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Solhi R, Pourhamzeh M, Zarrabi A, Hassan M, Mirzaei H, Vosough M. Novel biomarkers for monitoring and management of hepatocellular carcinoma. Cancer Cell Int 2024; 24:428. [PMID: 39719624 DOI: 10.1186/s12935-024-03600-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2024] [Accepted: 12/05/2024] [Indexed: 12/26/2024] Open
Abstract
Due to current challenges in the early detection, less than 40% of individuals diagnosed with hepatocellular carcinoma (HCC) are viable candidates for surgical intervention. Therefore, validating and launching of a novel precise diagnostic approach is essential for early diagnosis. Based on developing evidence using circulating tumor cells and their derivatives, circulating miRNAs, and extracellular vesicles (EVs), liquid biopsy may offer a reliable platform for the HCC's early diagnosis. Each liquid biopsy analyte may provide significant areas for diagnosis, prognostic assessment, and treatment monitoring of HCC patients depending on its kind, sensitivity, and specificity. The current review addresses potential clinical applications, current research, and future developments for liquid biopsy in HCC management.
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Affiliation(s)
- Roya Solhi
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Mahsa Pourhamzeh
- Departments of Pathology and Medicine, UC San Diego, La Jolla, CA, USA
| | - Ali Zarrabi
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, Istanbul, 34396, Turkey
| | - Moustapha Hassan
- Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institute, Stockholm, Sweden
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Islamic Republic of Iran.
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.
- Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institute, Stockholm, Sweden.
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Ning C, Cai P, Liu X, Li G, Bao P, Yan L, Ning M, Tang K, Luo Y, Guo H, Wang Y, Wang Z, Chen L, Lu ZJ, Yin J. A comprehensive evaluation of full-spectrum cell-free RNAs highlights cell-free RNA fragments for early-stage hepatocellular carcinoma detection. EBioMedicine 2023; 93:104645. [PMID: 37315449 PMCID: PMC10363443 DOI: 10.1016/j.ebiom.2023.104645] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 05/20/2023] [Accepted: 05/22/2023] [Indexed: 06/16/2023] Open
Abstract
BACKGROUND Various studies have reported cell-free RNAs (cfRNAs) as noninvasive biomarkers for detecting hepatocellular carcinoma (HCC). However, they have not been independently validated, and some results are contradictory. We provided a comprehensive evaluation of various types of cfRNA biomarkers and a full mining of the biomarker potential of new features of cfRNA. METHODS We first systematically reviewed reported cfRNA biomarkers and calculated dysregulated post-transcriptional events and cfRNA fragments. In 3 independent multicentre cohorts, we further selected 6 cfRNAs using RT-qPCR, built a panel called HCCMDP with AFP using machine learning, and internally and externally validated HCCMDP's performance. FINDINGS We identified 23 cfRNA biomarker candidates from a systematic review and analysis of 5 cfRNA-seq datasets. Notably, we defined the cfRNA domain to describe cfRNA fragments systematically. In the verification cohort (n = 183), cfRNA fragments were more likely to be verified, while circRNA and chimeric RNA candidates were neither abundant nor stable as qPCR-based biomarkers. In the algorithm development cohort (n = 287), we build and test the panel HCCMDP with 6 cfRNA markers and AFP. In the independent validation cohort (n = 171), HCCMDP can distinguish HCC patients from control groups (all: AUC = 0.925; CHB: AUC = 0.909; LC: AUC = 0.916), and performs well in distinguishing early-stage HCC patients (all: AUC = 0.936; CHB: AUC = 0.917; LC: AUC = 0.928). INTERPRETATION This study comprehensively evaluated full-spectrum cfRNA biomarker types for HCC detection, highlighted the cfRNA fragment as a promising biomarker type in HCC detection, and provided a panel HCCMDP. FUNDING National Natural Science Foundation of China, and The National Key Basic Research Program (973 program).
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Affiliation(s)
- Chun Ning
- Chinese Academy of Medical Sciences & Peking Union Medical College, No. 9 Dongdansantiao, Beijing, 100730, China; MOE Key Laboratory of Bioinformatics, Centre for Synthetic and Systems Biology, School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Peng Cai
- Department of Epidemiology, Naval Medical University, Key Laboratory of Biosafety Defense, Ministry of Education, Shanghai, 200433, China
| | - Xiaofan Liu
- MOE Key Laboratory of Bioinformatics, Centre for Synthetic and Systems Biology, School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Guangtao Li
- Department of Hepatobiliary Cancer, Liver Cancer Research Centre, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Centre for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Centre for Cancer, Tianjin, 300060, China
| | - Pengfei Bao
- MOE Key Laboratory of Bioinformatics, Centre for Synthetic and Systems Biology, School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Lu Yan
- MOE Key Laboratory of Bioinformatics, Centre for Synthetic and Systems Biology, School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Meng Ning
- Tianjin Third Central Hospital, 83 Jintang Road, Hedong District, Tianjin, 300170, China
| | - Kaichen Tang
- Chinese Academy of Medical Sciences & Peking Union Medical College, No. 9 Dongdansantiao, Beijing, 100730, China; MOE Key Laboratory of Bioinformatics, Centre for Synthetic and Systems Biology, School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Yi Luo
- Department of Hepatobiliary Cancer, Liver Cancer Research Centre, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Centre for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Centre for Cancer, Tianjin, 300060, China
| | - Hua Guo
- Department of Hepatobiliary Cancer, Liver Cancer Research Centre, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Centre for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Centre for Cancer, Tianjin, 300060, China
| | - Yunjiu Wang
- Department of Clinical Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200433, China
| | - Zhuoran Wang
- Department of Surgery, Eastern Hepatobiliary Surgery Hospital, Navy Medical University, Shanghai, 200433, China
| | - Lu Chen
- Department of Hepatobiliary Cancer, Liver Cancer Research Centre, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Centre for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Centre for Cancer, Tianjin, 300060, China.
| | - Zhi John Lu
- MOE Key Laboratory of Bioinformatics, Centre for Synthetic and Systems Biology, School of Life Sciences, Tsinghua University, Beijing, 100084, China.
| | - Jianhua Yin
- Department of Epidemiology, Naval Medical University, Key Laboratory of Biosafety Defense, Ministry of Education, Shanghai, 200433, China.
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Ait-Ahmed Y, Lafdil F. Novel insights into the impact of liver inflammatory responses on primary liver cancer development. LIVER RESEARCH 2023; 7:26-34. [PMID: 39959704 PMCID: PMC11791919 DOI: 10.1016/j.livres.2023.01.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 10/05/2022] [Accepted: 01/27/2023] [Indexed: 03/10/2023]
Abstract
Primary liver cancers rank among the deadliest cancers worldwide and often develop in patients with chronic liver diseases in an inflammatory context. This review highlights recent reports on the mechanisms of inflammatory-mediated hepatic cell transformation that trigger the tumorigenic process (initiation steps) and the impact of the immune response favoring tumor cell expansion (progression steps). Several cytokines, namely interleukin (IL)-6, IL-17, IL-1beta, and tumor necrosis factor-alpha, have been described to play a prominent role in the initiation of liver cancers. Additionally, inflammation contributes to cancer progression by favoring tumor escape from anti-tumor immune response, angiogenesis, and metastasis through tumor growth factor-beta and matrix metalloprotease upregulation. These recent studies allowed the development of novel therapeutic strategies aiming at regulating liver inflammation. These strategies are based on the use of anti-inflammatory agents, antibodies targeting immune checkpoint molecules such as programmed death ligand 1 and molecules targeting angiogenic factors, metastasis key factors, and microRNAs involved in tumor development. This review aims at summarizing the recent studies reporting different mechanisms by which the liver inflammatory responses could contribute to liver cancer development.
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Affiliation(s)
- Yeni Ait-Ahmed
- Université Paris-Est, UMR-S955, UPEC, Créteil, France
- Institut National de la Sante et de la Recherche Medicale (INSERM), U955, Créteil, France
| | - Fouad Lafdil
- Université Paris-Est, UMR-S955, UPEC, Créteil, France
- Institut National de la Sante et de la Recherche Medicale (INSERM), U955, Créteil, France
- Institut Universitaire de France (IUF), Paris, France
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Nazarnezhad MA, Barazesh M, Kavousipour S, Mohammadi S, Eftekhar E, Jalili S. The Computational Analysis of Single Nucleotide Associated with MicroRNA Affecting Hepatitis B Infection. Microrna 2022; 11:139-162. [PMID: 35579134 DOI: 10.2174/2211536611666220509103724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 02/16/2022] [Accepted: 03/15/2022] [Indexed: 01/01/2023]
Abstract
BACKGROUND MicroRNAs (miRNAs) have a pivotal role in Hepatitis B Virus (HBV) infection and its complications by targeting the cellular transcription factors required for gene expression or directly binding to HBV transcripts. Single Nucleotide Polymorphisms (SNPs) in miRNA genes affect their expression and the regulation of target genes, clinical course, diagnosis, and therapeutic interventions of HBV infection. METHODS Computational assessment and cataloging of miRNA gene polymorphisms targeting mRNA transcripts straightly or indirectly through the regulation of hepatitis B infection by annotating the functional impact of SNPs on mRNA-miRNA and miRNA-RBS (miRNA binding sites) interaction were screened by applying various universally available datasets such as the miRNA SNP3.0 software. RESULTS 2987 SNPs were detected in 139 miRNAs affecting hepatitis B infection. Among them, 313 SNPs were predicted to have a significant role in the progression of hepatitis B infection. The computational analysis also revealed that 45 out of the 313 SNPs were located in the seed region and were more important than others. Has-miR-139-3p had the largest number of SNPs in the seed region (n=6). On the other hand, proteoglycans in cancer, adherens junction, lysine degradation, NFkappa B signaling cascade, ECM-receptor binding, viral carcinogenesis, fatty acid metabolism, TGF-beta signaling pathway, p53 signaling pathway, immune evasion related pathways, and fatty acid biosynthesis were the most important pathways affected by these 139 miRNAs. CONCLUSION The results revealed 45 SNPs in the seed region of 25 miRNAs as the catalog in miRNA genes that regulated the hepatitis B infection. The results also showed the most important pathways regulated by these miRNAs that can be targeted for therapeutic purposes.
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Affiliation(s)
- Mirza Ali Nazarnezhad
- Infectious and Tropical Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Mahdi Barazesh
- Department of Biotechnology, School of Paramedical Sciences, Gerash University of Medical Sciences, Gerash, Iran
| | - Soudabeh Kavousipour
- Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas 7919915519, Iran
| | - Shiva Mohammadi
- Department of Medical Biotechnology, School of Medicine, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Ebrahim Eftekhar
- Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas 7919915519, Iran
| | - Sajad Jalili
- Department of Orthopedics, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
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Pelizzaro F, Cardin R, Penzo B, Pinto E, Vitale A, Cillo U, Russo FP, Farinati F. Liquid Biopsy in Hepatocellular Carcinoma: Where Are We Now? Cancers (Basel) 2021; 13:2274. [PMID: 34068786 PMCID: PMC8126224 DOI: 10.3390/cancers13092274] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 04/30/2021] [Accepted: 05/06/2021] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer related death worldwide. Diagnostic, prognostic, and predictive biomarkers are urgently needed in order to improve patient survival. Indeed, the most widely used biomarkers, such as alpha-fetoprotein (AFP), have limited accuracy as both diagnostic and prognostic tests. Liver biopsy provides an insight on the biology of the tumor, but it is an invasive procedure, not routinely used, and not representative of the whole neoplasia due to the demonstrated intra-tumoral heterogeneity. In recent years, liquid biopsy, defined as the molecular analysis of cancer by-products, released by the tumor in the bloodstream, emerged as an appealing source of new biomarkers. Several studies focused on evaluating extracellular vesicles, circulating tumor cells, cell-free DNA and non-coding RNA as novel reliable biomarkers. In this review, we aimed to provide a comprehensive overview on the most relevant available evidence on novel circulating biomarkers for early diagnosis, prognostic stratification, and therapeutic monitoring. Liquid biopsy seems to be a very promising instrument and, in the near future, some of these new non-invasive tools will probably change the clinical management of HCC patients.
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Affiliation(s)
- Filippo Pelizzaro
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padua, 35128 Padua, Italy; (F.P.); (R.C.); (B.P.); (E.P.); (F.P.R.)
| | - Romilda Cardin
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padua, 35128 Padua, Italy; (F.P.); (R.C.); (B.P.); (E.P.); (F.P.R.)
| | - Barbara Penzo
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padua, 35128 Padua, Italy; (F.P.); (R.C.); (B.P.); (E.P.); (F.P.R.)
| | - Elisa Pinto
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padua, 35128 Padua, Italy; (F.P.); (R.C.); (B.P.); (E.P.); (F.P.R.)
| | - Alessandro Vitale
- Hepatobiliary Surgery and Liver Transplantation Unit, Department of Surgery, Oncology and Gastroenterology, University of Padua, 35128 Padua, Italy; (A.V.); (U.C.)
| | - Umberto Cillo
- Hepatobiliary Surgery and Liver Transplantation Unit, Department of Surgery, Oncology and Gastroenterology, University of Padua, 35128 Padua, Italy; (A.V.); (U.C.)
| | - Francesco Paolo Russo
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padua, 35128 Padua, Italy; (F.P.); (R.C.); (B.P.); (E.P.); (F.P.R.)
| | - Fabio Farinati
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padua, 35128 Padua, Italy; (F.P.); (R.C.); (B.P.); (E.P.); (F.P.R.)
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Ghosh S, Bhowmik S, Majumdar S, Goswami A, Chakraborty J, Gupta S, Aggarwal S, Ray S, Chatterjee R, Bhattacharyya S, Dutta M, Datta S, Chowdhury A, Dhali GK, Banerjee S. The exosome encapsulated
microRNAs
as circulating diagnostic marker for hepatocellular carcinoma with low alpha‐fetoprotein. Int J Cancer 2020; 147:2934-2947. [PMID: 32441313 DOI: 10.1002/ijc.33111] [Citation(s) in RCA: 86] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Revised: 04/15/2020] [Accepted: 05/05/2020] [Indexed: 12/21/2022]
Affiliation(s)
- Suchandrima Ghosh
- Centre for Liver Research, School of Digestive and Liver Diseases Institute of Post Graduate Medical Education and Research Kolkata West Bengal India
| | - Sayantani Bhowmik
- Centre for Liver Research, School of Digestive and Liver Diseases Institute of Post Graduate Medical Education and Research Kolkata West Bengal India
| | - Swagata Majumdar
- Centre for Liver Research, School of Digestive and Liver Diseases Institute of Post Graduate Medical Education and Research Kolkata West Bengal India
| | - Avijit Goswami
- Department of Molecular Genetics Indian Institute of Chemical Biology Kolkata West Bengal India
| | | | - Subash Gupta
- Max Super Speciality Hospital Saket West Bengal India
| | | | - Sukanta Ray
- Division of Surgical Gastroenterology School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research Kolkata West Bengal India
| | | | | | - Moumita Dutta
- Division of Electron Microscopy National Institute of Cholera and Enteric Diseases Kolkata West Bengal India
| | - Simanti Datta
- Centre for Liver Research, School of Digestive and Liver Diseases Institute of Post Graduate Medical Education and Research Kolkata West Bengal India
| | - Abhijit Chowdhury
- Department of Hepatology, School of Digestive and Liver Diseases Institute of Post Graduate Medical Education and Research Kolkata West Bengal India
| | - Gopal Krishna Dhali
- Department Gastroenterology, School of Digestive and Liver Diseases Institute of Post Graduate Medical Education and Research Kolkata West Bengal India
| | - Soma Banerjee
- Centre for Liver Research, School of Digestive and Liver Diseases Institute of Post Graduate Medical Education and Research Kolkata West Bengal India
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Mohyeldeen M, Ibrahim S, Shaker O, Helmy H. Serum expression and diagnostic potential of long non-coding RNAs NEAT1 and TUG1 in viral hepatitis C and viral hepatitis C-associated hepatocellular carcinoma. Clin Biochem 2020; 84:38-44. [PMID: 32526227 DOI: 10.1016/j.clinbiochem.2020.06.005] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 06/04/2020] [Accepted: 06/06/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND The present study investigated the serum detectability and the diagnostic implications of long non-coding RNAs; nuclear enriched abundant transcript 1 (NEAT1) and taurine upregulated gene 1 (TUG1) in viral hepatitis C (HCV) and HCV-associated hepatocellular carcinoma (HCC). METHODS The study included twenty healthy controls, forty non-malignant HCV patients and forty HCV-associated HCC patients. The study assessed liver function tests, the antioxidant status, serum alpha fetoprotein, p53, NEAT1 and TUG1. RESULTS Diminished serum expression of NEAT1 and TUG1 was observed in HCV and HCV-associated HCC and was closely associated with deregulated liver function and elevated AFP levels. A model of NEAT1, TUG1 and AFP accurately differentiated between HCC patients and healthy controls with sensitivity greater than that of AFP alone. Additionally, the diagnostic performance of a model of TUG1, p53 and AFP was superior to that of each marker alone for predicting HCC in HCV patients. CONCLUSION Significant alterations in the serum expression of NEAT1 and TUG1 in HCV and HCV-associated HCC patients were recorded. We propose NEAT1 and TUG1 as non-invasive, cost-effective and complementary biomarkers that improve the diagnostic characteristics of AFP.
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Affiliation(s)
- Mai Mohyeldeen
- Biochemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Safinaz Ibrahim
- Biochemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Olfat Shaker
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Hebatullah Helmy
- Biochemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
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Mocan T, Simão AL, Castro RE, Rodrigues CMP, Słomka A, Wang B, Strassburg C, Wöhler A, Willms AG, Kornek M. Liquid Biopsies in Hepatocellular Carcinoma: Are We Winning? J Clin Med 2020; 9:jcm9051541. [PMID: 32443747 PMCID: PMC7291267 DOI: 10.3390/jcm9051541] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2020] [Revised: 04/18/2020] [Accepted: 05/11/2020] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) represents the sixth most common cancer worldwide and the third most common cause of cancer-related death. One of the major problems faced by researchers and clinicians in this area is the lack of reliable disease biomarkers, which would allow for an earlier diagnosis, follow-up or prediction of treatment response, among others. In this regard, the “HCC circulome”, defined as the pool of circulating molecules in the bloodstream derived from the primary tumor, represents an appealing target, the so called liquid biopsy. Such molecules encompass circulating tumor proteins, circulating tumor cells (CTCs), extracellular vesicles (EVs), tumor-educated platelets (TEPs), and circulating tumor nucleic acids, namely circulating tumor DNA (ctDNA) and circulating tumor RNA (ctRNA). In this article, we summarize recent findings highlighting the promising role of liquid biopsies as novel potential biomarkers in HCC, emphasizing on its clinical performance.
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Affiliation(s)
- Tudor Mocan
- Octavian Fodor Institute for Gastroenterology and Hepatology, Iuliu Haţieganu, University of Medicine and Pharmacy, 400162 Cluj-Napoca, Romania;
| | - André L. Simão
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal; (A.L.S.); (R.E.C.); (C.M.P.R.)
| | - Rui E. Castro
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal; (A.L.S.); (R.E.C.); (C.M.P.R.)
| | - Cecília M. P. Rodrigues
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal; (A.L.S.); (R.E.C.); (C.M.P.R.)
| | - Artur Słomka
- Department of Pathophysiology, Nicolaus Copernicus University in Toruń, Ludwik Rydygier Collegium Medicum, 85-094 Bydgoszcz, Poland;
| | - Bingduo Wang
- Department of Internal Medicine I, University Hospital of the Rheinische Friedrich-Wilhelms-University, 53127 Bonn, Germany; (B.W.); (C.S.)
| | - Christian Strassburg
- Department of Internal Medicine I, University Hospital of the Rheinische Friedrich-Wilhelms-University, 53127 Bonn, Germany; (B.W.); (C.S.)
| | - Aliona Wöhler
- Department of General, Visceral and Thoracic Surgery, German Armed Forces Central Hospital Koblenz, 56072 Koblenz, Germany; (A.W.); (A.G.W.)
| | - Arnulf G. Willms
- Department of General, Visceral and Thoracic Surgery, German Armed Forces Central Hospital Koblenz, 56072 Koblenz, Germany; (A.W.); (A.G.W.)
| | - Miroslaw Kornek
- Department of Internal Medicine I, University Hospital of the Rheinische Friedrich-Wilhelms-University, 53127 Bonn, Germany; (B.W.); (C.S.)
- Correspondence:
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Abstract
Abdominal tumors (AT) in children account for approximately 17% of all pediatric solid tumor cases, and frequently exhibit embryonal histological features that differentiate them from adult cancers. Current molecular approaches have greatly improved the understanding of the distinctive pathology of each tumor type and enabled the characterization of novel tumor biomarkers. As seen in abdominal adult tumors, microRNAs (miRNAs) have been increasingly implicated in either the initiation or progression of childhood cancer. Moreover, besides predicting patient prognosis, they represent valuable diagnostic tools that may also assist the surveillance of tumor behavior and treatment response, as well as the identification of the primary metastatic sites. Thus, the present study was undertaken to compile up-to-date information regarding the role of dysregulated miRNAs in the most common histological variants of AT, including neuroblastoma, nephroblastoma, hepatoblastoma, hepatocarcinoma, and adrenal tumors. Additionally, the clinical implications of dysregulated miRNAs as potential diagnostic tools or indicators of prognosis were evaluated.
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Abstract
In the present study, we investigated the role of miR-122 in hepatocarcinoma progression and explored the mechanism. In hepatocarcinoma tissues and cells, we used qRT-PCR to validate the miR-122 expression level. Next, we used colony formation by crystal violet staining assay to compare cell proliferation ability, and we used scratch test or Transwell assay to compare cell migration or invasion ability. We then conducted bioinformatics or luciferase reporter gene assay to prove the regulation effect of miR-122 on lamin B2 (LMNB2), and the biological function of LMNB2 was analyzed. We used nude mouse tumorigenicity assay to test the inhibition effect of miR-122 ASO therapy against hepatocarcinoma. miR-122 was reduced in hepatocarcinoma tissues compared to the paracarcinoma tissues, which was relatively low or high in hepatocarcinoma cell line SMMC7721 or Hep3B, and overexpressed miR-122 inhibited proliferation, migration, and invasion in hepatocarcinoma cells. Additionally, some reports showed that LMNB2 was regulated by miR-122, which inhibited the expression of LMNB2. Moreover, LMNB2 functioned to promote cell proliferation, migration, and invasion. We could achieve the inhibition of hepatocarcinoma using miR-122 therapy through decreasing LMNB2 expression in vivo. Our data indicated that miR-122 could inhibit hepatocellular carcinoma cell progression by targeting LMNB2 and as a therapeutic target for hepatocarcinoma treatment.
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Affiliation(s)
- Xiao-Na Li
- *The Department of General Surgery, Tongde Hospital of Zhejiang Province, Zhejiang Province, P.R. China
| | - Hong Yang
- †The Department of Medical Oncology, The First Hospital of Shijiazhuang, Shijiazhuang, Hebei Province, P.R. China
| | - Tao Yang
- ‡The Department of Hepatological Surgery, Tongde Hospital of Zhejiang Province, Zhejiang Province, P.R. 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: 31] [Impact Index Per Article: 6.2] [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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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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13
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Qu J, Yang J, Chen M, Cui L, Wang T, Gao W, Tian J, Wei R. MicroRNA-21 as a diagnostic marker for hepatocellular carcinoma: A systematic review and meta-analysis. Pak J Med Sci 2019; 35:1466-1471. [PMID: 31489028 PMCID: PMC6717466 DOI: 10.12669/pjms.35.5.685] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Background MicroRNA-21 (miR-21) is one of the oncogenic miRNAs which may be a potential diagnostic biomarker for hepatocellular carcinoma (HCC). Methods We systematically searched Medline, Embase, the Cochrane Library, ISI Web of Knowledge, Scopus from inception to August 15, 2018, and reference lists of identified primary studies. Two independent investigators extracted patient and study characteristics. The sensitivity and specificity of microRNA-21 for HCC detection and were analyzed with a random effect model. The area under summary receiver operating characteristic curve (AUC) was used to estimate overall test performance. Results A total of 515 HCC patients, and 338 healthy or chronic hepatitis controls from six published studies were enrolled in this meta-analysis. All articles were published in English with moderate-to-high quality. The overall pooled sensitivity and specificity were 85.2% (73.3% to 88.4%) and 79.2% (68.4% to 87.0%), respectively. The AUC area was 0.89 (95% CI: 0.85-0.91). The studies had moderate heterogeneity (I2=70.11%). None of the subgroups investigated-ethnicity, controls, sample source-could account for the heterogeneity. Conclusion MiR-21 is a helpful biomarker for early diagnosis of HCC. Nevertheless, the results of the test must be interpreted carefully in the context of medical history, erological tests and imaging examinations for HCC surveillance.
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Affiliation(s)
- Juan Qu
- Juan Qu, Department of Gastroenterology, Tianjin Nankai Hospital, Tianjin 300100, China
| | - Jizhi Yang
- Jizhi Yang, Department of Traditional Chinese Medicine, Chentangzhuang Hospital, Hexi District, Tianjin 300222, China
| | - Ming Chen
- Ming Chen, Department of Hepatopathy and Hepatic Oncology, Tianjin Nankai Hospital, Tianjin 300100, China
| | - Lihong Cui
- Lihong Cui, Department of Gastroenterology, Tianjin Nankai Hospital, Tianjin 300100, China
| | - Tianxi Wang
- Tianxi Wang, Department of Gastroenterology, Tianjin Nankai Hospital, Tianjin 300100, China
| | - Wei Gao
- Wei Gao, Department of Gastroenterology, Tianjin Nankai Hospital, Tianjin 300100, China
| | - Jingjing Tian
- Jingjing Tian, Department of Gastroenterology, Tianjin Nankai Hospital, Tianjin 300100, China
| | - Rongna Wei
- Rongna Wei, Department of Gastroenterology, Tianjin Nankai Hospital, Tianjin 300100, China
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15
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Balaceanu LA. Biomarkers vs imaging in the early detection of hepatocellular carcinoma and prognosis. World J Clin Cases 2019; 7:1367-1382. [PMID: 31363465 PMCID: PMC6656675 DOI: 10.12998/wjcc.v7.i12.1367] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Revised: 04/07/2019] [Accepted: 05/03/2019] [Indexed: 02/05/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the 5th most frequently diagnosed cancer in the world, according to the World Health Organization. The incidence of HCC is between 3/100000 and 78.1/100000, with a high incidence reported in areas with viral hepatitis B and hepatitis C, thus affecting Asia and Africa predominantly. Several international clinical guidelines address HCC diagnosis and are structured according to the geographical area involved. All of these clinical guidelines, however, share a foundation of diagnosis by ultrasound surveillance and contrast imaging techniques, particularly computed tomography, magnetic resonance imaging, and sometimes contrast-enhanced ultrasound. The primary objective of this review was to systematically summarize the recent published studies on the clinical utility of serum biomarkers in the early diagnosis of HCC and for the prognosis of this disease.
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Affiliation(s)
- Lavinia Alice Balaceanu
- Department of Internal Medicine, Carol Davila University of Medicine and Pharmacy, Sf. Ioan Clinical Emergency Hospital, Bucharest 42122, Romania
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16
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Bharali D, Banerjee BD, Bharadwaj M, Husain SA, Kar P. Expression Analysis of MicroRNA-21 and MicroRNA-122 in Hepatocellular Carcinoma. J Clin Exp Hepatol 2019; 9:294-301. [PMID: 31360021 PMCID: PMC6637083 DOI: 10.1016/j.jceh.2018.07.005] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2016] [Accepted: 07/07/2018] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND/OBJECTIVE Hepatocellular carcinoma (HCC) is a multistep process starting from chronic hepatitis (CH) that progress through cirrhosis to HCC. The expression level of microRNA (miRNA) was found to be deregulated in HCC. The study was designed to find out whether the expression level of miR-21 and miR-122 was deregulated in HCC compared to controls without HCC. METHODS Real-time quantitative polymerase chain reaction was performed to find out the miRNA expression level using Ct value followed by statistical analysis where P value ≤ 0.05 was considered as significant. RESULTS Overexpression of miR-21 and miR-122 in HCC was detected. All changes in the expression level of miR-21 and miR-122 were due to HCC compared with healthy control, CH, and liver cirrhosis. Hence miR-21 and miR-122 are suitable to differentiate HCC with an efficient diagnostic power of sensitivity, specificity, and expression level, but they might not have any role in patients' survival. CONCLUSION miR-21 and miR-122 could be considered as potential markers of HCC screening molecule in addition to other approved markers. However the current study is limited to expression levels of miRNAs from serum; therefore, it needs further validated study in a large group of population to fulfill all the criteria of a biomarker.
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Affiliation(s)
- Dipu Bharali
- Department of Medicine, Maulana Azad Medical College, New Delhi, 02, India
| | - Basu D. Banerjee
- Department of Biochemistry, University College of Medical Sciences, Dilshad Graden, Delhi, 65, India
| | - Mausumi Bharadwaj
- Division of Molecular Genetics, National Institute Cancer Prevention and Research, Noida, UP, India
| | - Syed A. Husain
- Department of Biosciences, Jamia Millia Islamia University, New Delhi, India
| | - Premashis Kar
- Department of Medicine, Maulana Azad Medical College, New Delhi, 02, India
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17
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Weis A, Marquart L, Calvopina DA, Genz B, Ramm GA, Skoien R. Serum MicroRNAs as Biomarkers in Hepatitis C: Preliminary Evidence of a MicroRNA Panel for the Diagnosis of Hepatocellular Carcinoma. Int J Mol Sci 2019; 20:E864. [PMID: 30781550 PMCID: PMC6412219 DOI: 10.3390/ijms20040864] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Revised: 02/13/2019] [Accepted: 02/14/2019] [Indexed: 12/13/2022] Open
Abstract
Early diagnosis of cirrhosis and hepatocellular carcinoma (HCC) due to chronic Hepatitis C (CHC) remain clinical priorities. In this pilot study, we assessed serum microRNA (miRNA) expression to distinguish cirrhosis and HCC, alone and in combination with the aminotransferase-to-platelet ratio (APRI), Fibrosis 4 (FIB-4), and alpha-fetoprotein (AFP). Sixty CHC patients were subdivided into 3 cohorts: Mild disease (fibrosis stage F0-2; n = 20); cirrhosis (n = 20); and cirrhosis with HCC (n = 20). Circulating miRNA signatures were determined using a liver-specific real-time quantitative reverse transcription PCR (qRT-PCR) microarray assessing 372 miRNAs simultaneously. Differentially-expressed miRNA candidates were independently validated using qRT-PCR. Serum miRNA-409-3p was increased in cirrhosis versus mild disease. In HCC versus cirrhosis, miRNA-486-5p was increased, whereas miRNA-122-5p and miRNA-151a-5p were decreased. A logistic regression model-generated panel, consisting of miRNA-122-5p + miRNA-409-3p, distinguished cirrhosis from mild disease (area under the curve, AUC = 0.80; sensitivity = 85%, specificity = 70%; p < 0.001). When combined with FIB-4 or APRI, performance was improved with AUC = 0.89 (p < 0.001) and 0.87 (p < 0.001), respectively. A panel consisting of miRNA-122-5p + miRNA-486-5p + miRNA-142-3p distinguished HCC from cirrhosis (AUC = 0.94; sensitivity = 80%, specificity = 95%; p < 0.001), outperforming AFP (AUC = 0.64, p = 0.065). Serum miRNAs are differentially expressed across the spectrum of disease severity in CHC. MicroRNAs have great potential as diagnostic biomarkers in CHC, particularly in HCC where they outperform the only currently-used biomarker, AFP.
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Affiliation(s)
- Anna Weis
- Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, 300 Herston Rd, Herston, QLD 4006, Australia.
- Faculty of Medicine, University of Queensland, Herston Road, Herston, QLD 4006, Australia.
| | - Louise Marquart
- QIMR Berghofer Statistics Unit, QIMR Berghofer Medical Research Institute, 300 Herston Rd, Herston, QLD 4006, Australia.
| | - Diego A Calvopina
- Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, 300 Herston Rd, Herston, QLD 4006, Australia.
- Faculty of Medicine, University of Queensland, Herston Road, Herston, QLD 4006, Australia.
| | - Berit Genz
- Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, 300 Herston Rd, Herston, QLD 4006, Australia.
- Faculty of Medicine, University of Queensland, Herston Road, Herston, QLD 4006, Australia.
| | - Grant A Ramm
- Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, 300 Herston Rd, Herston, QLD 4006, Australia.
- Faculty of Medicine, University of Queensland, Herston Road, Herston, QLD 4006, Australia.
| | - Richard Skoien
- Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, 300 Herston Rd, Herston, QLD 4006, Australia.
- Faculty of Medicine, University of Queensland, Herston Road, Herston, QLD 4006, Australia.
- Department of Gastroenterology and Hepatology, Royal Brisbane and Women's Hospital, Bowen Bridge Rd & Butterfield St, Herston, QLD 4029, Australia.
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18
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Dai M, Li L, Qin X. Clinical value of miRNA-122 in the diagnosis and prognosis of various types of cancer. Oncol Lett 2019; 17:3919-3929. [PMID: 30881509 PMCID: PMC6403504 DOI: 10.3892/ol.2019.10024] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Accepted: 02/06/2019] [Indexed: 02/06/2023] Open
Abstract
The present study aimed to systematically analyze the value of microRNA-122 (miRNA-122) in the diagnosis and prognosis of hepatocellular carcinoma (HCC) and other types of cancer. First, the reverse transcription-quantitative polymerase chain reaction method was used to detect the expression levels of miRNA-122 in the serum samples of patients with HCC, benign lesions and healthy volunteers. Next, miRNA-seq data of miRNA-122 from The Cancer Genome Atlas database were used to analyze the differential expression and overall survival rate associated with a variety of types of cancer. Meanwhile, the target gene prediction of miRNA-122 was performed using four different software programs. Finally, 353 significant target genes were identified for Gene Ontology and Kyoto Encyclopedia of Genes and Genomes functional enrichment analysis. Finally, it was demonstrated that the expression levels of miRNA-122 in the HCC group were increased compared with the healthy group (P<0.001), but decreased with respect to the benign group (P<0.001). In addition, the combination of the miRNA-122 and a fetoprotein may further improve the diagnostic accuracy between the HCC and healthy groups (area under the curve, 0.980; 95% confidence interval, 0.958–1.000). It was also demonstrated that miRNA-122 exhibited significantly differential expression and the overall survival rate was predicted for various other types of cancer, including colorectal cancer, renal carcinoma, cholangiocarcinoma, prostate cancer and thyroid carcinoma. Functional enrichment analysis demonstrated that the target genes of miRNA-122 may contribute to the composition of the nucleus and cytoplasm, and regulate a variety of biological processes, including cardiac muscle cell differentiation and glucose metabolic processes via protein biosynthesis, estrogen and glucagon associated signaling pathways. These results revealed that miRNA-122 may be an indispensable biomarker for the diagnosis, prognostic evaluation and targeted therapy in pan-cancer.
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Affiliation(s)
- Meiyu Dai
- Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Limin Li
- Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Xue Qin
- Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
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19
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Abstract
Hepatocellular carcinoma (HCC) is associated with chronic inflammation and fibrosis arising from different etiologies, including hepatitis B and C and alcoholic and nonalcoholic fatty liver diseases. The inflammatory cytokines tumor necrosis factor-α and interleukin-6 and their downstream targets nuclear factor kappa B (NF-κB), c-Jun N-terminal kinase (JNK), and signal transducer and activator of transcription 3 drive inflammation-associated HCC. Further, while adaptive immunity promotes immune surveillance to eradicate early HCC, adaptive immune cells, such as CD8+ T cells, Th17 cells, and B cells, can also stimulate HCC development. Thus, the role of the hepatic immune system in HCC development is a highly complex topic. This review highlights the role of cytokine signals, NF-κB, JNK, innate and adaptive immunity, and hepatic stellate cells in HCC and discusses whether these pathways could be therapeutic targets. The authors will also discuss cholangiocarcinoma and liver metastasis because biliary inflammation and tumor-associated stroma are essential for cholangiocarcinoma development and because primary tumor-derived inflammatory mediators promote the formation of a "premetastasis niche" in the liver.
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Affiliation(s)
- Yoon Mee Yang
- Division of Digestive and Liver Diseases, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California
| | - So Yeon Kim
- Division of Digestive and Liver Diseases, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California
| | - Ekihiro Seki
- Division of Digestive and Liver Diseases, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California
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20
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Han TS, Ban HS, Hur K, Cho HS. The Epigenetic Regulation of HCC Metastasis. Int J Mol Sci 2018; 19:ijms19123978. [PMID: 30544763 PMCID: PMC6321007 DOI: 10.3390/ijms19123978] [Citation(s) in RCA: 90] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Revised: 12/05/2018] [Accepted: 12/07/2018] [Indexed: 12/22/2022] Open
Abstract
Epigenetic alterations, such as histone modification, DNA methylation, and miRNA-mediated processes, are critically associated with various mechanisms of proliferation and metastasis in several types of cancer. To overcome the side effects and limited effectiveness of drugs for cancer treatment, there is a continuous need for the identification of more effective drug targets and the execution of mechanism of action (MOA) studies. Recently, epigenetic modifiers have been recognized as important therapeutic targets for hepatocellular carcinoma (HCC) based on their reported abilities to suppress HCC metastasis and proliferation in both in vivo and in vitro studies. Therefore, here, we introduce epigenetic modifiers and alterations related to HCC metastasis and proliferation, and their molecular mechanisms in HCC metastasis. The existing data suggest that the study of epigenetic modifiers is important for the development of specific inhibitors and diagnostic targets for HCC treatment.
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Affiliation(s)
- Tae-Su Han
- Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea.
| | - Hyun Seung Ban
- Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea.
| | - Keun Hur
- Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu 41944, Korea.
| | - Hyun-Soo Cho
- Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea.
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21
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Jeyaram C, Philip M, Perumal RC, Benny J, Jayakumari JM, Ramasamy MS. A Computational Approach to Identify Novel Potential Precursor miRNAs and their Targets from Hepatocellular Carcinoma Cells. Curr Bioinform 2018. [DOI: 10.2174/1574893613666180413150351] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Background:Recent advances in next-generation sequencing technology allow highthroughput RNA-Sequencing to be widely applied in studying coding and non-coding RNA profiling in cells. RNA-Seq data usually contains functional transcriptomic and other small and larger non-coding (nc) RNA sequences. </P><P> Objective: MicroRNAs (miRNAs), a small nc-RNA act as epigenetic markers and the expression of their target genes and pathways that regulate Hepatocellular Carcinoma (HCC), a primary malignancy of the liver. The unreported potential novel miRNAs targeting HCC pathways can be identified from the sequenced data.Methods:In this study, we performed a computational identification of novel putative miRNAs and their targets from publicly available high-throughput sequencing Fastq data of human HCC cells HepG2, NorHep and SKHep1, retrieved from NCBI-SRA.Results:Totally, 572 unique known precursor miRNAs and 1062 unique novel miRNAs were identified from HepG2, Nor and SKHep1 HCC cell lines. Interestingly, 140 novel miRNAs were predicted to be extensively involved in targeting genes of HCC related pathways such as apoptosis, cell signaling, cell division, cell-cycle arrest, GPCR, MAPK cascade, TOR signaling, TNFSF11 signaling and liver development.Conclusion:The predicted novel miRNAs reported in the paper might have a vital role in regulating the molecular mechanism of HCC and thus, further studies on these miRNAs will provide significant clues for researchers into the complex biological process of liver cancer.
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Affiliation(s)
- Chitra Jeyaram
- ISM/NP Lab, AU-KBC Research Centre, MIT Campus of Anna University, Chrompet, Chennai-600044, Tamil Nadu, India
| | - Manuel Philip
- AgriGenome Labs, Infopark - Smart City Short Rd, Kochi, Kerala-682030, India
| | | | - Jubina Benny
- AgriGenome Labs, Infopark - Smart City Short Rd, Kochi, Kerala-682030, India
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22
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Mann J, Reeves HL, Feldstein AE. Liquid biopsy for liver diseases. Gut 2018; 67:2204-2212. [PMID: 30177542 DOI: 10.1136/gutjnl-2017-315846] [Citation(s) in RCA: 76] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Revised: 07/24/2018] [Accepted: 07/25/2018] [Indexed: 12/12/2022]
Abstract
With the growing number of novel therapeutic approaches for liver diseases, significant research efforts have been devoted to the development of liquid biopsy tools for precision medicine. This can be defined as non-invasive reliable biomarkers that can supplement and eventually replace the invasive liver biopsy for diagnosis, disease stratification and monitoring of response to therapeutic interventions. Similarly, detection of liver cancer at an earlier stage of the disease, potentially susceptible to curative resection, can be critical to improve patient survival. Circulating extracellular vesicles, nucleic acids (DNA and RNA) and tumour cells have emerged as attractive liquid biopsy candidates because they fulfil many of the key characteristics of an ideal biomarker. In this review, we summarise the currently available information regarding these promising and potential transformative tools, as well as the issues still needed to be addressed for adopting various liquid biopsy approaches into clinical practice. These studies may pave the way to the development of a new generation of reliable, mechanism-based disease biomarkers.
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Affiliation(s)
- Jelena Mann
- Newcastle Fibrosis Research Group, Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Helen L Reeves
- Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK
| | - Ariel E Feldstein
- Department of Pediatrics, University of California, San Diego, California, USA
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23
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Su YH, Kim AK, Jain S. Liquid biopsies for hepatocellular carcinoma. Transl Res 2018; 201:84-97. [PMID: 30056068 PMCID: PMC6483086 DOI: 10.1016/j.trsl.2018.07.001] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Revised: 06/18/2018] [Accepted: 07/02/2018] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma (HCC) is the world's second leading cause of cancer death; 82.4% of patients die within 5 years. This grim prognosis is the consequence of a lack of effective early detection tools, limited treatment options, and the high frequency of HCC recurrence. Advances in the field of liquid biopsy hold great promise in improving early detection of HCC, advancing patient prognosis, and ultimately increasing the survival rate. In an effort to address the current challenges of HCC screening and management, several studies have identified and evaluated liver-cancer-associated molecular signatures such as genetic alterations, methylation, and noncoding RNA expression in the form of circulating biomarkers in body fluids and circulating tumor cells of HCC patients. In this review, we summarize the recent progress in HCC liquid biopsy, organized by the intended clinical application of the reported study.
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Affiliation(s)
- Ying-Hsiu Su
- The Baruch S. Blumberg Institute, Doylestown, Pennsylvania.
| | - Amy K Kim
- Department of Medicine, Division of Gastroenterology and Hepatology, Johns Hopkins School of Medicine, Baltimore Maryland.
| | - Surbhi Jain
- JBS Science, Inc., Doylestown, Pennsylvania.
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24
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Synergistic and independent action of endogenous microRNAs 122a and 199a for post-transcriptional liver detargeting of gene vectors. Sci Rep 2018; 8:15539. [PMID: 30341383 PMCID: PMC6195616 DOI: 10.1038/s41598-018-33801-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Accepted: 10/01/2018] [Indexed: 12/19/2022] Open
Abstract
In hepatocellular carcinoma (HCC), which usually develops in a cirrhotic liver, treatments preserving normal liver function and viability are vitally important. Here, we utilise the differential expression of miRNAs 122a and 199a between normal hepatocytes and HCC to generate vectors harbouring their binding sites for hepatocyte detargeting. Using a reporter gene, we observed a synergistic detargeting of cells expressing both miRNAs as well as cells expressing either of the miRNAs; while expression was retained in HCC cells negative for both miRNA122a and miRNA199a. Mimics and inhibitors for individual miRNAs were used to confirm these results. Furthermore, suicide gene therapy with cytosine deaminase (CD)/5-fluorocytosine system resulted in limited killing of cells expressing either of the two miRNAs. Finally, we report feasibility of using adeno associated virus (AAV) based vectors for delivery of this dual regulated gene delivery system. These results present a novel dual targeted system whereby miRNA122a and miRNA199a act either synergistically or independently in regulating transgene expression with vectors harbouring binding sites of both miRNAs and have implications in detargeting vectors from multiple cell types in the liver.
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25
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Sun D, Lu J, Hu C, Zhang Q, Wang X, Zhang Z, Hu S. Prognostic role of miR-760 in hepatocellular carcinoma. Oncol Lett 2018; 16:7239-7244. [PMID: 30546462 PMCID: PMC6256363 DOI: 10.3892/ol.2018.9546] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Accepted: 09/26/2018] [Indexed: 02/07/2023] Open
Abstract
Previous studies have demonstrated that microRNA (miR)-760 serves an important role in various cancer types. However, to the best of our knowledge, its role in hepatocellular carcinoma (HCC) has not been fully elucidated. The current study investigated the prognostic role of miR-760 in HCC by using the Kaplan-Meier plotter database. The current data indicated that low expression of miR-760 was associated with higher overall survival (OS) for all patients with HCC from both the RNA-seq [hazard ratio (HR)=2.04; 95% confidence interval (CI)=1.44–2.89; P=4.9×10−5] and the non-commercial spotted microarray (HR=1.71; CI=1.05–2.76; P=0.028). In the RNA-seq platform, a lower expression of miR-760 was strongly associated with improved OS in male patients with HCC, but not in female patients with HCC. Additionally, low expression of miR-760 was associated with improved OS in patients with stage I, II and III HCC, and was associated with improved OS in Asian and Caucasian patients. The current results indicated that miR-760 serves as an oncogene for HCC and high expression of miR-760 is significantly associated with tumor progression and poor prognosis in patients with HCC.
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Affiliation(s)
- Dong Sun
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China.,School of Basic Medical Sciences, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Jinghui Lu
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Chunxiao Hu
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Qiangbo Zhang
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Xiangdong Wang
- School of Basic Medical Sciences, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Zongli Zhang
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Sanyuan Hu
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
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Bharali D, Jebur HB, Baishya D, Kumar S, Sarma MP, Masroor M, Akhter J, Husain SA, Kar P. Expression Analysis of Serum microRNA-34a and microRNA-183 in Hepatocellular Carcinoma. Asian Pac J Cancer Prev 2018; 19:2561-2568. [PMID: 30256056 PMCID: PMC6249442 DOI: 10.22034/apjcp.2018.19.9.2561] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2018] [Accepted: 08/15/2018] [Indexed: 02/07/2023] Open
Abstract
Background/objective: HCC is a multistep process starting from chronic hepatitis that progress through cirrhosis to HCC. MicroRNA expression level was found to be deregulated in HCC. To find out whether the expression level of miR-34a and miR-183 was deregulated in HCC compared to controls without HCC. Methods: Real time quantitative PCR was done to find out the miRNA expression level in terms of Ct value followed by statistical analysis. Results: Over-expression of miR-183 and under-expression of miR-34a in HCC was detected. All changes in expression level of miR-34a and miR-183 were found to be due to HCC compared to controls without HCC. So both miR-34a and miR-183 were suitable to differentiate HCC from Cirrhosis and chronic hepatitis with an efficient diagnostic power of sensitivity, specificity and expression level. But they might not have any role in patients’ survival. Conclusion: miR- 34a and miR-183 might be considered as potential markers of HCC screening molecule in addition to other approved panel of marker. Our study warrants further expression level study.
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Affiliation(s)
- Dipu Bharali
- Department of Medicine, Maulana Azad Medical College, New Delhi, India.
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Dhungel B, Ramlogan-Steel CA, Layton CJ, Steel JC. MicroRNA199a-Based Post-transcriptional Detargeting of Gene Vectors for Hepatocellular Carcinoma. MOLECULAR THERAPY. NUCLEIC ACIDS 2018; 13:78-88. [PMID: 30245470 PMCID: PMC6148835 DOI: 10.1016/j.omtn.2018.08.016] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/17/2018] [Revised: 08/10/2018] [Accepted: 08/19/2018] [Indexed: 02/07/2023]
Abstract
A gene therapeutic platform needs to be both efficient and safe. The criterion of safety is particularly important for diseases like hepatocellular carcinoma (HCC), which develop in a background of an already compromised liver. Gene vectors can be constructed either by targeting HCC or by detargeting liver and/or other major organs. miRNA-based negative detargeting has gained considerable attention in recent times due to its effectiveness and the ease with which it can be adapted into current gene delivery vectors. In this study, we provide a proof-of-concept using miRNA199a as a negative targeting agent. We introduced vectors harboring reporters with miRNA199a binding sites in cells expressing high endogenous levels of miRNA199a and compared the reporter expression in HCC cells with low endogenous miRNA199a. We observed that the expression of reporters with miRNA199a binding sites is significantly inhibited in miRNA199a-positive cells, whereas minimal effect was observed in miRNA199a-negative HCC cells. In addition, we created a post-transcriptionally regulated suicide gene therapeutic system based on cytosine deaminase (CD)/5-fluorocytosine (5-FC) exploiting miRNA199a binding sites and observed significantly lower cell death for miRNA199a-positive cells. Furthermore, we observed a decrease in the levels of miRNA199 in 3D tumorspheres of miRNA199a-positive Hepa1-6 cells and a reduction in the inhibition of reporter expression after transfection in these 3D models when compared with 2D Hepa1-6 cells. In summary, we provide evidence of miRNA199a-based post-transcriptional detargeting with relevance to HCC gene therapy.
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Affiliation(s)
- Bijay Dhungel
- Gallipoli Medical Research Institute, Greenslopes Private Hospital, 102 Newdegate Street, Brisbane, QLD 4120, Australia; Faculty of Medicine, The University of Queensland, 288 Herston Road, Herston, Brisbane, QLD 4006, Australia; University of Queensland Diamantina Institute, Translational Research Institute, 37 Kent Street, Woolloongabba, QLD 4102, Australia
| | - Charmaine A Ramlogan-Steel
- Faculty of Medicine, The University of Queensland, 288 Herston Road, Herston, Brisbane, QLD 4006, Australia; School of Health, Medical and Applied Sciences, CQUniversity Australia, Bruce Highway, North Rockhampton, QLD 4702, Australia
| | - Christopher J Layton
- Faculty of Medicine, The University of Queensland, 288 Herston Road, Herston, Brisbane, QLD 4006, Australia
| | - Jason C Steel
- Faculty of Medicine, The University of Queensland, 288 Herston Road, Herston, Brisbane, QLD 4006, Australia; School of Health, Medical and Applied Sciences, CQUniversity Australia, Bruce Highway, North Rockhampton, QLD 4702, Australia.
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Vasuri F, Visani M, Acquaviva G, Brand T, Fiorentino M, Pession A, Tallini G, D’Errico A, de Biase D. Role of microRNAs in the main molecular pathways of hepatocellular carcinoma. World J Gastroenterol 2018; 24:2647-2660. [PMID: 29991871 PMCID: PMC6034147 DOI: 10.3748/wjg.v24.i25.2647] [Citation(s) in RCA: 67] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Revised: 05/18/2018] [Accepted: 06/16/2018] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver malignant neoplasia. HCC is characterized by a poor prognosis. The need to find new molecular markers for its diagnosis and prognosis has led to a progressive increase in the number of scientific studies on this topic. MicroRNAs (miRNAs) are small non-coding RNA that play a role in almost all main cellular pathways. miRNAs are involved in the regulation of expression of the major tumor-related genes in carcinogenesis, acting as oncogenes or tumor suppressor genes. The aim of this review was to identify papers published in 2017 investigating the role of miRNAs in HCC tumorigenesis. miRNAs were classified according to their role in the main molecular pathways involved in HCC tumorigenesis: (1) mTOR; (2) Wnt; (3) JAK/STAT; (4) apoptosis; and (5) MAPK. The role of miRNAs in prognosis/response prediction was taken into consideration. Bearing in mind that the analysis of miRNAs in serum and other body fluids would be crucial for clinical management, the role of circulating miRNAs in HCC patients was also investigated. The most represented miRNA-regulated pathway in HCC is mTOR, but apoptosis, Wnt, JAK/STAT or MAPK pathways are also influenced by miRNA expression levels. These miRNAs could thus be used in clinical practice as diagnostic, prognostic or therapeutic targets for HCC treatment.
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Affiliation(s)
- Francesco Vasuri
- Pathology Unit, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), S.Orsola-Malpighi Hospital, University of Bologna, Bologna 40138, Italy
| | - Michela Visani
- Department of Medicine (Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale), Molecular Diagnostic Unit, Azienda USL di Bologna, University of Bologna - School of Medicine, Bologna 40138, Italy
| | - Giorgia Acquaviva
- Department of Medicine (Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale), Molecular Diagnostic Unit, Azienda USL di Bologna, University of Bologna - School of Medicine, Bologna 40138, Italy
| | - Thomas Brand
- Department of Pharmacy and Biotechnology (Dipartimento di Farmacia e Biotecnologie), University of Bologna, Bologna 40127, Italy
| | - Michelangelo Fiorentino
- Pathology Unit, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), S.Orsola-Malpighi Hospital, University of Bologna, Bologna 40138, Italy
| | - Annalisa Pession
- Department of Pharmacy and Biotechnology (Dipartimento di Farmacia e Biotecnologie), Molecular Diagnostic Unit, Azienda USL di Bologna, University of Bologna, Bologna 40138, Italy
| | - Giovanni Tallini
- Department of Medicine (Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale), Molecular Diagnostic Unit, Azienda USL di Bologna, University of Bologna - School of Medicine, Bologna 40138, Italy
| | - Antonia D’Errico
- Pathology Unit, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), S.Orsola-Malpighi Hospital, University of Bologna, Bologna 40138, Italy
| | - Dario de Biase
- Department of Pharmacy and Biotechnology (Dipartimento di Farmacia e Biotecnologie), Molecular Diagnostic Unit, Azienda USL di Bologna, University of Bologna, Bologna 40138, Italy
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Extensive screening of microRNA populations identifies hsa-miR-375 and hsa-miR-133a-3p as selective markers for human rectal and colon cancer. Oncotarget 2018; 9:27256-27267. [PMID: 29930763 PMCID: PMC6007480 DOI: 10.18632/oncotarget.25535] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Accepted: 04/28/2018] [Indexed: 12/11/2022] Open
Abstract
MicroRNAs (miRNAs) are ∼22-nt molecules exerting control of protein expression in cancer tissues. The current study determined the full spectrum of miRNA dysregulation in freshly isolated human colon or rectal cancer biopsies as well as in controls of healthy adjacent tissue (total of n = 100) using an Illumina sequencing technology. In this work, we aimed to identify miRNAs that may serve as future marker to discern between these two subtypes. DESeq2 analysis revealed 53 significantly dysregulated miRNAs in colon cancer, 67 miRNAs in rectal cancer, and 97 miRNAs in both at a Padj value < 0.05 and ≥ 10 read counts. 65% of miRNAs were upregulated in colon as well as rectal cancer. Highest significant dysregulation (Padj < 0.00001) was detected for hsa-miR-21-5p, -215-5p and -378a in both colon and rectal cancer. Among the group of miRNAs with Padj < 0.05 and more than 2-fold expression differences, hsa-miR-375 was detected in rectal cancer only, and hsa-miR-133a-3p only in colon cancer. Receiver operating characteristic (ROC) analysis confirmed highly distinct sensitivities for hsa-miR-375 to detect rectal cancer (area under the curve (AUC): 0.9), while hsa-miR-133a-3p (AUC: 0.89) had the highest sensitivity for detecting colon cancer. We conclude that hsa-miR-375 and hsa-miR-133a-3p may serve as new markers of rectal or colon cancer and should be further investigated to search for different etiologies of colorectal cancer.
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Pezzuto F, Buonaguro L, Buonaguro FM, Tornesello ML. The Role of Circulating Free DNA and MicroRNA in Non-Invasive Diagnosis of HBV- and HCV-Related Hepatocellular Carcinoma. Int J Mol Sci 2018; 19:1007. [PMID: 29597259 PMCID: PMC5979406 DOI: 10.3390/ijms19041007] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Revised: 03/15/2018] [Accepted: 03/24/2018] [Indexed: 12/25/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the third and the fifth leading cause of cancer related death worldwide in men and in women, respectively. HCC generally has a poor prognosis, with a very low 5-year overall survival, due to delayed diagnosis and treatment. Early tumour detection and timely intervention are the best strategies to reduce morbidity and mortality in HCC patients. Histological evaluation of liver biopsies is the gold standard for cancer diagnosis, although it is an invasive, time-consuming and expensive procedure. Recently, the analysis of circulating free DNA (cfDNA) and RNA molecules released by tumour cells in body fluids, such as blood serum, saliva and urine, has attracted great interest for development of diagnostic assays based on circulating liver cancer molecular biomarkers. Such "liquid biopsies" have shown to be useful for the identification of specific molecular signatures in nucleic acids released by cancer cells, such as gene mutations and altered methylation of DNA as well as variations in the levels of circulating microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). Body fluids analysis may represent a valuable strategy to monitor liver disease progression in subjects chronically infected with hepatitis viruses or cancer relapse in HCC treated patients. Several studies showed that qualitative and quantitative assays evaluating molecular profiles of circulating cell-free nucleic acids could be successfully employed for early diagnosis and therapeutic management of HCC patients. This review describes the state of art on the use of liquid biopsy for cancer driver gene mutations, deregulated DNA methylation as well as miRNA levels in HCC diagnosis.
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Affiliation(s)
- Francesca Pezzuto
- Molecular Biology and Viral Oncology Unit, Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale", 80131 Napoli, Italy.
| | - Luigi Buonaguro
- Molecular Biology and Viral Oncology Unit, Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale", 80131 Napoli, Italy.
| | - Franco Maria Buonaguro
- Molecular Biology and Viral Oncology Unit, Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale", 80131 Napoli, Italy.
| | - Maria Lina Tornesello
- Molecular Biology and Viral Oncology Unit, Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale", 80131 Napoli, Italy.
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