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1
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Cinque A, Capasso A, Vago R, Floris M, Lee MW, Minnei R, Trevisani F. MicroRNA Signatures in the Upper Urinary Tract Urothelial Carcinoma Scenario: Ready for the Game Changer? Int J Mol Sci 2022; 23:2602. [PMID: 35269744 PMCID: PMC8910117 DOI: 10.3390/ijms23052602] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 02/20/2022] [Accepted: 02/24/2022] [Indexed: 12/18/2022] Open
Abstract
Upper urinary tract urothelial carcinoma (UTUC) represents a minor subgroup of malignancies arising in the urothelium of the renal pelvis or ureter. The estimated annual incidence is around 2 cases per 100,000 people, with a mean age at diagnosis of 73 years. UTUC is more frequently diagnosed in an invasive or metastatic stage. However, even though the incidence of UTUC is not high, UTUC tends to be aggressive and rapidly progressing with a poor prognosis in some patients. A significant challenge in UTUC is ensuring accurate and timely diagnosis, which is complicated by the non-specific nature of symptoms seen at the onset of disease. Moreover, there is a lack of biomarkers capable of identifying the early presence of the malignancy and guide-tailored medical treatment. However, the growing understanding of the molecular biology underlying UTUC has led to the discovery of promising new biomarkers. Among these biomarkers, there is a class of small non-coding RNA biomarkers known as microRNAs (miRNAs) that are particularly promising. In this review, we will analyze the main characteristics of UTUC and focus on microRNAs as possible novel tools that could enter clinical practice in order to optimize the current diagnostic and prognostic algorithm.
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Affiliation(s)
- Alessandra Cinque
- Biorek S.r.l., San Raffaele Scientific Institute, 20132 Milan, Italy;
| | - Anna Capasso
- Department of Medical Oncology Livestrong Cancer Institutes, Dell Medical School, University of Texas at Austin, Austin, TX 78723, USA;
| | - Riccardo Vago
- Urological Research Institute, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy;
- Faculty of Medicine and Surgery,, Università Vita-Salute San Raffaele, 20132 Milan, Italy
| | - Matteo Floris
- Nephrology, Dialysis, and Transplantation, Università degli Studi di Cagliari, G. Brotzu Hospital, 09134 Cagliari, Italy; (M.F.); (R.M.)
| | - Michael W. Lee
- Department of Medical Oncology and Medical Education, Dell Medical School, Livestrong Cancer Institutes, University of Texas at Austin, Austin, TX 78723, USA;
| | - Roberto Minnei
- Nephrology, Dialysis, and Transplantation, Università degli Studi di Cagliari, G. Brotzu Hospital, 09134 Cagliari, Italy; (M.F.); (R.M.)
| | - Francesco Trevisani
- Biorek S.r.l., San Raffaele Scientific Institute, 20132 Milan, Italy;
- Urological Research Institute, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy;
- Unit of Urology, San Raffaele Scientific Institute, 20132 Milan, Italy
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Aboelwafa RA, Ellakany WI, Gamaleldin MA, Saad MA. The expression of microRNA-331-3p and microRNA-23b3 in Egyptian patients with early-stage hepatocellular carcinoma in hepatitis C-related liver cirrhosis. EGYPTIAN LIVER JOURNAL 2021. [DOI: 10.1186/s43066-021-00122-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Hepatocellular carcinoma and hepatitis C are strongly associated. The current work aimed to study the expression levels of microRNA-331-3p and microRNA-23b-3p as propable biomarkers for detecting liver cancer (HCC) at its early stages in patients with HCV-related liver cirrhosis. The current prospective study included two hundred participants, divided into three groups: group I, 100 patients with HCV-related liver cirrhosis; group II, 50 HCC patients at early stages; and group III, 50 apparentlyhealthy controls. All patients had routine laboratory workup and ultrasound hepatic assessment. Values of microRNA-331-3p and microRNA-23b-3p were measured by real-time quantitative PCR.
Results
Levels of miR-331-3p were significantly higher in HCC patients than in cirrhotic patients and controls (p < 0.001), while levels of miR-23b-3p were significantly lower in HCC patients compared to cirrhotics and controls (p < 0.001). ROC curve revealed that miR-23b-3p had 80% sensitivity and 74% specificity, miR-331-3p had 66% sensitivity and 61% specificity, and AFP had 64% sensitivity and 61% specificity of 61% in discrimination between HCC patients from controls.
Conclusion
Serum miR-23b-3p is a more effective predictor than miR-331-3p and AFP for the development of hepatocellular carcinoma in hepatitis C (HCV)-related cirrhotic patients.
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3
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Li J, Jin B, Wang T, Li W, Wang Z, Zhang H, Song Y, Li N. Serum microRNA expression profiling identifies serum biomarkers for HCV-related hepatocellular carcinoma. Cancer Biomark 2020; 26:501-512. [PMID: 31658041 DOI: 10.3233/cbm-181970] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND The identification of high-sensitivity biomarkers for detection of hepatocellular carcinoma (HCC) from high-risk individuals is essential. OBJECTIVE The present study was undertaken to identify and validate serum microRNAs (miRNAs) as potential biomarkers for hepatitis C virus (HCV)-related HCC. METHODS Illumina sequencing was employed to screen the expression profiles of miRNAs in serum samples of HCV-related HCC patients and liver cirrhosis (LC) patients. RT-qPCR was used to confirm the altered miRNAs between the two groups. Moreover, candidate miRNAs were examined in serum samples of 40 HCC patients, 54 LC patients, 55 patients with chronic HCV hepatitis and 45 healthy controls. Receiver operating characteristic (ROC) curve analysis was used to evaluate the diagnostic performance of the miRNAs for the detection of HCC. RESULTS Four miRNAs (miR-122-5p, miR-331-3p, miR-494-3p, miR-224-5p) were significantly increased and two miRNAs (miR-185-5p, miR-23b-3p) were significantly decreased in HCC patients compared to LC patients. ROC curve analysis demonstrated that the six miRNAs could be used as potential biomarkers for HCC detection. Combination of the six miRNAs could efficiently detect HCC in LC patients with the area under the ROC curve (AUC) of 0.995 and combination of the six miRNAs also provided high diagnostic accuracy (AUC = 0.961) for detection of HCC in non-HCC subjects. CONCLUSIONS The six serum miRNAs can be utilized as a surrogate and non-invasive biomarker for HCV-related HCC diagnosis.
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Affiliation(s)
- Jian Li
- Department of Hepatobiliary Surgery, Hospital Affiliated to Chengde Medical University, Chengde, Hebei, China.,Department of Hepatobiliary Surgery, You'an Hospital Affiliated to Capital Medical University, Beijing, China
| | - Boxun Jin
- Department of Hepatobiliary Surgery, You'an Hospital Affiliated to Capital Medical University, Beijing, China
| | - Tiezheng Wang
- Department of Hepatobiliary Surgery, You'an Hospital Affiliated to Capital Medical University, Beijing, China
| | - Wenlei Li
- Department of Hepatobiliary Surgery, You'an Hospital Affiliated to Capital Medical University, Beijing, China
| | - Zhenshun Wang
- Department of Hepatobiliary Surgery, You'an Hospital Affiliated to Capital Medical University, Beijing, China
| | - Haitao Zhang
- Department of Hepatobiliary Surgery, You'an Hospital Affiliated to Capital Medical University, Beijing, China
| | - Yunjun Song
- Department of Hepatobiliary Surgery, You'an Hospital Affiliated to Capital Medical University, Beijing, China
| | - Ning Li
- Department of Hepatobiliary Surgery, You'an Hospital Affiliated to Capital Medical University, Beijing, China
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Sun Q, Li J, Jin B, Wang T, Gu J. Evaluation of miR-331-3p and miR-23b-3p as serum biomarkers for hepatitis c virus-related hepatocellular carcinoma at early stage. Clin Res Hepatol Gastroenterol 2020; 44:21-28. [PMID: 31053500 DOI: 10.1016/j.clinre.2019.03.011] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Revised: 03/21/2019] [Accepted: 03/26/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS This study aimed to investigate the diagnostic values of serum miR-331-3p and miR-23b-3p as tumor markers for the diagnosis of hepatocellular carcinoma (HCC) at early stage. METHODS A total of 191 subjects were enrolled and consisted of 45 healthy controls (HC), 106 hepatitis c virus (HCV)-related chronic liver disease (CLD) patients, and 40 early-stage HCC patients. CLD patients were subdivided according to Metavir fibrosis-scoring. Serum miR-331-3p and miR-23b-3p were measured. The area under curves (AUC) was calculated for each microRNA and compared with that for alpha-fetoprotein (AFP) in the detection of HCC at early stage. RESULTS Serum miR-331-3p was significantly higher in early-stage HCC than that in CLD and HC respectively, and it decreased significantly after surgery in early-stage HCC. Contrarily, serum miR-23b-3p was significantly lower in early-stage HCC and increased significantly after surgery. Further, receiver operating characteristic analysis demonstrated AUC was 0.806 (95%CI: 0.728-0.883; sensitivity: 85.85%, specificity: 65.00%) for serum miR-23b-3p in discriminating early-stage HCC from CLD patients, higher than that for AFP (AUC:0.660, 95%CI: 0.556-0.764; sensitivity: 70.00%, specificity: 56.60%). In discrimination early-stage HCC from severe fibrosis/cirrhosis (F3 + F4) patients, both miR-23b-3p (AUC: 0.796, 95%CI: 0.703-0.889; sensitivity: 85.11%, specificity: 65.00%) and miR-331-3p (AUC:0.832, 95%CI: 0.812-0.953; sensitivity: 75.00%, specificity: 85.11%) had better diagnostic performances than AFP (AUC:0.632, 95%CI: 0.512-0.753; sensitivity: 50.00%, specificity: 55.32%). Serum miR-331-3p levels also showed a significant correlation with BCLC stages of HCC. CONCLUSION Serum miR-331-3p and miR-23b-3p could be used as novel invasive biomarkers in the early detection of HCC in high-risk patients.
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Affiliation(s)
- Qiyu Sun
- Department of Clinical Laboratory, Affiliated Hospital of Chengde Medical University, 36, Nanyingzi Road, Chengde, 067000, PR China.
| | - Jian Li
- Department of Hepatobiliary Surgery, Affiliated Hospital of Chengde Medical University, 36, Nanyingzi Road, Chengde, 067000, PR China
| | - Boxun Jin
- Department of Hepatobiliary Surgery, YouAn Hospital Affiliated to Capital Medical University, 8, Xitoutiao Road, Beijing, 100069, PR China
| | - Tiezheng Wang
- Department of Hepatobiliary Surgery, YouAn Hospital Affiliated to Capital Medical University, 8, Xitoutiao Road, Beijing, 100069, PR China
| | - Jiannan Gu
- Department of Hepatobiliary Surgery, Affiliated Hospital of Chengde Medical University, 36, Nanyingzi Road, Chengde, 067000, PR China
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Kaur H, Dhall A, Kumar R, Raghava GPS. Identification of Platform-Independent Diagnostic Biomarker Panel for Hepatocellular Carcinoma Using Large-Scale Transcriptomics Data. Front Genet 2020; 10:1306. [PMID: 31998366 PMCID: PMC6967266 DOI: 10.3389/fgene.2019.01306] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Accepted: 11/26/2019] [Indexed: 12/20/2022] Open
Abstract
The high mortality rate of hepatocellular carcinoma (HCC) is primarily due to its late diagnosis. In the past, numerous attempts have been made to design genetic biomarkers for the identification of HCC; unfortunately, most of the studies are based on small datasets obtained from a specific platform or lack reasonable validation performance on the external datasets. In order to identify a universal expression-based diagnostic biomarker panel for HCC that can be applicable across multiple platforms, we have employed large-scale transcriptomic profiling datasets containing a total of 2,316 HCC and 1,665 non-tumorous tissue samples. These samples were obtained from 30 studies generated by mainly four types of profiling techniques (Affymetrix, Illumina, Agilent, and High-throughput sequencing), which are implemented in a wide range of platforms. Firstly, we scrutinized overlapping 26 genes that are differentially expressed in numerous datasets. Subsequently, we identified a panel of three genes (FCN3, CLEC1B, and PRC1) as HCC biomarker using different feature selection techniques. Three-genes-based HCC biomarker identified HCC samples in training/validation datasets with an accuracy between 93 and 98%, Area Under Receiver Operating Characteristic curve (AUROC) in a range of 0.97 to 1.0. A reasonable performance, i.e., AUROC 0.91–0.96 achieved on validation dataset containing peripheral blood mononuclear cells, concurred their non-invasive utility. Furthermore, the prognostic potential of these genes was evaluated on TCGA-LIHC and GSE14520 cohorts using univariate survival analysis. This analysis revealed that these genes are prognostic indicators for various types of the survivals of HCC patients (e.g., Overall Survival, Progression-Free Survival, Disease-Free Survival). These genes significantly stratified high-risk and low-risk HCC patients (p-value <0.05). In conclusion, we identified a universal platform-independent three-genes-based biomarker that can predict HCC patients with high precision and also possess significant prognostic potential. Eventually, we developed a web server HCCpred based on the above study to facilitate scientific community (http://webs.iiitd.edu.in/raghava/hccpred/).
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Affiliation(s)
- Harpreet Kaur
- Bioinformatics Center, CSIR-Institute of Microbial Technology, Chandigarh, India.,Department of Computational Biology, Indraprastha Institute of Information Technology, New Delhi, India
| | - Anjali Dhall
- Department of Computational Biology, Indraprastha Institute of Information Technology, New Delhi, India
| | - Rajesh Kumar
- Bioinformatics Center, CSIR-Institute of Microbial Technology, Chandigarh, India.,Department of Computational Biology, Indraprastha Institute of Information Technology, New Delhi, India
| | - Gajendra P S Raghava
- Department of Computational Biology, Indraprastha Institute of Information Technology, New Delhi, India
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6
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Elemeery MN, Mohamed MA, Madkour MA, Shamseya MM, Issa NM, Badr AN, Ghareeb DA, Pan CH. MicroRNA signature in patients with hepatocellular carcinoma associated with type 2 diabetes. World J Gastroenterol 2019; 25:6322-6341. [PMID: 31754293 PMCID: PMC6861851 DOI: 10.3748/wjg.v25.i42.6322] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Revised: 10/29/2019] [Accepted: 11/07/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Nonalcoholic steatohepatitis-related cirrhosis is one of the liver complications in type 2 diabetes mellitus (T2DM) and reported to be a risk factor for developing hepatocellular carcinoma (HCC). A reliable screening biomarker of liver cirrhosis (LC) and HCC among T2DM patients is important to reduce the morbidity and mortality of this disease. MicroRNA (miRNA) is considered a key player in HCC and T2DM, and it might be a hidden culprit in diabetes-associated HCC, making it a promising reliable prognostic tool.
AIM To investigate the signature of serum miRNAs as early biomarkers for the screening of HCC among diabetic patients.
METHODS Expression profiles of miRNAs in serum samples of diabetic LC and diabetic HCC patients were assessed using Illumina sequencing; then, RT-qPCR was used to validate significantly altered miRNAs between the two groups. Candidate miRNAs were tested in serum samples of 200 T2DM patients, 270 LC patients, 200 HCC patients, and 225 healthy control subjects. Additionally, receiver operating characteristic (ROC) analysis, with area under the curve (AUC), was performed to assess the diagnostic performance of the screened miRNAs for discriminating HCC from LC and nonmalignant patients (LC + T2DM).
RESULTS Expression of the sequenced miRNAs in serum was different in HCC vs LC-positive T2DM patients. Two miRNAs (miR-34a, miR-221) were significantly up-regulated and five miRNAs (miR-16, miR-23-3p, miR-122-5p, miR-198, miR-199a-3p) were significantly down-regulated in HCC compared to LC patients. Analysis of ROC curve demonstrated that the combination of these seven miRNAs can be used as a reliable biomarker for detection of HCC in diabetic patients, as it could identify HCC with high diagnostic accuracy in diabetic LC patients (AUC = 0.993) and in diabetic nonmalignant patients (AUC = 0.961).
CONCLUSION This study validates a panel of serum miRNAs that can be used as a reliable noninvasive screening biomarker of HCC among T2DM cirrhotic and noncirrhotic patients. The study recommends further research to shed light on a possible role of c-Met in T2DM-associated HCC via the miRNA regulatory pathway.
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Affiliation(s)
- Moustafa Nouh Elemeery
- Département de Neurosciences, CRCHUM, Université de Montréal, Montréal, Quebec H2X 3E4, Canada
- Medical Biotechnology Laboratory, Genetic Engineering and Biotechnology Research Division, National Research Centre, Cairo 12622, Egypt
- Natural Product Informatics Research Center, KIST Gangneung Institute of Natural Products, Gangneung 25451, South Korea
- Division of Bio-Medical Science and Technology, KIST School, Korea University of Science and Technology, Seoul 02792, South Korea
| | - Marwa Anwar Mohamed
- Department of Chemical Pathology, Medical Research Institute, Alexandria University, Alexandria 21511, Egypt
| | - Marwa Ahmed Madkour
- Experimental and Clinical Internal Medicine Department, Medical Research Institute, Alexandria University, Alexandria 21511, Egypt
| | - Mohammed Mohammed Shamseya
- Experimental and Clinical Internal Medicine Department, Medical Research Institute, Alexandria University, Alexandria 21511, Egypt
| | - Noha Mahmoud Issa
- Human Genetics Department, Medical Research Institute, Alexandria University, Alexandria 21511, Egypt
| | - Ahmed Noah Badr
- Food Toxicology and Contaminates Department, National Research Centre, Dokki, Cairo 12622, Egypt
| | - Doaa Ahmed Ghareeb
- Bioscreening and preclinical trial lab, Biochemistry Department, Faculty of Science, Alexandria University, Alexandria 12522, Egypt
- Pharmaceutical and fermentation industries development center, the city of scientific research and technological applications, Alexandria 26411, Egypt
| | - Cheol-Ho Pan
- Natural Product Informatics Research Center, KIST Gangneung Institute of Natural Products, Gangneung 25451, South Korea
- Division of Bio-Medical Science and Technology, KIST School, Korea University of Science and Technology, Seoul 02792, South Korea
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Mjelle R, Dima SO, Bacalbasa N, Chawla K, Sorop A, Cucu D, Herlea V, Sætrom P, Popescu I. Comprehensive transcriptomic analyses of tissue, serum, and serum exosomes from hepatocellular carcinoma patients. BMC Cancer 2019; 19:1007. [PMID: 31660891 PMCID: PMC6816220 DOI: 10.1186/s12885-019-6249-1] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Accepted: 10/10/2019] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND The expression of microRNAs (miRNAs) is a promising prognostic and diagnostic tool in hepatocellular carcinoma (HCC). Here we performed small RNA sequencing (sRNA-seq) of tissue, serum and serum exosomes to investigate changes in miRNA expression between the different sample types and correlated the expression with clinical parameters. We also performed gene expression arrays on tumor and normal tissue. RESULTS Paired tissue, serum and serum exosomes sequencing revealed consistent positive correlation of miR-21 between serum exosomes and tumor tissue, indicating that miR-21 could be exported from tissue to circulation via exosomes. We found that let-7 miRNAs are generally upregulated in serum exosomes compared to whole serum, indicating that these miRNAs could be preferentially loaded into exosomes. Comparing serum from HCC patients with serum from healthy individuals revealed a global increase of miRNAs in serum from HCC patients, including an almost 4-fold increase of several miRNAs, including the liver-specific miR-122. When correlating miRNA expression with clinical parameters we detected significant association between hepatitis B virus (HBV) infection and miR-122 in serum as well as several serum and tissue-miRNAs that correlated with surgery type. We found that miR-141 and miR-146 correlated with cirrhosis in tumor tissue and normal tissue, respectively. Finally, high expression of miR-21 in tumors were associated with poor survival. Focusing on gene expression we found several significant messenger RNAs (mRNAs) between tumor and normal tissue and a Gene Ontology (GO) analysis revealed that these changes were mainly related to cell cycle and metabolism. Further, we detected mRNAs that correlated with cirrhosis and HBV infection in tissue. Finally, GO analysis of predicted targets for miRNAs down-regulated in tumor found that these were enriched for functions related to collagen synthesis. CONCLUSIONS Our combined data point to altered miRNA and mRNA expression contributing to both generally impaired lipid metabolism and increased cell proliferation and a miRNA-driven increase in collagen synthesis in HCC. Our results further indicate a correlation in miRNA expression between exosomes, serum, and tissue samples suggesting export from tumors via exosomes. This correlation could provide a basis for a more tumor-specific miRNA profile in serum.
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Affiliation(s)
- Robin Mjelle
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, NTNU, Erling Skjalgssons gt 1, 7030, Trondheim, Norway. .,Department of Computer Science, Norwegian University of Science and Technology, NTNU, Trondheim, Norway.
| | - Simona O Dima
- Center of Digestive Diseases and Liver Transplantation, Fundeni Clinical Institute, Bucharest, Romania.,Center of Excellence in Translational Medicine, Fundeni Clinical Institute, Bucharest, Romania
| | - Nicolae Bacalbasa
- Center of Digestive Diseases and Liver Transplantation, Fundeni Clinical Institute, Bucharest, Romania.,Center of Excellence in Translational Medicine, Fundeni Clinical Institute, Bucharest, Romania
| | - Konika Chawla
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, NTNU, Erling Skjalgssons gt 1, 7030, Trondheim, Norway.,Bioinformatics Core Facility-BioCore, Norwegian University of Science and Technology, NTNU, Trondheim, Norway
| | - Andrei Sorop
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, Bucharest, Romania
| | - Dana Cucu
- Department of Anatomy, Physiology, and Biophysics, Faculty of Biology, University of Bucharest, Bucharest, Romania
| | - Vlad Herlea
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, Bucharest, Romania.,K.G. Jebsen Center for Genetic Epidemiology, Norwegian University of Science and Technology, NTNU, Trondheim, Norway
| | - Pål Sætrom
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, NTNU, Erling Skjalgssons gt 1, 7030, Trondheim, Norway.,Department of Computer Science, Norwegian University of Science and Technology, NTNU, Trondheim, Norway.,Bioinformatics Core Facility-BioCore, Norwegian University of Science and Technology, NTNU, Trondheim, Norway.,K.G. Jebsen Center for Genetic Epidemiology, Norwegian University of Science and Technology, NTNU, Trondheim, Norway
| | - Irinel Popescu
- Center of Digestive Diseases and Liver Transplantation, Fundeni Clinical Institute, Bucharest, Romania.,Center of Excellence in Translational Medicine, Fundeni Clinical Institute, Bucharest, Romania.,Acad. Nicolae Cajal Institute of Medical Scientific Research, Titu Maiorescu University, Bucharest, Romania
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8
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Ning S, Liu H, Gao B, Wei W, Yang A, Li J, Zhang L. miR-155, miR-96 and miR-99a as potential diagnostic and prognostic tools for the clinical management of hepatocellular carcinoma. Oncol Lett 2019; 18:3381-3387. [PMID: 31452818 DOI: 10.3892/ol.2019.10606] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2018] [Accepted: 06/13/2019] [Indexed: 12/20/2022] Open
Abstract
Increasing evidence has demonstrated that circulating microRNAs (miRNAs) can be utilized as potential biomarkers for the diagnosis of cancer, as well as a prognostic tool for the management of the disease. Therefore, the present study aimed to evaluate the predictive ability of miRNA (miR)-155, miR-96 and miR-99a for the diagnosis and prognosis of hepatocellular carcinoma (HCC). Tissues were collected from 30 patients with HCC and their matched adjacent normal liver tissues, as well as from serum samples from 30 patients with HCC and 30 healthy controls. Reverse transcription-quantitative PCR was used to measure the expression levels of miR-155, miR-96 and miR-99a. The expression levels of miR-155 and miR-96 were upregulated in the tissues and serum of patients with HCC, whereas miR-99a expression levels were decreased. Receiver operating characteristics (ROC) curve analysis revealed that circulating miR-155, miR-96, miR-99a and a combination of these three miRNAs could serve as diagnostic biomarkers for HCC with areas under the curve (AUC) of 0.84, 0.824, 0.799 and 0.931, respectively. Serum α-fetoprotein (AFP) was detected using electrochemiluminescence immunoassay analyzer. The addition of AFP with the combination of these three miRNAs offered a higher accuracy of HCC diagnosis (AUC, 0.979; sensitivity, 90.0%; specificity, 100.0%). In addition, elevated expression levels of miR-155 and miR-96 were associated with poor survival time of patients with HCC. The panel of miR-155, miR-96, miR-99a and AFP had a higher sensitivity and specificity for the diagnosis of HCC when compared with a single marker. Furthermore, the present data suggested that miR-155 and miR-96 may be potential prognostic markers for the clinical management of patients with HCC.
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Affiliation(s)
- Shufang Ning
- Department of Research, The Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Haizhou Liu
- Department of Research, The Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Bing Gao
- Department of Research, The Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Wene Wei
- Department of Research, The Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Aifang Yang
- Department of Research, The Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Jilin Li
- Department of Research, The Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Litu Zhang
- Department of Research, The Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
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9
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Cui XW, Qian ZL, Li C, Cui SC. Identification of miRNA and mRNA expression profiles by PCR microarray in hepatitis B virus‑associated hepatocellular carcinoma. Mol Med Rep 2018; 18:5123-5132. [PMID: 30272372 DOI: 10.3892/mmr.2018.9516] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2018] [Accepted: 08/23/2018] [Indexed: 02/07/2023] Open
Abstract
The present study aimed to identify differentially expressed microRNAs (miRNAs) and mRNAs in hepatitis B virus‑associated hepatocellular carcinoma (HCC). A total of five HCC tissues and paired adjacent non‑tumor tissues were screened to identify the differentially expressed miRNAs and target mRNAs using polymerase chain reaction microarrays. The interaction between differential miRNA and mRNA expression was concurrently analyzed using bioinformatics methods. A total of 32 differentially expressed miRNAs (four upregulated miRNAs and 28 downregulated miRNAs) and 16 differentially expressed mRNAs (11 upregulated mRNAs and five downregulated mRNAs) were identified. Among these, upregulated hsa‑miRNA (miR)‑96‑5p and hsa‑miR‑18b‑5p suppressed their target mRNAs forkhead box O1 and MET transcriptional regulator MACC1 (MACC1). Downregulation of hsa‑miR‑199a‑5p led to upregulation of its target mRNAs, cyclin dependent kinase 4 and insulin like growth factor 2 (IGF2). The high‑level expression of IGF2 mRNA and cyclin E1 mRNA was due to the low‑level expression of hsa‑miR‑145‑5p, hsa‑miR‑181a‑5p, hsa‑miR‑199a‑5p and hsa‑miR‑223a‑3p, and hsa‑miR‑26a‑5p and hsa‑miR‑26b‑5p, respectively. The low‑level expression of coronin 1A mRNA and MACC1 mRNA was due to overexpression of hsa‑miR‑517a‑3p and hsa‑miR‑18a‑5p, and hsa‑miR‑18b‑5p, respectively. Numerous gene ontology terms were associated with oncogenesis. The most enriched pathways targeted by the dysregulated miRNAs and mRNAs were associated with cancer and oncogenesis pathways. The present data suggested that differential miRNA and mRNA expression is present in HCC. Thus, interactions between certain miRNAs and mRNAs may be involved in the pathogenesis of HCC.
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Affiliation(s)
- Xiong-Wei Cui
- Interventional Center for Oncology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, P.R. China
| | - Zhi-Ling Qian
- Interventional Center for Oncology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, P.R. China
| | - Cong Li
- Interventional Center for Oncology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, P.R. China
| | - Shi-Chang Cui
- Interventional Center for Oncology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, P.R. China
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Ashida R, Okamura Y, Ohshima K, Kakuda Y, Uesaka K, Sugiura T, Ito T, Yamamoto Y, Sugino T, Urakami K, Kusuhara M, Yamaguchi K. The down-regulation of the CYP2C19 gene is associated with aggressive tumor potential and the poorer recurrence-free survival of hepatocellular carcinoma. Oncotarget 2018; 9:22058-22068. [PMID: 29774122 PMCID: PMC5955155 DOI: 10.18632/oncotarget.25178] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Accepted: 04/05/2018] [Indexed: 02/07/2023] Open
Abstract
Project HOPE (High-tech Omics-based Patient Evaluation) began in 2014 using integrated gene expression profiling (GEP) of cancer tissues as well as diathesis of each patient who underwent an operation at our institution. The aim of this study was to clarify the association between the expression of cytochrome P450s (CYP) genes and recurrence of hepatocellular carcinoma (HCC). The present study included 92 patients. Genes with aberrant expression were selected based on a ≥10-fold difference in the expression between tumor and non-tumor tissues. The GEP analysis showed that the down-regulated genes in tumor tissue were CYP3A4 in 56 patients (61%), CYP2C8 in 44 patients (48%), CYP2C19 in 30 patients (33%), CYP2D6 in 11 patients (12%), CYP3A5 in 7 patients (8%) and CYP1B1 in 2 patients (2%). There was no patients with down-regulation of the CYP17A1 gene. A multivariate analysis revealed that the presence of microscopic portal invasion (hazard ratio [HR] 2.57, 95% confidence interval [CI] 1.30–5.05 P = 0.006), the presence of intrahepatic-metastasis (HR 3.09 95% CI 1.52–6.29 P = 0.002) and down-regulation of the CYP2C19 gene (HR 3.69 95% CI 1.83–7.46 P < 0.001) were independent predictors for the recurrence-free survival (RFS). The down-regulation of the CYP2C19 gene were correlated with the RFS in HCC.
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Affiliation(s)
- Ryo Ashida
- Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, Shizuoka, Japan
| | - Yukiyasu Okamura
- Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, Shizuoka, Japan
| | - Keiichi Ohshima
- Medical Genetics Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan
| | - Yuko Kakuda
- Division of Pathology, Shizuoka Cancer Center, Shizuoka, Japan
| | - Katsuhiko Uesaka
- Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, Shizuoka, Japan
| | - Teiichi Sugiura
- Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, Shizuoka, Japan
| | - Takaaki Ito
- Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, Shizuoka, Japan
| | - Yusuke Yamamoto
- Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, Shizuoka, Japan
| | - Takashi Sugino
- Division of Pathology, Shizuoka Cancer Center, Shizuoka, Japan
| | - Kenichi Urakami
- Cancer Diagnostics Research Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan
| | - Masatoshi Kusuhara
- Regional Resources Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan
| | - Ken Yamaguchi
- Shizuoka Cancer Center Hospital and Research Institute, Shizuoka, 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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