, Han LF, Zhang DC, Wei C. Accuracy of microRNAs for the diagnosis of hepatocellular carcinoma: A systematic review and meta-analysis. Clin Res Hepatol Gastroenterol 2016; 40:405-17. [PMID: 27016891 DOI: 10.1016/j.clinre.2016.02.001] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2015] [Revised: 02/01/2016] [Accepted: 02/17/2016] [Indexed: 02/04/2023]
Abstract
Due to the high morbidity, mortality and late detection of hepatocellular carcinoma (HCC), it becomes a major public health challenge. MicroRNAs (miRNAs) have been reported to be aberrantly expressed in patients with HCC and thus may serve as potential diagnostic biomarkers. The aim of this study was to systematically assess the diagnostic accuracy of miRNAs as biomarkers for diagnosing HCC through a meta-analysis. Our results indicated that serum miRNAs had a relatively high diagnostic value for HCC diagnosis; the combination of serum α-fetoprotein (AFP) and miRNAs displayed a better diagnostic accuracy than using AFP or miRNAs alone; the combination of multiple miRNAs assay in serum had the highest diagnostic accuracy in HCC diagnosis based on the published data. In conclusion, our meta-analysis suggests that miRNAs, especially serum miRNAs, had a relatively high diagnostic value for HCC diagnosis, which can discriminate HCC from healthy subjects and those with chronic hepatitis and cirrhosis easily, and may serve as a novel, less-invasive screening tool.
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Affiliation(s)
- Song He
- Maanshan Center for Clinical Laboratory, Maanshan Municipal Hospital Group, 45, Hubei Road, Maanshan 243000, China.
| | - Xiao-Wu Hu
- Maanshan Center for Clinical Laboratory, Maanshan Municipal Hospital Group, 45, Hubei Road, Maanshan 243000, China
| | - Dong Wang
- Maanshan Center for Clinical Laboratory, Maanshan Municipal Hospital Group, 45, Hubei Road, Maanshan 243000, China
| | - Ling-Fei Han
- Maanshan Center for Clinical Laboratory, Maanshan Municipal Hospital Group, 45, Hubei Road, Maanshan 243000, China
| | - De-Chun Zhang
- Molecular Medicine & Tumor Research Center, Chongqing Medical University, Chongqing 400016, China
| | - Cheng Wei
- Maanshan Center for Clinical Laboratory, Maanshan Municipal Hospital Group, 45, Hubei Road, Maanshan 243000, China
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Fiorino S, Bacchi-Reggiani ML, Visani M, Acquaviva G, Fornelli A, Masetti M, Tura A, Grizzi F, Zanello M, Mastrangelo L, Lombardi R, Di Tommaso L, Bondi A, Sabbatani S, Domanico A, Fabbri C, Leandri P, Pession A, Jovine E, de Biase D. MicroRNAs as possible biomarkers for diagnosis and prognosis of hepatitis B- and C-related-hepatocellular-carcinoma. World J Gastroenterol 2016; 22:3907-3936. [PMID: 27099435 PMCID: PMC4823242 DOI: 10.3748/wjg.v22.i15.3907] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Revised: 03/05/2016] [Accepted: 03/18/2016] [Indexed: 02/06/2023] Open
Abstract
Aim of the present review is to summarize the current knowledge about the potential relationship between miRNAs and hepatitis B virus (HBV)-hepatitis C virus (HCV) related liver diseases. A systematic computer-based search of published articles, according to the Preferred Reporting Items for Systematic reviews and Meta-Analysis Statement, was performed to identify relevant studies on usefulness of serum/plasma/urine miRNAs, as noninvasive biomarkers for early detection of HBV and HCV-induced hepatocellular carcinoma (HCC) development, as well as for its prognostic evaluation. The used Medical Subject Headings terms and keywords were: "HBV", "HCV", "hepatocellular carcinoma", "microRNAs", "miRNAs", "diagnosis", "prognosis", "therapy", "treatment". Some serum/plasma miRNAs, including miR-21, miR-122, mi-125a/b, miR-199a/b, miR-221, miR-222, miR-223, miR-224 might serve as biomarkers for early diagnosis/prognosis of HCC, but, to date, not definitive results or well-defined panels of miRNAs have been obtained. More well-designed studies, focusing on populations of different geographical areas and involving larger series of patients, should be carried out to improve our knowledge on the potential role of miRNAs for HCC early detection and prognosis.
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Huang JT, Liu SM, Ma H, Yang Y, Zhang X, Sun H, Zhang X, Xu J, Wang J. Systematic Review and Meta-Analysis: Circulating miRNAs for Diagnosis of Hepatocellular Carcinoma. J Cell Physiol 2016; 231:328-335. [PMID: 26291451 DOI: 10.1002/jcp.25135] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2015] [Accepted: 08/14/2015] [Indexed: 12/17/2022]
Abstract
Because early-stage hepatocellular carcinoma (HCC) is difficult to diagnose using the existing techniques, identifying better biomarkers would likely improve the patients' prognoses. We performed a systematic review and meta-analysis of published studies to appraise the utility of microRNAs (miRNAs) for the early diagnosis of HCC. Pertinent literature was collected from the Medline, Embase, and Chinese National Knowledge Infrastructure databases. We analyzed 50 studies that included 3423 cases of HCC, 2403 chronic hepatic disease (CH) patients, and 1887 healthy controls in 16 articles. Summary receiver operating characteristic analyses of all miRNAs showed an area under the curve (AUC) of 0.82, with 75.8% sensitivity and 75.0% specificity in discriminating patients with HCC from healthy controls. miR-21 and miR-122 individually distinguished patients with HCC from healthy controls, with an AUC of 0.88 for miR-21 and 0.77 for miR-122. The sensitivity and specificity for miR-21 were 86.6% and 79.5%, respectively, those for miR-122 were 68.0% and 73.3%. We conclude that circulating miRNAs, particularly miR-21, and miR-122, are promising biomarkers for the early diagnosis of HCC.
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Affiliation(s)
- Jing-Tao Huang
- Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, P. R. China
| | - Song-Mei Liu
- Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, P. R. China
| | - Haiqing Ma
- Department of Oncology, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, Guangdong, P. R. China
| | - Ying Yang
- Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, P. R. China
| | - Xuan Zhang
- Scientific Research Center, Shanghai Public Health Clinical Center, Shanghai, Jinshan District, P. R. China
| | - Huanhuan Sun
- Department of Oncology, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, Guangdong, P. R. China
| | - Xiaoyan Zhang
- Scientific Research Center, Shanghai Public Health Clinical Center, Shanghai, Jinshan District, P. R. China
| | - Jianqing Xu
- Scientific Research Center, Shanghai Public Health Clinical Center, Shanghai, Jinshan District, P. R. China
| | - Jin Wang
- Scientific Research Center, Shanghai Public Health Clinical Center, Shanghai, Jinshan District, P. R. China
- Department of Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
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48
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Louten J, Beach M, Palermino K, Weeks M, Holenstein G. MicroRNAs Expressed during Viral Infection: Biomarker Potential and Therapeutic Considerations. Biomark Insights 2016; 10:25-52. [PMID: 26819546 PMCID: PMC4718089 DOI: 10.4137/bmi.s29512] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2015] [Revised: 10/22/2015] [Accepted: 10/24/2015] [Indexed: 12/13/2022] Open
Abstract
MicroRNAs (miRNAs) are short sequences of noncoding single-stranded RNAs that exhibit inhibitory effects on complementary target mRNAs. Recently, it has been discovered that certain viruses express their own miRNAs, while other viruses activate the transcription of cellular miRNAs for their own benefit. This review summarizes the viral and/or cellular miRNAs that are transcribed during infection, with a focus on the biomarker and therapeutic potential of miRNAs (or their antagomirs). Several human viruses of clinical importance are discussed, namely, herpesviruses, polyomaviruses, hepatitis B virus, hepatitis C virus, human papillomavirus, and human immunodeficiency virus.
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Affiliation(s)
- Jennifer Louten
- Department of Molecular and Cellular Biology, Kennesaw State University, Kennesaw, GA, USA
| | - Michael Beach
- Department of Molecular and Cellular Biology, Kennesaw State University, Kennesaw, GA, USA
| | - Kristina Palermino
- Department of Molecular and Cellular Biology, Kennesaw State University, Kennesaw, GA, USA
| | - Maria Weeks
- Department of Molecular and Cellular Biology, Kennesaw State University, Kennesaw, GA, USA
| | - Gabrielle Holenstein
- Department of Molecular and Cellular Biology, Kennesaw State University, Kennesaw, GA, USA
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49
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Wang Y, Tian Y. miRNA for diagnosis and clinical implications of human hepatocellular carcinoma. Hepatol Res 2016; 46:89-99. [PMID: 26284466 DOI: 10.1111/hepr.12571] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2015] [Revised: 06/12/2015] [Accepted: 08/10/2015] [Indexed: 12/14/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies, as a result of being asymptomatic at early stage, subsequent late clinical confirmation and poor prognosis. It is urgent to search more accurate biomarkers for diagnosing early HCC and predicting prognosis. Many factors participate in liver carcinogenesis, including dysregulation of miRNA. miRNA were endogenously expressed non-coding single-stranded small RNA with 19-25 nucleotides. Accumulating evidences have showed that miRNA from circulation and solitary tumors may be useful to classify the differentiation degree and stages of HCC, detect the hepatitis B/C virus-related HCC, and predict the survival rate after surgical resection or orthotopic liver transplantation. In this review, we summarize dysregulated miRNA, their roles in diagnosis and clinical implications of HCC.
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Affiliation(s)
- Yurong Wang
- Core Laboratory of Translational Medicine, Chinese PLA General Hospital, Beijing, China.,School of Medicine, Nankai University, Tianjin, China
| | - Yaping Tian
- Core Laboratory of Translational Medicine, Chinese PLA General Hospital, Beijing, China.,School of Medicine, Nankai University, Tianjin, China
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50
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Serum microRNAs as potential noninvasive biomarkers for glioma. Tumour Biol 2015; 37:1407-10. [PMID: 26628296 DOI: 10.1007/s13277-015-4515-7] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2015] [Accepted: 11/25/2015] [Indexed: 12/20/2022] Open
Abstract
Gliomas are derived from astroglial precursors or astrocytes, accounting for 40 % central nervous system tumors. MicroRNAs (miRNAs) are a class of endogenous, small (19- to 23-nucleotides) non-coding RNAs involved in cancer progression. Recent studies show that circulating miRNAs are associated with the clinicopathological features and prognosis of gliomas. Serum miRNAs may serve as novel biomarkers for gliomas diagnosis. This review explores the possibilities of using serum miRNAs as prognostic, diagnostic markers, and therapeutic targets in gliomas.
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