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de Scordilli M, Bortolot M, Torresan S, Noto C, Rota S, Di Nardo P, Fumagalli A, Guardascione M, Ongaro E, Foltran L, Puglisi F. Precision oncology in biliary tract cancer: the emerging role of liquid biopsy. ESMO Open 2025; 10:105079. [PMID: 40311184 PMCID: PMC12084404 DOI: 10.1016/j.esmoop.2025.105079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2024] [Revised: 03/01/2025] [Accepted: 04/04/2025] [Indexed: 05/03/2025] Open
Abstract
Liquid biopsy has already proven effective in aiding diagnosis, risk stratification and treatment personalization in several malignancies, and it could represent a practice-changing tool also in biliary tract cancer, even though clinical applications are currently still limited. It is promising for early diagnosis, especially in high-risk populations, and several studies on circulating free DNA (cfDNA), circulating tumour cells and differential microRNA (miRNA) profiles in this setting are ongoing. Circulating tumour DNA (ctDNA) also appears as a feasible noninvasive biomarker in the curative setting, in detecting minimal residual disease after resection and in monitoring disease recurrence. As of today, it can be particularly valuable in biliary tract cancer for genomic profiling, with a good concordance with tissue samples for most molecular alterations. CtDNA analysis may especially be considered in clinical practice when the tumour tissue is not sufficient for next-generation sequencing, or when urgent therapeutic decisions are needed. Moreover, it offers the possibility of providing a real-time picture to monitor treatment response and dynamically identify resistance mutations, potentially representing a way to optimize treatment strategies.
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Affiliation(s)
- M de Scordilli
- Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy; Department of Medicine, University of Udine, Udine, Italy
| | - M Bortolot
- Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy; Department of Medicine, University of Udine, Udine, Italy
| | - S Torresan
- Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy; Department of Medicine, University of Udine, Udine, Italy
| | - C Noto
- Department of Medicine, University of Udine, Udine, Italy; Medical Oncology, ASUGI, Ospedale Maggiore, Trieste, Italy
| | - S Rota
- Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy; Department of Medicine, University of Udine, Udine, Italy
| | - P Di Nardo
- Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy
| | - A Fumagalli
- Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy
| | - M Guardascione
- Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy
| | - E Ongaro
- Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy
| | - L Foltran
- Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy.
| | - F Puglisi
- Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy; Department of Medicine, University of Udine, Udine, Italy
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Kotsifa E, Saffioti F, Mavroeidis VK. Cholangiocarcinoma: The era of liquid biopsy. World J Gastroenterol 2025; 31:104170. [PMID: 40124277 PMCID: PMC11924015 DOI: 10.3748/wjg.v31.i11.104170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Revised: 01/28/2025] [Accepted: 02/14/2025] [Indexed: 03/13/2025] Open
Abstract
Cholangiocarcinoma (CCA) is a highly aggressive and heterogeneous malignancy arising from the epithelial cells of the biliary tract. The limitations of the current methods in the diagnosis of CCA highlight the urgent need for new, accurate tools for early cancer detection, better prognostication and patient monitoring. Liquid biopsy (LB) is a modern and non-invasive technique comprising a diverse group of methodologies aiming to detect tumour biomarkers from body fluids. These biomarkers include circulating tumour cells, cell-free DNA, circulating tumour DNA, RNA and extracellular vesicles. The aim of this review is to explore the current and potential future applications of LB in CCA management, with a focus on diagnosis, prognostication and monitoring. We examine both its significant potential and the inevitable limitations associated with this technology. We conclude that LB holds considerable promise, but further research is necessary to fully integrate it into precision oncology for CCA.
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Affiliation(s)
- Evgenia Kotsifa
- The Second Propaedeutic Department of Surgery, National and Kapodistrian University of Athens, General Hospital of Athens “Laiko”, Athens 11527, Greece
| | - Francesca Saffioti
- Department of Gastroenterology and Hepatology, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 9DU, United Kingdom
- University College London Institute for Liver and Digestive Health and Sheila Sherlock Liver Unit, Royal Free Hospital and University College London, London NW3 2QG, United Kingdom
- Division of Clinical and Molecular Hepatology, Department of Clinical and Experimental Medicine, University Hospital of Messina, Messina 98124, Italy
| | - Vasileios K Mavroeidis
- Department of Transplant Surgery, North Bristol NHS Trust, Southmead Hospital, Bristol BS10 5NB, United Kingdom
- Department of Gastrointestinal Surgery, North Bristol NHS Trust, Southmead Hospital, Bristol BS10 5NB, United Kingdom
- Department of HPB Surgery, Bristol Royal Infirmary, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol BS2 8HW, United Kingdom
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Xiao C, Zhao X, Hu Z, Long G. MFSD2A Overexpression Inhibits Hepatocellular Carcinoma Through TGF-β/Smad Signaling. Mol Carcinog 2025; 64:597-611. [PMID: 39763282 DOI: 10.1002/mc.23875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 10/11/2024] [Accepted: 12/10/2024] [Indexed: 02/13/2025]
Abstract
Hepatocellular carcinoma (HCC) is a common primary malignancy of the liver and has a high mortality. Major facilitator superfamily domain containing 2 (MFSD2A) was previously demonstrated to inhibit tumor progression in several cancers. Here, we elucidated the association between MFSD2A expression and HCC progression and also investigated the underlying mechanism. The online tools were utilized to evaluate MFSD2A expression in HCC samples and predict the prognostic significance of MFSD2A in HCC patients. The biological role of MFSD2A in HCC cellular processes was examined by colony formation, wound healing, transwell, and western blotting. The in vivo role of MFSD2A in HCC was investigated in a xenograft tumor model. The miRNAs and RNA-binding proteins potentially targeting MFSD2A were identified using bioinformatics prediction tools. Luciferase reporter, RNA immunoprecipitation, actinomycin D, and immunofluorescence assays were performed to investigate the molecule mechanisms of MFSD2A. Transforming growth factor (TGF)-β1/Small mothers against decapentaplegic (Smad) signaling was detected using western blot analysis. We found that MFSD2A expression was significantly downregulated in HCC patients and cells and its downregulation predicted a poor prognosis. MFSD2A overexpression repressed HCC cell proliferation, migration, invasion, the epithelial-to-mesenchymal transition in vitro, as well as inhibited HCC tumor growth in vivo. MFSD2A was targeted by miR-3189-3p. High-density lipoprotein binding protein (HDLBP) inhibited MFSD2A expression by binding to and destabilizing MFSD2A mRNA. MFSD2A significantly suppressed activation of TGF-β/Smad signaling in HCC cells. Knockdown of MFSD2A abrogated the inhibitory effect of miR-3189-3p inhibitor on HCC cellular processes, and overexpression of MFSD2A reversed the tumor-promoting effect of HDLBP overexpression. Overall, MFSD2A exerts a tumor-inhibiting effect in HCC via suppression of TGF-β/Smad signaling, suggesting that MFSD2A may be a promising target for HCC therapy.
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Affiliation(s)
- Chaowen Xiao
- Department of Hepatobiliary Surgery, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Xinyang Zhao
- Department of Hepatobiliary Surgery, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Zouxiao Hu
- Department of Hepatobiliary Surgery, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Guanbao Long
- Department of Hepatobiliary Surgery, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
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Ala U, Fagoonee S. RNA-binding protein transcripts as potential biomarkers for detecting Primary Sclerosing Cholangitis and for predicting its progression to Cholangiocarcinoma. Front Mol Biosci 2024; 11:1388294. [PMID: 38903178 PMCID: PMC11187294 DOI: 10.3389/fmolb.2024.1388294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Accepted: 05/13/2024] [Indexed: 06/22/2024] Open
Abstract
Primary Sclerosing Cholangitis (PSC) is a persistent inflammatory liver condition that affects the bile ducts and is commonly diagnosed in young individuals. Despite efforts to incorporate various clinical, biochemical and molecular parameters for diagnosing PSC, it remains challenging, and no biomarkers characteristic of the disease have been identified hitherto. PSC is linked with an uncertain prognosis, and there is a pressing need to explore multiomics databases to establish a new biomarker panel for the early detection of PSC's gradual progression into Cholangiocarcinoma (CCA) and for the development of effective therapeutic interventions. Apart from non-coding RNAs, other components of the Ribonucleoprotein (RNP) complex, such as RNA-Binding Proteins (RBPs), also hold great promise as biomarkers due to their versatile expression in pathological conditions. In the present review, an update on the RBP transcripts that show dysregulated expression in PSC and CCA is provided. Moreover, by utilizing a bioinformatic data mining approach, we give insight into those RBP transcripts that also exhibit differential expression in liver and gall bladder, as well as in body fluids, and are promising as biomarkers for diagnosing and predicting the prognosis of PSC. Expression data were bioinformatically extracted from public repositories usingTCGA Bile Duct Cancer dataset for CCA and specific NCBI GEO datasets for both PSC and CCA; more specifically, RBPs annotations were obtained from RBP World database. Interestingly, our comprehensive analysis shows an elevated expression of the non-canonical RBPs, FANCD2, as well as the microtubule dynamics regulator, ASPM, transcripts in the body fluids of patients with PSC and CCA compared with their respective controls, with the same trend in expression being observed in gall bladder and liver cancer tissues. Consequently, the manipulation of tissue expression of RBP transcripts might be considered as a strategy to mitigate the onset of CCA in PSC patients, and warrants further experimental investigation. The analysis performed herein may be helpful in the identification of non-invasive biomarkers for the early detection of PSC and for predicting its progression into CCA. In conclusion, future clinical research should investigate in more depth the full potential of RBP transcripts as biomarkers for human pathologies.
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Affiliation(s)
- Ugo Ala
- Department of Veterinary Sciences, University of Turin, Turin, Italy
| | - Sharmila Fagoonee
- Institute of Biostructure and Bioimaging (CNR), Molecular Biotechnology Center “Guido Tarone”, Turin, Italy
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Zhang Y, Liu Y, Huo W, He L, Li B, Wang H, Meng F, Duan C, Zhou B, Wu J, Chen R, Xing J, Wan Y. The Role of miRNA and Long Noncoding RNA in Cholestatic Liver Diseases. THE AMERICAN JOURNAL OF PATHOLOGY 2024; 194:879-893. [PMID: 38417698 DOI: 10.1016/j.ajpath.2024.02.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Revised: 02/05/2024] [Accepted: 02/16/2024] [Indexed: 03/01/2024]
Abstract
Cholestatic liver diseases encompass a range of organic damages, metabolic disorders, and dysfunctions within the hepatobiliary system, arising from various pathogenic causes. These factors contribute to disruptions in bile production, secretion, and excretion. Cholestatic liver diseases can be classified into intrahepatic and extrahepatic cholestasis, according to the location of occurrence. The etiology of cholestatic liver diseases is complex, and includes drugs, poisons, viruses, parasites, bacteria, autoimmune responses, tumors, and genetic metabolism. The pathogenesis of cholelstatic liver disease is not completely clarified, and effective therapy is lacking. Clarifying its mechanism to find more effective therapeutic targets and drugs is an unmet need. Increasing evidence demonstrates that miRNA and long noncoding RNA are involved in the progression of cholestatic liver diseases. This review provides a comprehensive summary of the research progress on the roles of miRNA and long noncoding RNA in cholestatic liver diseases. The aim of the review is to enhance the understanding of their potential diagnostic, therapeutic, and prognostic value for patients with cholestasis.
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Affiliation(s)
- Yudian Zhang
- School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
| | - Ying Liu
- School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
| | - Wen Huo
- Functional Experiment Center, College of Basic and Legal Medicine, North Sichuan Medical College, Nanchong, China
| | - Longfei He
- School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
| | - Bowen Li
- School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
| | - Hui Wang
- School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
| | - Fanyin Meng
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Richard L. Roudebush VA Medical Center, Indianapolis, Indiana
| | - Chenggang Duan
- School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
| | - Bingru Zhou
- School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
| | - Jinbo Wu
- Department of Otolaryngology-Head and Neck Surgery, Luzhou Maternal and Child Health Hospital (Luzhou Second People's Hospital), Luzhou, China
| | - Rong Chen
- School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
| | - Juan Xing
- School of Basic Medical Sciences, Southwest Medical University, Luzhou, China.
| | - Ying Wan
- School of Basic Medical Sciences, Southwest Medical University, Luzhou, China.
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Lee SH, Song SY. Recent Advancement in Diagnosis of Biliary Tract Cancer through Pathological and Molecular Classifications. Cancers (Basel) 2024; 16:1761. [PMID: 38730713 PMCID: PMC11083053 DOI: 10.3390/cancers16091761] [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: 02/23/2024] [Revised: 04/24/2024] [Accepted: 04/29/2024] [Indexed: 05/13/2024] Open
Abstract
Biliary tract cancers (BTCs), including intrahepatic, perihilar, and distal cholangiocarcinomas, as well as gallbladder cancer, are a diverse group of cancers that exhibit unique molecular characteristics in each of their anatomic and pathological subtypes. The pathological classification of BTCs compromises distinct growth patterns, including mass forming, periductal infiltrating, and intraductal growing types, which can be identified through gross examination. The small-duct and large-duct types of intrahepatic cholangiocarcinoma have been recently introduced into the WHO classification. The presentation of typical clinical symptoms, as well as the extensive utilization of radiological, endoscopic, and molecular diagnostic methods, is thoroughly detailed in the description. To overcome the limitations of traditional tissue acquisition methods, new diagnostic modalities are being explored. The treatment landscape is also rapidly evolving owing to the emergence of distinct subgroups with unique molecular alterations and corresponding targeted therapies. Furthermore, we emphasize the crucial aspects of diagnosing BTC in practical clinical settings.
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Affiliation(s)
- Sang-Hoon Lee
- Department of Internal Medicine, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul 05030, Republic of Korea;
| | - Si Young Song
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03772, Republic of Korea
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7
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Umezu T, Tanaka S, Kubo S, Enomoto M, Tamori A, Ochiya T, Taguchi Y, Kuroda M, Murakami Y. Characterization of circulating miRNAs in the treatment of primary liver tumors. Cancer Rep (Hoboken) 2024; 7:e1964. [PMID: 38146079 PMCID: PMC10849994 DOI: 10.1002/cnr2.1964] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2023] [Revised: 11/13/2023] [Accepted: 12/06/2023] [Indexed: 12/27/2023] Open
Abstract
BACKGROUND AND AIM Circulating micro RNAs (miRNAs) indicate clinical pathologies such as inflammation and carcinogenesis. In this study, we aimed to investigate whether miRNA expression level patterns in could be used to diagnose hepatocellular carcinoma (HCC) and biliary tract cancer (BTC), and the relationship miRNA expression patterns and cancer etiology. METHODS Patients with HCC and BTC with indications for surgery were selected for the study. Total RNA was extracted from the extracellular vesicle (EV)-rich fraction of the serum and analyzed using Toray miRNA microarray. Samples were divided into two cohorts in order of collection, the first 85 HCC were analyzed using a microarray based on miRBase ver.2.0 (hereafter v20 cohort), and the second 177 HCC and 43 BTC were analyzed using a microarray based on miRBase ver.21 (hereafter v21 cohort). RESULTS Using miRNA expression patterns, we found that HCC and BTC could be identified with an area under curve (AUC) 0.754 (v21 cohort). Patients with anti-hepatitis C virus (HCV) treatment (SVR-HCC) and without antiviral treatment (HCV-HCC) could be distinguished by an AUC 0.811 (v20 cohort) and AUC 0.798 (v21 cohort), respectively. CONCLUSIONS In this study, we could diagnose primary hepatic malignant tumor using miRNA expression patterns. Moreover, the difference of miRNA expression in SVR-HCC and HCV-HCC can be important information for enclosing cases that are prone to carcinogenesis after being cured with antiviral agents, but also for uncovering the mechanism for some carcinogenic potential remains even after persistent virus infection has disappeared.
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Affiliation(s)
- Tomohiro Umezu
- Department of Molecular PathologyTokyo Medical UniversityTokyoJapan
| | - Shogo Tanaka
- Department of Hepato‐Biliary‐Pancreatic SurgeryOsaka Metropolitan University, Graduate School of MedicineOsakaJapan
| | - Shoji Kubo
- Department of Hepato‐Biliary‐Pancreatic SurgeryOsaka Metropolitan University, Graduate School of MedicineOsakaJapan
| | - Masaru Enomoto
- Department of Hepatology, Graduate School of MedicineOsaka Metropolitan University, Graduate School of MedicineOsakaJapan
| | - Akihiro Tamori
- Department of Hepatology, Graduate School of MedicineOsaka Metropolitan University, Graduate School of MedicineOsakaJapan
| | - Takahiro Ochiya
- Department of Molecular and Cellular Medicine, Institute of Medical ScienceTokyo Medical UniversityTokyoJapan
| | | | - Masahiko Kuroda
- Department of Molecular PathologyTokyo Medical UniversityTokyoJapan
| | - Yoshiki Murakami
- Department of Molecular PathologyTokyo Medical UniversityTokyoJapan
- Department of DentistryAsahi UniversityGifuJapan
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Liu F, Hao X, Liu B, Liu S, Yuan Y. Bile liquid biopsy in biliary tract cancer. Clin Chim Acta 2023; 551:117593. [PMID: 37839517 DOI: 10.1016/j.cca.2023.117593] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Revised: 10/08/2023] [Accepted: 10/10/2023] [Indexed: 10/17/2023]
Abstract
Biliary tract cancers are heterogeneous in etiology, morphology and molecular characteristics thus impacting disease management. Diagnosis is complex and prognosis poor. The advent of liquid biopsy has provided a unique approach to more thoroughly understand tumor biology in general and biliary tract cancers specifically. Due to their minimally invasive nature, liquid biopsy can be used to serially monitor disease progression and allow real-time monitoring of tumor genetic profiles as well as therapeutic response. Due to the unique anatomic location of biliary tract cancer, bile provides a promising biologic fluid for this purpose. This review focuses on the composition of bile and the use of these various components, ie, cells, extracellular vesicles, nucleic acids, proteins and metabolites as potential biomarkers. Based on the disease characteristics and research status of biliary tract cancer, considerable effort should be made to increase understanding of this disease, promote research and development into early diagnosis, develop efficient diagnostic, therapeutic and prognostic markers.
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Affiliation(s)
- Fusheng Liu
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, PR China; Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan, 430071, Hubei, PR China
| | - Xingyuan Hao
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, PR China; Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan, 430071, Hubei, PR China
| | - Bin Liu
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, PR China; Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan, 430071, Hubei, PR China
| | - Songmei Liu
- Department of Clinical Laboratory, Center for Gene Diagnosis, and Program of Clinical Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, PR China
| | - Yufeng Yuan
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, PR China; Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan, 430071, Hubei, PR China; TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430071, Hubei, PR China.
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Catanzaro E, Gringeri E, Burra P, Gambato M. Primary Sclerosing Cholangitis-Associated Cholangiocarcinoma: From Pathogenesis to Diagnostic and Surveillance Strategies. Cancers (Basel) 2023; 15:4947. [PMID: 37894314 PMCID: PMC10604939 DOI: 10.3390/cancers15204947] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 10/09/2023] [Accepted: 10/10/2023] [Indexed: 10/29/2023] Open
Abstract
Cholangiocarcinoma (CCA) is the most common malignancy in patients with primary sclerosing cholangitis (PSC), accounting for 2-8% of cases and being the leading cause of death in these patients. The majority of PSC-associated CCAs (PSC-CCA) develop within the first few years after PSC diagnosis. Older age and male sex, as well as concomitant inflammatory bowel disease (IBD) or high-grade biliary stenosis, are some of the most relevant risk factors. A complex combination of molecular mechanisms involving inflammatory pathways, direct cytopathic damage, and epigenetic and genetic alterations are involved in cholangiocytes carcinogenesis. The insidious clinical presentation makes early detection difficult, and the integration of biochemical, radiological, and histological features does not always lead to a definitive diagnosis of PSC-CCA. Surveillance is mandatory, but current guideline strategies failed to improve early detection and consequently a higher patient survival rate. MicroRNAs (miRNAs), gene methylation, proteomic and metabolomic profile, and extracellular vesicle components are some of the novel biomarkers recently applied in PSC-CCA detection with promising results. The integration of these new molecular approaches in PSC diagnosis and monitoring could contribute to new diagnostic and surveillance strategies.
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Affiliation(s)
- Elisa Catanzaro
- Gastroenterology, Department of Surgery, Oncology, and Gastroenterology, Padova University Hospital, 35128 Padova, Italy
- Multivisceral Transplant Unit, Department of Surgery, Oncology, and Gastroenterology, Padova University Hospital, 35128 Padova, Italy
| | - Enrico Gringeri
- Hepatobiliary Surgery and Liver Transplantation Center, Department of Surgery, Oncology, and Gastroenterology, Padova University Hospital, 35128 Padova, Italy
| | - Patrizia Burra
- Gastroenterology, Department of Surgery, Oncology, and Gastroenterology, Padova University Hospital, 35128 Padova, Italy
- Multivisceral Transplant Unit, Department of Surgery, Oncology, and Gastroenterology, Padova University Hospital, 35128 Padova, Italy
| | - Martina Gambato
- Gastroenterology, Department of Surgery, Oncology, and Gastroenterology, Padova University Hospital, 35128 Padova, Italy
- Multivisceral Transplant Unit, Department of Surgery, Oncology, and Gastroenterology, Padova University Hospital, 35128 Padova, Italy
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Zhong B, Liao Q, Wang X, Wang X, Zhang J. The roles of epigenetic regulation in cholangiocarcinogenesis. Biomed Pharmacother 2023; 166:115290. [PMID: 37557012 DOI: 10.1016/j.biopha.2023.115290] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Revised: 08/01/2023] [Accepted: 08/04/2023] [Indexed: 08/11/2023] Open
Abstract
Cholangiocarcinoma (CCA), a heterogeneous malignancy of bile duct epithelial cells, is characterized by aggressiveness, difficult diagnosis, and poor prognosis due to limited understanding and lack of effective therapeutic strategies. Genetic and epigenetic alterations accumulated in CCA cells can cause the aberrant regulation of oncogenes and tumor suppressors. Epigenetic alterations with histone modification, DNA methylation, and noncoding RNA modulation are associated with the carcinogenesis of CCA. Mutation or silencing of genes by various mechanisms can be a frequent event during CCA development. Alterations in histone acetylation/deacetylation at the posttranslational level, DNA methylation at promoters, and noncoding RNA regulation contribute to the heterogeneity of CCA and drive tumor development. In this review article, we mainly focus on the roles of epigenetic regulation in cholangiocarcinogenesis. Alterations in epigenetic modification can be potential targets for the therapeutic management of CCA, and epigenetic targets may become diagnostic biomarkers of CCA.
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Affiliation(s)
- Baiyin Zhong
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Gannan Medical University, Ganzhou 341000, China
| | - Qicheng Liao
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Gannan Medical University, Ganzhou 341000, China
| | - Xin Wang
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Gannan Medical University, Ganzhou 341000, China
| | - Xiaonong Wang
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Gannan Medical University, Ganzhou 341000, China
| | - Jianhong Zhang
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Gannan Medical University, Ganzhou 341000, China; Ganzhou Key Laboratory of Hepatocellular Carcinoma, First Affiliated Hospital of Gannan Medical University, Ganzhou 341000, China.
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11
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Kuniyoshi N, Imazu H, Masuzaki R, Yamazaki M, Hamana S, Nomura S, Hayama J, Osawa R, Yamada K, Fujisawa M, Saito K, Kogure H. Diagnostic utility of quantitative analysis of microRNA in bile samples obtained during endoscopic retrograde cholangiopancreatography for malignant biliary strictures. PLoS One 2023; 18:e0289537. [PMID: 37561751 PMCID: PMC10414614 DOI: 10.1371/journal.pone.0289537] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Accepted: 07/20/2023] [Indexed: 08/12/2023] Open
Abstract
BACKGROUND The sensitivity of bile cytology for malignant biliary strictures is not adequate. To overcome this limitation, we evaluated whether quantitative analysis of microRNAs (miRNAs) in bile can provide a precise diagnosis of malignant biliary strictures due to pancreatic cancer (PC) and biliary tract cancer (BTC). METHODS This was a retrospective evaluation of miRNA levels in stored bile samples of patients with PC, BTC or benign biliary stricture obtained during biliary drainage from April 2019 to December 2021 at our institution. A total of 113 patients (PC; n = 40, BTC; n = 38, control; n = 35) were enrolled. The miRNA candidates to be quantified were determined with microarray analysis from each 3 patients with PC, BTC and controls. RESULTS Using microarray analysis, we confirmed four significantly up-regulated miRNAs (miR-1275, miR-6891-5p, miR-7107-5p, miR-3197) in patients with PC and BTC compared to control patients. Quantitative PCR was then performed in 113 bile samples for these miRNAs. miR-1275 was significantly upregulated in PC (p = 0.003) and BTC (p = 0.049) compared to controls, miR-6891-5p was significantly upregulated in PC compared to controls (p = 0.025). In particular, a combination of bile cytology and miR-1275 in bile showed a sensitivity of 77.5% (95% CI, 70.7-77.5%), specificity of 100% (95% CI, 92.2-100%) and an area under the curve (AUC) of 0.93, and provided a significantly greater additional diagnostic effect than bile cytology alone (p = 0.014). CONCLUSIONS This study suggest that bile miRNAs could be potential biomarkers for pancreato-biliary diseases, particularly miR-1275 and miR-6891-5p may be helpful in the diagnosis of PC and BTC.
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Affiliation(s)
- Noriyuki Kuniyoshi
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo, Japan
| | - Hiroo Imazu
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Chiyoda-ku, Tokyo, Japan
| | - Ryota Masuzaki
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo, Japan
| | - Motomi Yamazaki
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo, Japan
| | - Suguru Hamana
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo, Japan
| | - Shuzo Nomura
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo, Japan
| | - Jo Hayama
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo, Japan
| | - Rota Osawa
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Chiyoda-ku, Tokyo, Japan
| | - Koji Yamada
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Chiyoda-ku, Tokyo, Japan
| | - Mariko Fujisawa
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo, Japan
| | - Kei Saito
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo, Japan
| | - Hirofumi Kogure
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo, Japan
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12
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Hochberg JT, Sohal A, Handa P, Maliken BD, Kim TK, Wang K, Gochanour E, Li Y, Rose JB, Nelson JE, Lindor KD, LaRusso NF, Kowdley KV. Serum miRNA profiles are altered in patients with primary sclerosing cholangitis receiving high-dose ursodeoxycholic acid. JHEP Rep 2023; 5:100729. [PMID: 37179785 PMCID: PMC10172698 DOI: 10.1016/j.jhepr.2023.100729] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 02/02/2023] [Accepted: 02/27/2023] [Indexed: 05/15/2023] Open
Abstract
Background & Aims Primary sclerosing cholangitis (PSC) is a chronic, progressive cholestatic liver disease that can lead to end-stage liver disease and cholangiocarcinoma. High-dose ursodeoxycholic acid (hd-UDCA, 28-30 mg/kg/day) was evaluated in a previous multicentre, randomised placebo-controlled trial; however, the study was discontinued early because of increased liver-related serious adverse events (SAEs), despite improvement in serum liver biochemical tests. We investigated longitudinal changes in serum miRNA and cytokine profiles over time among patients treated with either hd-UDCA or placebo in this trial as potential biomarkers for PSC and response to hd-UDCA, as well as to understand the toxicity associated with hd-UDCA treatment. Methods Thirty-eight patients with PSC were enrolled in a multicentred, randomised, double-blinded trial of hd-UDCA vs. placebo. Results Significant alterations in serum miRNA profiles were found over time in both patients treated with hd-UDCA or placebo. Additionally, there were striking differences between miRNA profiles in patients treated with hd-UDCA compared with placebo. In patients treated with placebo, the changes in concentration of serum miRNAs miR-26a, miR-199b-5p, miR-373, and miR-663 suggest alterations of inflammatory and cell proliferative processes consistent with disease progression. However, patients treated with hd-UDCA exhibited a more pronounced differential expression of serum miRNAs, suggesting that hd-UDCA induces significant cellular miRNA changes and tissue injury. Pathway enrichment analysis for UDCA-associated miRNAs suggested unique dysregulation of cell cycle and inflammatory response pathways. Conclusions Patients with PSC have distinct miRNAs in the serum and bile, although the implications of these unique patterns have not been studied longitudinally or in relation to adverse events related to hd-UDCA. Our study demonstrates marked changes in miRNA serum profiles with hd-UDCA treatment and suggests mechanisms for the increased liver toxicity with therapy. Impact and implications Using serum samples from patients with PSC enrolled in a clinical trial comparing hd-UDCA with placebo, our study found distinct miRNA changes in patients with PSC who are treated with hd-UDCA over a period of time. Our study also noted distinct miRNA patterns in patients who developed SAEs during the study period.
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Affiliation(s)
- Jessica T. Hochberg
- Liver Institute Northwest, Seattle, WA, USA
- Seattle Children’s Hospital/University of Washington, Seattle, WA, USA
- Miami Transplant Institute at University of Miami, Miami, FL, USA
| | | | - Priya Handa
- Benaroya Research Institute, Seattle, WA, USA
| | | | | | - Kai Wang
- Institute for Systems Biology, Seattle, WA, USA
| | | | - Yu Li
- Benaroya Research Institute, Seattle, WA, USA
| | | | | | - Keith D. Lindor
- Division of Gastroenterology and Hepatology, Mayo Clinic Rochester, MN, USA
| | | | - Kris V. Kowdley
- Liver Institute Northwest, Seattle, WA, USA
- Corresponding author. Address: Liver Institute Northwest, 3216 NE 45th Pl Suite 212, Seattle, WA 98105, USA; Tel.: +1(206) 536-3030.
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13
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Zaki MB, Abulsoud AI, Elshaer SS, Fathi D, Abdelmaksoud NM, El-Mahdy HA, Ismail A, Elsakka EG, Sallam AAM, Doghish AS. The interplay of signaling pathways with miRNAs in cholangiocarcinoma pathogenicity and targeted therapy. Pathol Res Pract 2023; 245:154437. [PMID: 37030167 DOI: 10.1016/j.prp.2023.154437] [Citation(s) in RCA: 44] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 03/31/2023] [Accepted: 04/02/2023] [Indexed: 04/08/2023]
Abstract
Cholangiocarcinoma (CCA), the second most frequent liver cancer after hepatocellular carcinoma, has been rising worldwide in recent epidemiological research. This neoplasia's pathogenesis is poorly understood. Yet, recent advances have illuminated the molecular processes of cholangiocyte malignancy and growth. Late diagnosis, ineffective therapy, and resistance to standard treatments contribute to this malignancy's poor prognosis. So, to develop efficient preventative and therapy methods, the molecular pathways that cause this cancer must be better understood. MicroRNAs (miRNAs) are non-coding ribonucleic acids (ncRNAs) that influence gene expression. Biliary carcinogenesis involves abnormally expressed miRNAs that act as oncogenes or tumor suppressors (TSs). The miRNAs regulate multiple gene networks and are involved in cancer hallmarks like reprogramming of cellular metabolism, sustained proliferative signaling, evasion of growth suppressors, replicative immortality, induction/access to the vasculature, activation of invasion and metastasis, and avoidance of immune destruction. In addition, numerous ongoing clinical trials are demonstrating the efficacy of therapeutic strategies based on miRNAs as powerful anticancer agents. Here, we will update the research on CCA-related miRNAs and explain their regulation involved in the molecular pathophysiology of this malignancy. Eventually, we will disclose their potential as clinical biomarkers and therapeutic tools in CCA.
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14
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LaPelusa M, Heumann T, Goff L, Agarwal R. Targeted therapies in advanced biliary tract cancers-a narrative review. Chin Clin Oncol 2023; 12:14. [PMID: 36946186 PMCID: PMC10175163 DOI: 10.21037/cco-22-93] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Accepted: 02/23/2023] [Indexed: 03/14/2023]
Abstract
BACKGROUND AND OBJECTIVE Biliary tract cancers (BTCs), including cholangiocarcinoma and gallbladder cancer, are a relatively rare group of cancers with a poor prognosis. Over the past decade, the utilization of next-generation sequencing has led to the identification of multiple actionable somatic aberrations in BTCs. Subsequently, new therapies have been created to target these molecular alterations and have been incorporated into clinical practice. In this review, we outline therapies that have been previously studied, and those that are under investigation, to target genomic alterations with the goal of improving survival in patients with advanced disease. METHODS A literature search was performed to identify phase I, II, and III trials of targeted therapies in patients with advanced BTCs published between January 1, 2010 and October 1, 2022. Medline (via PubMed) and ClinicalTrials.gov were searched for relevant studies and 415 trials were identified. The search strategy was performed using keywords including: biliary tract cancer, cholangiocarcinoma, gallbladder cancer, chemotherapy, targeted therapy, randomized trials, controlled trials, phase I, phase II, and phase III. Search results were imported into EndNote X 9.1. KEY CONTENT AND FINDINGS Overall, immune checkpoint inhibitors, fibroblast growth factor receptor (FGFR) inhibitors, isocitrate dehydrogenase (IDH) inhibitors, and human epidermal growth factor receptor 2 (HER2)-directed therapies have all shown promising results with regard to efficacy in patients with advanced BTCs studied in clinical trials. A number of other agents have also been studied in early-phase trials. CONCLUSIONS Targeted agents can improve survival in patients with advanced BTCs and have substantially increased the number of potential therapeutic options in patients with refractory disease. The therapeutic landscape of targeted therapies for patients with advanced BTCs continues to evolve based on improvements in detection of genomic alterations.
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Affiliation(s)
- Michael LaPelusa
- Department of Internal Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Thatcher Heumann
- Department of Internal Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
- Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Laura Goff
- Department of Internal Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
- Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Rajiv Agarwal
- Department of Internal Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
- Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA
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15
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Cadamuro M, Al-Taee A, Gonda TA. Advanced endoscopy meets molecular diagnosis of cholangiocarcinoma. J Hepatol 2023; 78:1063-1072. [PMID: 36740048 DOI: 10.1016/j.jhep.2023.01.027] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 12/22/2022] [Accepted: 01/18/2023] [Indexed: 02/07/2023]
Abstract
Cholangiocarcinoma remains an aggressive and deadly malignancy that is often diagnosed late. Intrinsic tumour characteristics and the growth pattern of cancer cells contribute to the challenges of diagnosis and chemoresistance. However, establishing an early and accurate diagnosis, and in some instances identifying targetable changes, has the potential to impact survival. Primary sclerosing cholangitis, a chronic cholangiopathy prodromal to the development of a minority of cholangiocarcinomas, poses a particular diagnostic challenge. We present our diagnostic and theranostic approach to the initial evaluation of cholangiocarcinomas, focusing on extrahepatic cholangiocarcinoma. This involves a multipronged strategy incorporating advanced imaging, endoscopic methods, multiple approaches to tissue sampling, and molecular markers. We also provide an algorithm for the sequential use of these tools.
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Affiliation(s)
| | - Ahmad Al-Taee
- Carle Illinois College of Medicine, University of Illinois Urbaba-Champaign, Champaign County, IL, USA
| | - Tamas A Gonda
- Division of Gastroenterology and Hepatology, New York University, New York, NY, USA.
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16
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Ohaegbulam KC, Koethe Y, Fung A, Mayo SC, Grossberg AJ, Chen EY, Sharzehi K, Kardosh A, Farsad K, Rocha FG, Thomas CR, Nabavizadeh N. The multidisciplinary management of cholangiocarcinoma. Cancer 2023; 129:184-214. [PMID: 36382577 DOI: 10.1002/cncr.34541] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 10/11/2022] [Accepted: 10/14/2022] [Indexed: 11/17/2022]
Abstract
Cholangiocarcinoma is a lethal malignancy of the biliary epithelium that can arise anywhere along the biliary tract. Surgical resection confers the greatest likelihood of long-term survivability. However, its insidious onset, difficult diagnostics, and resultant advanced presentation render the majority of patients unresectable, highlighting the importance of early detection with novel biomarkers. Developing liver-directed therapies and emerging targeted therapeutics may offer improved survivability for patients with unresectable or advanced disease. In this article, the authors review the current multidisciplinary standards of care in resectable and unresectable cholangiocarcinoma, with an emphasis on novel biomarkers for early detection and nonsurgical locoregional therapy options.
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Affiliation(s)
- Kim C Ohaegbulam
- Department of Radiation Medicine, Oregon Health & Science University, Portland, Oregon, USA
| | - Yilun Koethe
- Department of Interventional Radiology, Oregon Health & Science University, Portland, Oregon, USA
| | - Alice Fung
- Department of Diagnostic Radiology, Oregon Health & Science University, Portland, Oregon, USA
| | - Skye C Mayo
- Department of Surgical Oncology, Oregon Health & Science University, Portland, Oregon, USA
| | - Aaron J Grossberg
- Department of Radiation Medicine, Oregon Health & Science University, Portland, Oregon, USA
| | - Emerson Y Chen
- Division of Hematology/Medical Oncology, Oregon Health & Science University, Portland, Oregon, USA
| | - Kaveh Sharzehi
- Division of Gastroenterology and Hepatology, Oregon Health & Science University, Portland, Oregon, USA
| | - Adel Kardosh
- Division of Hematology/Medical Oncology, Oregon Health & Science University, Portland, Oregon, USA
| | - Khashayar Farsad
- Department of Interventional Radiology, Oregon Health & Science University, Portland, Oregon, USA
| | - Flavio G Rocha
- Department of Surgical Oncology, Oregon Health & Science University, Portland, Oregon, USA
| | - Charles R Thomas
- Department of Radiation Medicine, Oregon Health & Science University, Portland, Oregon, USA.,Department of Radiation Oncology, Dartmouth School of Medicine, Hanover, New Hampshire, USA
| | - Nima Nabavizadeh
- Department of Radiation Medicine, Oregon Health & Science University, Portland, Oregon, USA
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17
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Li YC, Li KS, Liu ZL, Tang YC, Hu XQ, Li XY, Shi AD, Zhao LM, Shu LZ, Lian S, Yan ZD, Huang SH, Sheng GL, Song Y, Liu YJ, Huan F, Zhang MH, Zhang ZL. Research progress of bile biomarkers and their immunoregulatory role in biliary tract cancers. Front Immunol 2022; 13:1049812. [PMID: 36389727 PMCID: PMC9649822 DOI: 10.3389/fimmu.2022.1049812] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Accepted: 10/12/2022] [Indexed: 11/30/2022] Open
Abstract
Biliary tract cancers (BTCs), including cholangiocarcinoma and gallbladder carcinoma, originate from the biliary epithelium and have a poor prognosis. Surgery is the only choice for cure in the early stage of disease. However, most patients are diagnosed in the advanced stage and lose the chance for surgery. Early diagnosis could significantly improve the prognosis of patients. Bile has complex components and is in direct contact with biliary tract tumors. Bile components are closely related to the occurrence and development of biliary tract tumors and may be applied as biomarkers for BTCs. Meanwhile, arising evidence has confirmed the immunoregulatory role of bile components. In this review, we aim to summarize and discuss the relationship between bile components and biliary tract cancers and their ability as biomarkers for BTCs, highlighting the role of bile components in regulating immune response, and their promising application prospects.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | - Zong-li Zhang
- Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
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18
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Su F, Gao Z, Liu Y, Zhou G, Gao W, Deng C, Liu Y, Zhang Y, Ma X, Wang Y, Guan L, Zhang Y, Liu B. Prioritizing key synergistic circulating microRNAs for the early diagnosis of biliary tract cancer. Front Oncol 2022; 12:968412. [PMID: 36276146 PMCID: PMC9582275 DOI: 10.3389/fonc.2022.968412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Accepted: 09/20/2022] [Indexed: 11/13/2022] Open
Abstract
Biliary tract cancer (BTC) is a highly aggressive malignant tumor. Serum microRNAs (ser-miRNAs) serve as noninvasive biomarkers to identify high risk individuals, thereby facilitating the design of precision therapies. The study is to prioritize key synergistic ser-miRNAs for the diagnosis of early BTC. Sampling technology, significant analysis of microarrays, Pearson Correlation Coefficients, t-test, decision tree, and entropy weight were integrated to develop a global optimization algorithm of decision forest. The source code is available at https://github.com/SuFei-lab/GOADF.git. Four key synergistic ser-miRNAs were prioritized and the synergistic classification performance was better than the single miRNA’ s. In the internal feature evaluation dataset, the area under the receiver operating characteristic curve (AUC) for each single miRNA was 0.8413 (hsa-let-7c-5p), 0.7143 (hsa-miR-16-5p), 0.8571 (hsa-miR-17-5p), and 0.9365 (hsa-miR-26a-5p), respectively, whereas the synergistic AUC value increased to 1.0000. In the internal test dataset, the single AUC was 0.6500, 0.5125, 0.6750, and 0.7500, whereas the synergistic AUC increased to 0.8375. In the independent test dataset, the single AUC was 0.7280, 0.8313, 0.8957, and 0.8303, and the synergistic AUC was 0.9110 for discriminating between BTC patients and healthy controls. The AUC for discriminating BTC from pancreatic cancer was 0.9000. Hsa-miR-26a-5p was a predictor of prognosis, patients with high expression had shorter survival than those with low expression. In conclusion, hsa-let-7c-5p, hsa-miR-16-5p, hsa-miR-17-5p, and hsa-miR-26a-5p may act as key synergistic biomarkers and provide important molecular mechanisms that contribute to pathogenesis of BTC.
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Affiliation(s)
- Fei Su
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Ziyu Gao
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
- Department of Anatomy, Harbin Medical University, Harbin, China
| | - Yueyang Liu
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Guiqin Zhou
- Department of Immunology, Harbin Medical University, Harbin, China
| | - Wei Gao
- Laboratory of Medical Genetics, Harbin Medical University, Harbin, China
| | - Chao Deng
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
- Department of Anatomy, Harbin Medical University, Harbin, China
| | - Yuyu Liu
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
- Department of Anatomy, Harbin Medical University, Harbin, China
| | - Yihao Zhang
- Department of Anatomy, Harbin Medical University, Harbin, China
| | - Xiaoyan Ma
- Department of Anatomy, Harbin Medical University, Harbin, China
| | - Yongxia Wang
- Department of Anatomy, Harbin Medical University, Harbin, China
| | - Lili Guan
- Department of Information Management, Shanghai Lixin University of Accounting and Finance, Shanghai, China
- *Correspondence: Baoquan Liu, ; Yafang Zhang, ; Lili Guan,
| | - Yafang Zhang
- Department of Anatomy, Harbin Medical University, Harbin, China
- *Correspondence: Baoquan Liu, ; Yafang Zhang, ; Lili Guan,
| | - Baoquan Liu
- Department of Anatomy, Harbin Medical University, Harbin, China
- Department of Modern Medicine and Pharmacy, University of Tibetan Medicine, Lhasa, China
- *Correspondence: Baoquan Liu, ; Yafang Zhang, ; Lili Guan,
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Prinz C, Frese R, Grams M, Fehring L. Emerging Role of microRNA Dysregulation in Diagnosis and Prognosis of Extrahepatic Cholangiocarcinoma. Genes (Basel) 2022; 13:1479. [PMID: 36011390 PMCID: PMC9407895 DOI: 10.3390/genes13081479] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 08/11/2022] [Accepted: 08/12/2022] [Indexed: 12/01/2022] Open
Abstract
Extrahepatic cholangiocarcinomas, also called bile duct carcinomas, represent a special entity in gastrointestinal tumors, and histological specimens of the tumors are often difficult to obtain. A special feature of these tumors is the strong neovascularization, which can often be seen in the endoluminal endoscopic procedure called cholangioscopy, performed alone or in combination with laserscanning techniques. The additional analysis of microRNA expression profiles associated with inflammation and neovascularization in bile duct tumors or just the bile duct fluid of these patients could be of enormous additional importance. In particular, the dysregulation of microRNA in these cholangiocarcinomas (CCA) was previously reported to affect epigenetics (reported for miR-148, miR-152), inflammation (determined for miR-200, miR-125, and miR-605), and chemoresistance (miR-200b, 204) in patients with cholangiocarcinoma. More importantly, in the context of malignant neovascularization, well-defined microRNAs including miR-141, miR-181, miR-191, and miR-200b have been found to be dysregulated in cholangiocarcinoma and have been associated with an increased proliferation and vascularization in CCA. Thus, a panel of these microRNA molecules together with the clinical aspects of these tumors might facilitate tumor diagnosis and early treatment. To our knowledge, this is the first review that outlines the unique potential of combining macroscopic findings from cholangioscopy with microRNA expression.
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Affiliation(s)
- Christian Prinz
- Medizinische Klinik 2, Helios Universitätsklinikum, 42283 Wuppertal, Germany
- Lehrstuhl für Innere Medizin 1 der, University of Witten gGmbH, 42283 Wuppertal, Germany
| | - Robin Frese
- Medizinische Klinik 2, Helios Universitätsklinikum, 42283 Wuppertal, Germany
- Lehrstuhl für Innere Medizin 1 der, University of Witten gGmbH, 42283 Wuppertal, Germany
| | - Mashiba Grams
- Medizinische Klinik 2, Helios Universitätsklinikum, 42283 Wuppertal, Germany
- Lehrstuhl für Innere Medizin 1 der, University of Witten gGmbH, 42283 Wuppertal, Germany
| | - Leonard Fehring
- Medizinische Klinik 2, Helios Universitätsklinikum, 42283 Wuppertal, Germany
- Lehrstuhl für Innere Medizin 1 der, University of Witten gGmbH, 42283 Wuppertal, Germany
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20
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Bao F, Liu J, Chen H, Miao L, Xu Z, Zhang G. Diagnosis Biomarkers of Cholangiocarcinoma in Human Bile: An Evidence-Based Study. Cancers (Basel) 2022; 14:cancers14163921. [PMID: 36010914 PMCID: PMC9406189 DOI: 10.3390/cancers14163921] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 08/03/2022] [Accepted: 08/08/2022] [Indexed: 11/23/2022] Open
Abstract
Simple Summary A liquid biopsy has the characteristics of low trauma and easy acquisition in the diagnosis of cholangiocarcinoma. Many researchers try to find diagnostic or prognostic biomarkers of CCA through blood, urine, bile and other body fluids. Due to the close proximity of bile to the lesion and the stable nature, bile gradually comes into people’s view. The evaluation of human bile diagnostic biomarkers is not only to the benefit of screening more suitable clinical markers but also of exploring the pathological changes of the disease. Abstract Cholangiocarcinoma (CCA) is a multifactorial malignant tumor of the biliary tract, and the incidence of CCA is increasing in recent years. At present, the diagnosis of CCA mainly depends on imaging and invasive examination, with limited specificity and sensitivity and late detection. The early diagnosis of CCA always faces the dilemma of lacking specific diagnostic biomarkers. Non-invasive methods to assess the degree of CAA have been developed throughout the last decades. Among the many specimens looking for CCA biomarkers, bile has gotten a lot of attention lately. This paper mainly summarizes the recent developments in the current research on the diagnostic biomarkers for CCA in human bile at the levels of the gene, protein, metabolite, extracellular vesicles and volatile organic compounds.
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Affiliation(s)
- Fang Bao
- Institute of Integrative Medicine, Dalian Medical University, No. 9, South Road of Lvshun, Dalian 116044, China
- Department of General Surgery, Pancreatic-Biliary Center, The First Affiliated Hospital of Dalian Medical University, No. 222, Zhongshan Road, Dalian 116011, China
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023, China
| | - Jiayue Liu
- Institute of Integrative Medicine, Dalian Medical University, No. 9, South Road of Lvshun, Dalian 116044, China
- Department of General Surgery, Pancreatic-Biliary Center, The First Affiliated Hospital of Dalian Medical University, No. 222, Zhongshan Road, Dalian 116011, China
| | - Haiyang Chen
- Institute of Integrative Medicine, Dalian Medical University, No. 9, South Road of Lvshun, Dalian 116044, China
- Department of General Surgery, Pancreatic-Biliary Center, The First Affiliated Hospital of Dalian Medical University, No. 222, Zhongshan Road, Dalian 116011, China
| | - Lu Miao
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023, China
| | - Zhaochao Xu
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023, China
- Correspondence: (Z.X.); (G.Z.)
| | - Guixin Zhang
- Institute of Integrative Medicine, Dalian Medical University, No. 9, South Road of Lvshun, Dalian 116044, China
- Department of General Surgery, Pancreatic-Biliary Center, The First Affiliated Hospital of Dalian Medical University, No. 222, Zhongshan Road, Dalian 116011, China
- Correspondence: (Z.X.); (G.Z.)
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Liu X, Papukashvili D, Wang Z, Liu Y, Chen X, Li J, Li Z, Hu L, Li Z, Rcheulishvili N, Lu X, Ma J. Potential utility of miRNAs for liquid biopsy in breast cancer. Front Oncol 2022; 12:940314. [PMID: 35992785 PMCID: PMC9386533 DOI: 10.3389/fonc.2022.940314] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 07/04/2022] [Indexed: 12/18/2022] Open
Abstract
Breast cancer (BC) remains the most prevalent malignancy due to its incidence rate, recurrence, and metastasis in women. Conventional strategies of cancer detection– mammography and tissue biopsy lack the capacity to detect the complete cancer genomic landscape. Besides, they often give false- positive or negative results. The presence of this and other disadvantages such as invasiveness, high-cost, and side effects necessitates developing new strategies to overcome the BC burden. Liquid biopsy (LB) has been brought to the fore owing to its early detection, screening, prognosis, simplicity of the technique, and efficient monitoring. Remarkably, microRNAs (miRNAs)– gene expression regulators seem to play a major role as biomarkers detected in the samples of LB. Particularly, miR-21 and miR-155 among other possible candidates seem to serve as favorable biomarkers in the diagnosis and prognosis of BC. Hence, this review will assess the potential utility of miRNAs as biomarkers and will highlight certain promising candidates for the LB approach in the diagnosis and management of BC that may optimize the patient outcome.
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Affiliation(s)
- Xiangrong Liu
- Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, China
| | - Dimitri Papukashvili
- Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, China
| | - Zhixiang Wang
- Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, China
| | - Yan Liu
- Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, China
| | - Xiaoxia Chen
- Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, China
| | - Jianrong Li
- Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, China
| | - Zhiyuan Li
- Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, China
| | - Linjie Hu
- Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, China
| | - Zheng Li
- Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, China
| | - Nino Rcheulishvili
- Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, China
| | - Xiaoqing Lu
- Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, China
- *Correspondence: Xiaoqing Lu, ; Jinfeng Ma,
| | - Jinfeng Ma
- Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, China
- *Correspondence: Xiaoqing Lu, ; Jinfeng Ma,
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22
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Liver transplantation and intrahepatic cholangiocarcinoma: time to go forward again? Curr Opin Organ Transplant 2022; 27:320-328. [PMID: 36354258 DOI: 10.1097/mot.0000000000000983] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
PURPOSE OF REVIEW Liver transplantation for intrahepatic cholangiocarcinoma (iCCA) has been mired in controversy. High rates of recurrence posttransplant combined with donor organ scarcity resulted in most transplant centers treating iCCA as a contraindication for liver transplantation. RECENT FINDINGS Recent studies have shown that carefully selected patients with unresectable iCCA can have good outcomes after liver transplantation. Better outcomes have been seen in patients with smaller tumors and favorable tumor biology. SUMMARY Because many patients are diagnosed with iCCA at later stages, tumor biology and genetics are useful tools to identify patients who will have excellent overall and recurrence-free survival after liver transplantation. Further larger multicenter prospective studies are needed to identify patients who would benefit from liver transplantation with good outcomes. Additional advances will come through early diagnosis and utilizing a combination of chemotherapy and locoregional modalities as a bridge to transplant. There is also a need to recognize and develop additional neo- and adjuvant therapies for patients whose tumor biology currently precludes their inclusion on the liver transplantation waitlist.
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23
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Arrichiello G, Nacca V, Paragliola F, Giunta EF. Liquid biopsy in biliary tract cancer from blood and bile samples: current knowledge and future perspectives. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2022; 3:362-374. [PMID: 36045913 PMCID: PMC9400719 DOI: 10.37349/etat.2022.00087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Accepted: 04/18/2022] [Indexed: 12/05/2022] Open
Abstract
Biliary tract cancer (BTC) is an aggressive tumor characterized by a poor prognosis. In the latest years, targetable genetic alterations have been discovered in BTC patients, leading to the approval of new targeted therapies. Liquid biopsy, which is a non-invasive method for detecting tumor biomarkers from fluid samples, is a useful tool for diagnosis and molecular characterization, but also for prognosis assessment and monitoring of treatment response. In this review, recent works on liquid biopsy in BTC patients were analyzed, focusing on some relevant aspects for clinical use and trying to depict the future role of this technique. Moreover, differences between plasma and bile samples were pointed out, in light of the peculiar biology of BTC and the possibility of using bile as an alternative source of cell-free DNA (cfDNA) for genomic analysis. In the era of precision oncology, the increasing adoption of liquid biopsy in BTC patients will certainly improve the management of this disease.
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Affiliation(s)
- Gianluca Arrichiello
- Oncology Unit, Department of Precision Medicine, Università degli Studi della Campania Luigi Vanvitelli, 80131 Naples, Italy
| | - Valeria Nacca
- Oncology Unit, Department of Precision Medicine, Università degli Studi della Campania Luigi Vanvitelli, 80131 Naples, Italy
| | - Fernando Paragliola
- Oncology Unit, Department of Precision Medicine, Università degli Studi della Campania Luigi Vanvitelli, 80131 Naples, Italy
| | - Emilio Francesco Giunta
- Department of Experimental Medicine, Università degli Studi della Campania Luigi Vanvitelli, 80138 Naples, Italy
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24
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Mukherji R, Yin C, Hameed R, Alqahtani AZ, Kulasekaran M, He AR, Weinberg BA, Marshall JL, Hartley ML, Noel MS. The current state of molecular profiling in gastrointestinal malignancies. Biol Direct 2022; 17:15. [PMID: 35668531 PMCID: PMC9172079 DOI: 10.1186/s13062-022-00322-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Accepted: 02/19/2022] [Indexed: 11/10/2022] Open
Abstract
This is a review of the current state of molecular profiling in gastrointestinal (GI) cancers and what to expect from this evolving field in the future. Individualized medicine is moving from broad panel testing of numerous genes or gene products in tumor biopsy samples, identifying biomarkers of prognosis and treatment response, to relatively noninvasive liquid biopsy assays, building on what we have learned in our tumor analysis and growing into its own evolving predictive and prognostic subspecialty. Hence, the field of GI precision oncology is exploding, and this review endeavors to summarize where we are now in preparation for the journey ahead.
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Affiliation(s)
- Reetu Mukherji
- The Ruesch Center for the Cure of GI Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 3800 Reservoir Rd. NW, Washington, DC, 20007, USA
- MedStar Georgetown University Hospital, 3800 Reservoir Rd. NW, Washington, DC, 20007, USA
| | - Chao Yin
- The Ruesch Center for the Cure of GI Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 3800 Reservoir Rd. NW, Washington, DC, 20007, USA
- MedStar Georgetown University Hospital, 3800 Reservoir Rd. NW, Washington, DC, 20007, USA
| | - Rumaisa Hameed
- The Ruesch Center for the Cure of GI Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 3800 Reservoir Rd. NW, Washington, DC, 20007, USA
- MedStar Georgetown University Hospital, 3800 Reservoir Rd. NW, Washington, DC, 20007, USA
| | - Ali Z Alqahtani
- The Ruesch Center for the Cure of GI Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 3800 Reservoir Rd. NW, Washington, DC, 20007, USA
- MedStar Georgetown University Hospital, 3800 Reservoir Rd. NW, Washington, DC, 20007, USA
| | - Monika Kulasekaran
- The Ruesch Center for the Cure of GI Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 3800 Reservoir Rd. NW, Washington, DC, 20007, USA
- MedStar Georgetown University Hospital, 3800 Reservoir Rd. NW, Washington, DC, 20007, USA
| | - Aiwu R He
- The Ruesch Center for the Cure of GI Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 3800 Reservoir Rd. NW, Washington, DC, 20007, USA
- MedStar Georgetown University Hospital, 3800 Reservoir Rd. NW, Washington, DC, 20007, USA
| | - Benjamin A Weinberg
- The Ruesch Center for the Cure of GI Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 3800 Reservoir Rd. NW, Washington, DC, 20007, USA
- MedStar Georgetown University Hospital, 3800 Reservoir Rd. NW, Washington, DC, 20007, USA
| | - John L Marshall
- The Ruesch Center for the Cure of GI Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 3800 Reservoir Rd. NW, Washington, DC, 20007, USA
- MedStar Georgetown University Hospital, 3800 Reservoir Rd. NW, Washington, DC, 20007, USA
| | - Marion L Hartley
- The Ruesch Center for the Cure of GI Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 3800 Reservoir Rd. NW, Washington, DC, 20007, USA
| | - Marcus S Noel
- The Ruesch Center for the Cure of GI Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 3800 Reservoir Rd. NW, Washington, DC, 20007, USA.
- MedStar Georgetown University Hospital, 3800 Reservoir Rd. NW, Washington, DC, 20007, USA.
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25
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Shen N, Zhu B, Zhang W, Nian B, Xu X, Yu L, Ruan X, Chen S, Liu Y, Cao X, Shi X, Li Z, Huang X, Wang X, Chen C, Xiong L, Zhang D, Fu X, Zhang Y. Comprehensive Evaluation and Application of a Novel Method to Isolate Cell-Free DNA Derived From Bile of Biliary Tract Cancer Patients. Front Oncol 2022; 12:891917. [PMID: 35600407 PMCID: PMC9116272 DOI: 10.3389/fonc.2022.891917] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 03/29/2022] [Indexed: 12/24/2022] Open
Abstract
Cell-free DNA (cfDNA) exists in various types of bodily fluids, including plasma, urine, bile, and others. Bile cfDNA could serve as a promising liquid biopsy for biliary tract cancer (BTC) patients, as bile directly contacts tumors in the biliary tract system. However, there is no commercial kit or widely acknowledged method for bile cfDNA extraction. In this study, we established a silica-membrane-based method, namely 3D-BCF, for bile cfDNA isolation, exhibiting effective recovery of DNA fragments in the spike-in assay. We then compared the 3D-BCF method with four other commercial kits: the BIOG cfDNA Easy Kit (BIOG), QIAamp DNA Mini Kit (Qiagen), MagMAXTM Cell-Free DNA Isolation Kit (Thermo Fisher), and NORGEN Urine Cell-Free Circulating DNA Purification Mini Kit (Norgen Biotek). The proposed 3D-BCF method exhibited the highest cfDNA isolation efficiency (p < 0.0001) from patient bile samples, and bile cfDNA of short, medium or long fragments could all be extracted effectively. To test whether the extracted bile cfDNA from patients carries tumor-related genomic information, we performed next-generation sequencing on the cfDNA and verified the gene-mutation results by polymerase chain reaction (PCR)-Sanger chromatograms and copy-number-variation (CNV) detection by fluorescence in situ hybridization (FISH) of tumor tissues. The 3D-BCF method could efficiently extract cfDNA from bile samples, providing technical support for bile cfDNA as a promising liquid biopsy for BTC patient diagnosis and prognosis.
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Affiliation(s)
- Ningjia Shen
- Department of Biliary Surgery, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University/Navy Medical University, Shanghai, China
| | - Bin Zhu
- Department of Biliary Surgery, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University/Navy Medical University, Shanghai, China
| | | | | | | | - Lianghe Yu
- Department of Biliary Surgery, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University/Navy Medical University, Shanghai, China
| | - Xiang Ruan
- Department of Biliary Surgery, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University/Navy Medical University, Shanghai, China
| | | | - Yang Liu
- Department of Biliary Surgery, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University/Navy Medical University, Shanghai, China
| | | | - Xintong Shi
- Department of Biliary Surgery, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University/Navy Medical University, Shanghai, China
| | | | - Xingfeng Huang
- Department of Biliary Surgery, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University/Navy Medical University, Shanghai, China
| | - Xiang Wang
- Department of Biliary Surgery, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University/Navy Medical University, Shanghai, China
| | | | | | | | - Xiaohui Fu
- Department of Biliary Surgery, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University/Navy Medical University, Shanghai, China
| | - Yongjie Zhang
- Department of Biliary Surgery, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University/Navy Medical University, Shanghai, China
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26
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Ohtsubo K, Miyake K, Arai S, Fukuda K, Suzuki C, Kotani H, Tanimoto A, Nishiyama A, Nanjo S, Yamashita K, Takeuchi S, Yano S. Methylation of Tumor Suppressive miRNAs in Plasma from Patients With Pancreaticobiliary Diseases. CANCER DIAGNOSIS & PROGNOSIS 2022; 2:378-383. [PMID: 35530650 PMCID: PMC9066530 DOI: 10.21873/cdp.10120] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Accepted: 03/04/2022] [Indexed: 06/14/2023]
Abstract
BACKGROUND/AIM We previously reported the usefulness of aberrant methylation of tumor suppressive miRNAs in bile to discriminate pancreaticobiliary cancers (PBCs) from benign pancreaticobiliary diseases (BD). Here we performed a methylation analysis of plasma miRNAs to identify miRNAs specific for PBCs. PATIENTS AND METHODS Plasma was collected from 80 patients with pancreatic cancer (PC); 18 with biliary tract cancer (BTC) and 28 with BD. Sequences encoding 3 tumor suppressive miRNAs (miR-200a, -200b, and -1247) were PCR amplified and sequenced, and their methylation rates were determined. RESULTS The methylation rate of miR-1247 was significantly higher in patients with BTC than in those with BD, and tended to be higher in patients with PC than in those with BD. Furthermore, it was significantly higher in three patients with stages I/II BTC than in those with BD. CONCLUSION Methylation of miR-1247 in plasma may be useful to distinguish BTC from BD.
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Affiliation(s)
- Koushiro Ohtsubo
- Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Kunio Miyake
- Department of Health Sciences, School of Medicine, University of Yamanashi, Chuo, Japan
| | - Sachiko Arai
- Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Koji Fukuda
- Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Chiaki Suzuki
- Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Hiroshi Kotani
- Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Azusa Tanimoto
- Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Akihiro Nishiyama
- Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Shigeki Nanjo
- Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Kaname Yamashita
- Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Shinji Takeuchi
- Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Seiji Yano
- Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
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27
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Losurdo G, Gravina AG, Maroni L, Gabrieletto EM, Ianiro G, Ferrarese A. Future challenges in gastroenterology and hepatology, between innovations and unmet needs: A SIGE Young Editorial Board's perspective. Dig Liver Dis 2022; 54:583-597. [PMID: 34509394 DOI: 10.1016/j.dld.2021.08.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 08/09/2021] [Accepted: 08/12/2021] [Indexed: 02/08/2023]
Abstract
Gastroenterology, Digestive Endoscopy and Hepatology have faced significant improvements in terms of diagnosis and therapy in the last decades. However, many fields still remain poorly explored, and many questions unanswered. Moreover, basic-science, as well as translational and clinical discoveries, together with technology advancement will determine further steps toward a better, refined care for many gastroenterological disorders in the future. Therefore, the Young Investigators of the Italian Society of Gastroenterology (SIGE) joined together, offering a perspective on major future innovations in some hot clinical topics in Gastroenterology, Endoscopy, and Hepatology, as well as the current pitfalls and the grey zones.
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Affiliation(s)
- Giuseppe Losurdo
- Gastroenterology Unit, Department of Emergency and Organ Transplantation, University 'Aldo Moro' of Bari; PhD Course in Organs and Tissues Transplantation and Cellular Therapies, Department of Emergency and Organ Transplantation, University 'Aldo Moro' of Bari.
| | - Antonietta Gerarda Gravina
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Luca Maroni
- Department of Gastroenterology, Marche Polytechnic University, Ancona, Italy
| | | | - Gianluca Ianiro
- Digestive Disease Center, Policlinico Universitario Agostino Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, Italy
| | - Alberto Ferrarese
- Gastroenterology and Hepatology, Azienda Ospedaliera Universitaria Integrata, Ospedale Borgo Trento, Verona, Italy
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28
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Uchihata Y, Arihiro K, Kaneko Y, Shimizu T, Marubashi Y, Aoki C, Murakami T, Ochi M, Niihara N, Ohtsuka K, Unehara R, Araki Y, Seki Y, Mori K, Oda M, Ishida K. Analysis of MicroRNA in Bile Cytologic Samples Is Useful for Detection and Diagnosis of Extrahepatic Cholangiocarcinoma. Am J Clin Pathol 2022; 158:122-131. [PMID: 35157005 DOI: 10.1093/ajcp/aqac015] [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: 09/19/2021] [Accepted: 01/13/2022] [Indexed: 11/13/2022] Open
Abstract
OBJECTIVES This study aimed to develop reliable biomarkers that improve the ability of bile cytology to diagnose cholangiocarcinoma vs benign biliary lesions. METHODS Many studies indicate that microRNAs (miRNAs) are potential candidates for the early diagnosis of cancer. We analyzed the expression of five tumor-associated miRNAs (miR-31-5p, miR-122-5p, miR-378d, miR-182-5p, and miR-92a-3p) in cytology samples using quantitative reverse transcription polymerase chain reaction. We collected 52 surgically resected tissue samples, 84 cytologic specimens from smears (53 cases of cancer and 31 cases of noncancer), and 40 residual sediments after smearing for routine cytology at Hiroshima University Hospital. RESULTS The expression of miR-31-5p, miR-378d, and miR-122-5p was significantly higher in cancer tissues than those in normal tissues, while miR-182-5p expression was lower. The expression of miR-31-5p, miR-378d, miR-182-5p, and miR-92a-3p was significantly higher in detached cell samples from smears of cholangiocarcinoma cases than in those from noncancer cases. CONCLUSIONS These results suggest that the analysis of miRNAs in bile cytologic specimens is a promising auxiliary tool for distinguishing cholangiocarcinoma from benign biliary lesions.
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Affiliation(s)
- Yukari Uchihata
- Department of Anatomical Pathology, Hiroshima University Hospital, Hiroshima, Japan
| | - Koji Arihiro
- Department of Anatomical Pathology, Hiroshima University Hospital, Hiroshima, Japan
| | - Yoshie Kaneko
- Department of Anatomical Pathology, Hiroshima University Hospital, Hiroshima, Japan
| | - Tomomi Shimizu
- Department of Anatomical Pathology, Hiroshima University Hospital, Hiroshima, Japan
| | - Yukari Marubashi
- Department of Anatomical Pathology, Hiroshima University Hospital, Hiroshima, Japan
| | - Chie Aoki
- Department of Anatomical Pathology, Hiroshima University Hospital, Hiroshima, Japan
| | - Takuya Murakami
- Department of Anatomical Pathology, Hiroshima University Hospital, Hiroshima, Japan
| | - Mayu Ochi
- Department of Anatomical Pathology, Hiroshima University Hospital, Hiroshima, Japan
| | - Nanaka Niihara
- Department of Anatomical Pathology, Hiroshima University Hospital, Hiroshima, Japan
| | - Kohei Ohtsuka
- Department of Anatomical Pathology, Hiroshima University Hospital, Hiroshima, Japan
| | - Rimu Unehara
- Department of Anatomical Pathology, Hiroshima University Hospital, Hiroshima, Japan
| | - Yusuke Araki
- Department of Molecular and Internal Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan
| | - Yoshinaga Seki
- Department of Anatomical Pathology, Hiroshima University Hospital, Hiroshima, Japan
| | - Keiichi Mori
- Department of Anatomical Pathology, Hiroshima University Hospital, Hiroshima, Japan
| | - Miyo Oda
- Department of Anatomical Pathology, Hiroshima University Hospital, Hiroshima, Japan
| | - Katsunari Ishida
- Department of Anatomical Pathology, Hiroshima University Hospital, Hiroshima, Japan
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29
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Manne A, Woods E, Tsung A, Mittra A. Biliary Tract Cancers: Treatment Updates and Future Directions in the Era of Precision Medicine and Immuno-Oncology. Front Oncol 2021; 11:768009. [PMID: 34868996 PMCID: PMC8634105 DOI: 10.3389/fonc.2021.768009] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Accepted: 10/13/2021] [Indexed: 12/12/2022] Open
Abstract
The effective management of biliary tract cancers (BTCs) has been hampered by limited options for systemic therapy. In recent years, the focus on precision medicine has made technologies such as next-generation sequencing (NGS) accessible to clinicians to identify targetable mutations in BTCs in tumor tissue (primarily) as well as blood, and to treat them with targeted therapies when possible. It has also expanded our understanding of functional pathways associated with genetic alterations and opened doors for identifying novel targets for treatment. Recent advances in the precision medicine approach allowed us to identify new molecular markers in BTCs, such as epigenetic changes (methylation and histone modification) and non-DNA markers such as messenger RNA, microRNA, and long non-coding RNA. It also made detecting these markers from non-traditional sources such as blood, urine, bile, and cytology (from fine-needle aspiration and biliary brushings) possible. As these tests become more accessible, we can see the integration of different molecular markers from all available sources to aid physicians in diagnosing, assessing prognosis, predicting tumor response, and screening BTCs. Currently, there are a handful of approved targeted therapies and only one class of immunotherapy agents (immune checkpoint inhibitors or ICIs) to treat BTCs. Early success with new targets, vascular endothelial growth factor receptor (VEGFR), HER2, protein kinase receptor, and Dickkopf-1 (DKK1); new drugs for known targets, fibroblast growth factor receptors (FGFRs) such as futabatinib, derazantinib, and erdafitinib; and ICIs such as durvalumab and tremelimumab is encouraging. Novel immunotherapy agents such as bispecific antibodies (bintrafusp alfa), arginase inhibitors, vaccines, and cellular therapy (chimeric antigen receptor-T cell or CAR-T, natural killer cells, tumor-infiltrating lymphocytes) have the potential to improve outcomes of BTCs in the coming years.
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Affiliation(s)
- Ashish Manne
- Department of Internal Medicine, Division of Medical Oncology at the Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center, Columbus, OH, United States
| | - Edward Woods
- Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH, United States
| | - Allan Tsung
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Cancer Hospital and Solove Research Institute, Columbus, OH, United States
| | - Arjun Mittra
- Department of Internal Medicine, Division of Medical Oncology at the Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center, Columbus, OH, United States
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30
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Gadour E, Hassan Z. Meta-analysis and systematic review of liver transplantation as an ultimate treatment option for secondary sclerosing cholangitis. PRZEGLAD GASTROENTEROLOGICZNY 2021; 17:1-8. [PMID: 35371357 PMCID: PMC8942010 DOI: 10.5114/pg.2021.110483] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Accepted: 02/28/2021] [Indexed: 11/19/2022]
Abstract
INTRODUCTION Secondary sclerosing cholangitis (SSC) is a chronic cholestatic biliary disease, characterized by inflammation, obliterative fibrosis of the bile ducts, stricture formation, and progressive destruction of the biliary tree, which leads to biliary cirrhosis. In recent years, the development of secondary sclerosing cholangitis in critically ill patients (SSC-CIP) has increasingly been perceived as a separate disease entity. AIM To perform a systematic review and meta-analysis of secondary sclerosing cholangitis and ischaemic cholangiopathy in post organ transplant patients and intensive care unit (ICU). MATERIAL AND METHODS A comprehensive search strategy using the PubMed, Biosis, and EMBASE databases was designed to retrieve relevant clinical data from the published literature up to 2020. Demographic characteristics, laboratory, transplantation, mortality rate, and follow-up data undergoing liver transplantation were extracted from the inclusion studies. We used DerSimonian-Laird random-effects meta-analysis. Analysis was carried out using R statistical software version 4.02. RESULTS A total of 862 patients with SSC-CIP were extracted from 16 studies. Eighteen studies were searched for the meta-analysis, out of which 16 studies were eligible for the meta-analysis and 2 were excluded. A proportion meta-analysis was performed on liver transplant patients with SSC-CIP and on mortality rate. Significant results were found (Prop = 0.30, 95% CI: 0.12-0.49, p < 0.01), with high heterogeneity among the studies (I 2 = 98%, p < 0.01) and (Prop = 0.45; 95% CI: 0.35-0.56 with I 2 = 80, p < 0.01), respectively. No indication of publication bias, as confirmed by the funnel plot and the risk of bias in the included studies, shows that the study reporting is adequate to judge that no major or minor sources of bias are likely to influence results. CONCLUSIONS The systematic review and meta-analysis show that liver transplantation is a valid option for patients with SSC-CIP, with excellent long-term outcome and improvement of quality of life.
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Affiliation(s)
- Eyad Gadour
- University Hospitals of Morecambe Bay NHS Foundation Trust, Lancaster, United Kingdom
| | - Zeinab Hassan
- Faculty of Medicine, The National Ribat University, Khartoum, Sudan
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Barrera-Saldaña HA, Fernández-Garza LE, Barrera-Barrera SA. Liquid biopsy in chronic liver disease. Ann Hepatol 2021; 20:100197. [PMID: 32444248 DOI: 10.1016/j.aohep.2020.03.008] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Accepted: 03/25/2020] [Indexed: 02/04/2023]
Abstract
Chronic liver diseases account for a considerable toll of incapacities, suffering, deaths, and resources of the nation's health systems. They can be prevented, treated or even cured when the diagnosis is made on time. Traditional liver biopsy remains the gold standard to diagnose liver diseases, but it has several limitations. Liquid biopsy is emerging as a superior alternative to surgical biopsy given that it surpasses the limitations: it is more convenient, readily and repeatedly accessible, safe, cheap, and provides a more detailed molecular and cellular representation of the individual patient's disease. Progress in understanding the molecular and cellular bases of diseased tissues and organs that normally release cells and cellular components into the bloodstream is catapulting liquid biopsy as a source of biomarkers for diagnosis, prognosis, and prediction of therapeutic response, thus supporting the realization of the promises of precision medicine. The review aims to summarize the evidence of the usefulness of liquid biopsy in liver diseases, including the presence of different biomarkers as circulating epithelial cells, cell-free nucleic acids, specific species of DNA and RNA, and the content of extracellular vesicles.
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Affiliation(s)
- Hugo A Barrera-Saldaña
- Innbiogem SC at National Laboratory for Services of Research, Development, and Innovation for the Pharma and Biotech Industries (LANSEDI) of CONACyT Vitaxentrum group, Monterrey, N.L., Mexico; Center for Biotechnological Genomics of National Polytechnical Institute, Reynosa, Tamps., Mexico.
| | - Luis E Fernández-Garza
- Innbiogem SC at National Laboratory for Services of Research, Development, and Innovation for the Pharma and Biotech Industries (LANSEDI) of CONACyT Vitaxentrum group, Monterrey, N.L., Mexico
| | - Silvia A Barrera-Barrera
- Innbiogem SC at National Laboratory for Services of Research, Development, and Innovation for the Pharma and Biotech Industries (LANSEDI) of CONACyT Vitaxentrum group, Monterrey, N.L., Mexico; National Institute of Pediatrics, Mexico City, Mexico
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Ney A, Garcia-Sampedro A, Goodchild G, Acedo P, Fusai G, Pereira SP. Biliary Strictures and Cholangiocarcinoma - Untangling a Diagnostic Conundrum. Front Oncol 2021; 11:699401. [PMID: 34660269 PMCID: PMC8515053 DOI: 10.3389/fonc.2021.699401] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Accepted: 09/15/2021] [Indexed: 12/12/2022] Open
Abstract
Cholangiocarcinoma is an uncommon and highly aggressive biliary tract malignancy with few manifestations until late disease stages. Diagnosis is currently achieved through a combination of clinical, biochemical, radiological and histological techniques. A number of reported cancer biomarkers have the potential to be incorporated into diagnostic pathways, but all lack sufficient sensitivity and specificity limiting their possible use in screening and early diagnosis. The limitations of standard serum markers such as CA19-9, CA125 and CEA have driven researchers to identify multiple novel biomarkers, yet their clinical translation has been slow with a general requirement for further validation in larger patient cohorts. We review recent advances in the diagnostic pathway for suspected CCA as well as emerging diagnostic biomarkers for early detection, with a particular focus on non-invasive approaches.
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Affiliation(s)
- Alexander Ney
- Institute for Liver and Digestive Health, University College London, London, United Kingdom
| | - Andres Garcia-Sampedro
- Institute for Liver and Digestive Health, University College London, London, United Kingdom
| | - George Goodchild
- St. Bartholomew's hospital, Barts Health NHS Trust, London, United Kingdom
| | - Pilar Acedo
- Institute for Liver and Digestive Health, University College London, London, United Kingdom
| | - Giuseppe Fusai
- Division of Surgery and Interventional Science - University College London, London, United Kingdom
| | - Stephen P Pereira
- Institute for Liver and Digestive Health, University College London, London, United Kingdom
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Martinez M, Perito ER, Valentino P, Mack CL, Aumar M, Broderick A, Draijer LG, Fagundes ED, Furuya KN, Gupta N, Horslen S, Jonas MM, Kamath BM, Kerkar N, Kim KM, Kolho KL, Koot BGP, Laborda TJ, Lee CK, Loomes KM, Miloh T, Mogul D, Mohammed S, Ovchinsky N, Rao G, Ricciuto A, Schwarz KB, Smolka V, Tanaka A, Tessier MEM, Venkat VL, Vitola BE, Woynarowski M, Zerofsky M, Deneau MR, Deneau MR. Recurrence of Primary Sclerosing Cholangitis After Liver Transplant in Children: An International Observational Study. Hepatology 2021; 74:2047-2057. [PMID: 34008252 PMCID: PMC8530456 DOI: 10.1002/hep.31911] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 05/11/2021] [Accepted: 05/12/2021] [Indexed: 12/28/2022]
Abstract
BACKGROUND AND AIMS Recurrent primary sclerosing cholangitis (rPSC) following liver transplant (LT) has a negative impact on graft and patient survival; little is known about risk factors for rPSC or disease course in children. APPROACH AND RESULTS We retrospectively evaluated risk factors for rPSC in 140 children from the Pediatric PSC Consortium, a multicenter international registry. Recipients underwent LT for PSC and had >90 days of follow-up. The primary outcome, rPSC, was defined using Graziadei criteria. Median follow-up after LT was 3 years (interquartile range 1.1-6.1). rPSC occurred in 36 children, representing 10% and 27% of the subjects at 2 years and 5 years following LT, respectively. Subjects with rPSC were younger at LT (12.9 vs. 16.2 years), had faster progression from PSC diagnosis to LT (2.5 vs. 4.1 years), and had higher alanine aminotransferase (112 vs. 66 IU/L) at LT (all P < 0.01). Inflammatory bowel disease was more prevalent in the rPSC group (86% vs. 66%; P = 0.025). After LT, rPSC subjects had more episodes of biopsy-proved acute rejection (mean 3 vs. 1; P < 0.001), and higher prevalence of steroid-refractory rejection (41% vs. 20%; P = 0.04). In those with rPSC, 43% developed complications of portal hypertension, were relisted for LT, or died within 2 years of the diagnosis. Mortality was higher in the rPSC group (11.1% vs. 2.9%; P = 0.05). CONCLUSIONS The incidence of rPSC in this cohort was higher than previously reported, and was associated with increased morbidity and mortality. Patients with rPSC appeared to have a more aggressive, immune-reactive phenotype. These findings underscore the need to understand the immune mechanisms of rPSC, to lay the foundation for developing new therapies and improve outcomes in this challenging population.
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Affiliation(s)
| | | | | | - Cara L Mack
- University of Colorado School of Medicine, Aurora, CO
| | | | - Annemarie Broderick
- Children’s Health Ireland at Crumlin & University College Dublin, Dublin, Ireland
| | | | | | - Katryn N. Furuya
- Mayo Clinic, Rochester, MN and Medical College of Wisconsin, Milwaukee, WI
| | - Nitika Gupta
- Emory University School of Medicine, Atlanta, GA
| | | | - Maureen M Jonas
- Boston Children’s Hospital and Harvard Medical School, Boston, MA
| | | | - Nanda Kerkar
- University of Rochester Medical Center, Rochester, NY
| | | | - Kaija-Leena Kolho
- University of Helsinki Hospital and Tampere University, Helsinki, Finland
| | - Bart GP Koot
- Amsterdam University Medical Center Amsterdam, The Netherlands
| | - Trevor J Laborda
- University of Utah and Intermountain Primary Children’s Hospital, Salt Lake City, UT
| | | | | | | | | | | | - Nadia Ovchinsky
- Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY
| | | | | | - Kathleen B Schwarz
- University of California San Diego, San Diego, CA and Johns Hopkins University, Baltimore, MD
| | | | | | | | | | | | - Marek Woynarowski
- Faculty of Medicine and Health Sciences, UJK Kielce, Poland (former IP CZD Warsaw)
| | | | - Mark R. Deneau
- University of Utah and Intermountain Primary Children’s Hospital, Salt Lake City, UT
| | - Mark R. Deneau
- Department of Pediatrics University of Utah and Intermountain Primary Children’s Hospital Salt Lake City UT
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[Influence of molecular pathology on oncological surgery of liver and bile duct tumors]. Chirurg 2021; 92:1003-1010. [PMID: 34519849 DOI: 10.1007/s00104-021-01495-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/03/2021] [Indexed: 10/20/2022]
Abstract
BACKGROUND Molecular pathology is increasingly being used to guide treatment in oncology. Approximately 25% of all hepatocellular carcinomas (HCC) and 50% of cholangiocarcinomas (CCA) present with known cancer-relevant mutations; however, the impact of the mutations on the treatment of these tumors is not yet sufficiently understood. PURPOSE To evaluate the current literature on molecular pathological advances in HCC/CCA and the potential impact on oncological surgery. MATERIAL AND METHODS A comprehensive search of the available literature on currently known molecular biomarkers in HCC/CCA was performed in PubMed and clinitrials.gov. Following review, the potential impact of these biomarkers on oncological surgery was analyzed and is discussed. CONCLUSION Molecular pathological investigations can be used to support the classification of tumors and to determine the dignity of HCC/CCA. Predictive molecular biomarkers are not yet established in routine diagnostics but can be used to individualize advanced oncological treatment.
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Next-Generation Biomarkers for Cholangiocarcinoma. Cancers (Basel) 2021; 13:cancers13133222. [PMID: 34203269 PMCID: PMC8269024 DOI: 10.3390/cancers13133222] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Revised: 06/16/2021] [Accepted: 06/22/2021] [Indexed: 12/13/2022] Open
Abstract
Simple Summary Early and non-invasive diagnosis of cholangiocarcinoma (CCA) is still challenging, thus largely contributing to the increased mortality rates observed worldwide. Consequently, several efforts have been made in order to report novel biomarkers for CCA, that would aid on diagnosis and also to predict prognosis and therapy response. We herein aim to provide an in-depth and critical revision on the next-generation biomarkers for CCA that have been recently proposed. Abstract The increasing mortality rates of cholangiocarcinoma (CCA) registered during the last decades are, at least in part, a result of the lack of accurate non-invasive biomarkers for early disease diagnosis, making the identification of patients who might benefit from potentially curative approaches (i.e., surgery) extremely challenging. The obscure CCA pathogenesis and associated etiological factors, as well as the lack of symptoms in patients with early tumor stages, highly compromises CCA identification and to predict tumor development in at-risk populations. Currently, CCA diagnosis is accomplished by the combination of clinical/biochemical features, radiological imaging and non-specific serum tumor biomarkers, although a tumor biopsy is still needed to confirm disease diagnosis. Furthermore, prognostic and predictive biomarkers are still lacking and urgently needed. During the recent years, high-throughput omics-based approaches have identified novel circulating biomarkers (diagnostic and prognostic) that might be included in large, international validation studies in the near future. In this review, we summarize and discuss the most recent advances in the field of biomarker discovery in CCA, providing new insights and future research directions.
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Ge X, Tang L, Wang Y, Wang N, Zhou J, Deng X, Zhong Y, Li Q, Wang F, Jiang G, Miao L. The diagnostic value of exosomal miRNAs in human bile of malignant biliary obstructions. Dig Liver Dis 2021; 53:760-765. [PMID: 33257140 DOI: 10.1016/j.dld.2020.11.010] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Revised: 11/05/2020] [Accepted: 11/09/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND Diagnosis of malignant biliary obstruction is complicated and lacks accuracy. Exosomes may be secreted by malignant tumors; intact miRNAs from exosomes might serve as potential biomarkers for the disease. AIM To identify exosomal microRNAs in human bile among benign and malignant biliary obstructions. METHODS Bile samples were collected from patients undergoing therapeutic endoscopic retrograde cholangiopancreatography for biliary obstruction. Exosome microRNAs were determined by RNA-sequencing in the discovery cohort, which comprising benign (n = 5) cases and malignant biliary obstruction (n = 5) cases. Then, the diagnostic performance of the two up-regulated microRNAs (mir-483-5p and mir-126-3p) of bile exosomes was verified by analysis of 82 patients with a diagnosis of malignant (n=37) or nonmalignant (n=45) biliary obstruction. RESULTS In both cohorts, the expressions of mir-483-5p and mir-126-3p were significantly higher in bile exosomes samples from patients with malignant biliary obstructions than controls. In the verification cohort, the two miRNAs can distinguished the benign and malignant groups with high diagnostic accuracy and specificity; the diagnostic values of the two microRNAs were better than serum carbohydrate antigen 19-9 (CA19-9), area under the curve (AUC) were 0.81 and 0.74. CONCLUSION The expression of exosomal mir-483-5p and mir-126-3p in the bile samples discriminates between patients with malignant and nonmalignant biliary obstructions. CLINICAL TRIAL REGISTRATION NO NCT03102268.
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Affiliation(s)
- Xianxiu Ge
- Institute of Digestive Endoscopy and Medical Center for Digestive Diseases, Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Lingyu Tang
- Institute of Digestive Endoscopy and Medical Center for Digestive Diseases, Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Youli Wang
- Department of Clinical Laboratory, Nanjing First Hospital, Nanjing, China
| | - Ni Wang
- Institute of Digestive Endoscopy and Medical Center for Digestive Diseases, Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jian Zhou
- Institute of Digestive Endoscopy and Medical Center for Digestive Diseases, Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xueting Deng
- Institute of Digestive Endoscopy and Medical Center for Digestive Diseases, Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yuan Zhong
- Institute of Digestive Endoscopy and Medical Center for Digestive Diseases, Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Quanpeng Li
- Institute of Digestive Endoscopy and Medical Center for Digestive Diseases, Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Fei Wang
- Institute of Digestive Endoscopy and Medical Center for Digestive Diseases, Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Guobin Jiang
- Institute of Digestive Endoscopy and Medical Center for Digestive Diseases, Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Lin Miao
- Institute of Digestive Endoscopy and Medical Center for Digestive Diseases, Second Affiliated Hospital of Nanjing Medical University, Nanjing, China.
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Rompianesi G, Di Martino M, Gordon-Weeks A, Montalti R, Troisi R. Liquid biopsy in cholangiocarcinoma: Current status and future perspectives. World J Gastrointest Oncol 2021; 13:332-350. [PMID: 34040697 PMCID: PMC8131901 DOI: 10.4251/wjgo.v13.i5.332] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 03/02/2021] [Accepted: 03/31/2021] [Indexed: 02/06/2023] Open
Abstract
Cholangiocarcinoma (CCA) are a heterogeneous group of tumors in terms of aetiology, natural history, morphological subtypes, molecular alterations and management, but all sharing complex diagnosis, management, and poor prognosis. Several mutated genes and epigenetic changes have been detected in CCA, with the potential to identify diagnostic and prognostic biomarkers and therapeutic targets. Accessing tumoral components and genetic material is therefore crucial for the diagnosis, management and selection of targeted therapies; but sampling tumor tissue, when possible, is often risky and difficult to be repeated at different time points. Liquid biopsy (LB) represents a way to overcome these issues and comprises a diverse group of methodologies centering around detection of tumor biomarkers from fluid samples. Compared to the traditional tissue sampling methods LB is less invasive and can be serially repeated, allowing a real-time monitoring of the tumor genetic profile or the response to therapy. In this review, we analysis the current evidence on the possible roles of LB (circulating DNA, circulating RNA, exosomes, cytokines) in the diagnosis and management of patients affected by CCA.
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Affiliation(s)
- Gianluca Rompianesi
- Hepato-Bilio-Pancreatic, Minimally Invasive and Robotic Surgery Unit, Department of Clinical Medicine and Surgery, Federico II University Hospital, Napoli 80131, Italy
| | - Marcello Di Martino
- Hepato-Bilio-Pancreatic Surgery Unit, Department of General and Digestive Surgery, Hospital Universitario La Princesa, Madrid 28006, Spain
| | - Alex Gordon-Weeks
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford OX3 9DU, United Kingdom
| | - Roberto Montalti
- Hepato-Bilio-Pancreatic, Minimally Invasive and Robotic Surgery Unit, Department of Clinical Medicine and Surgery, Federico II University Hospital, Napoli 80131, Italy
| | - Roberto Troisi
- Hepato-Bilio-Pancreatic, Minimally Invasive and Robotic Surgery Unit, Department of Clinical Medicine and Surgery, Federico II University Hospital, Napoli 80131, Italy
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Fung BM, Tabibian JH. Primary sclerosing cholangitis-associated cholangiocarcinoma: special considerations and best practices. Expert Rev Gastroenterol Hepatol 2021; 15:487-496. [PMID: 33682586 DOI: 10.1080/17474124.2021.1900732] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 03/05/2021] [Indexed: 10/22/2022]
Abstract
Introduction: Primary sclerosing cholangitis (PSC) is a rare, heterogenous, chronic cholestatic liver disease that causes fibro-inflammatory destruction of the intra- and/or extrahepatic bile ducts. The disease course may be variable, though in many cases it ultimately leads to biliary cirrhosis and its associated complications. PSC is also associated with malignancies, in particular cholangiocarcinoma (CCA), a dreaded neoplasm of the biliary tract with a poor prognosis. Risk stratification and surveillance for this malignancy are important components of the care of patients with PSC.Areas covered: In this review, we discuss important considerations in the clinical epidemiology, risk factors, diagnosis, and surveillance of PSC-associated CCA.Expert opinion: Despite growing awareness of PSC, high-quality evidence regarding the management of PSC and its associated risk of CCA remains limited. Early diagnosis of PSC-associated CCA remains difficult, and treatment options are limited, especially when diagnosed at later stages. The recent introduction of recommendations for CCA surveillance will likely improve outcomes, though an optimal surveillance approach has yet to be validated prospectively. Further research is needed in the development of high-accuracy (and noninvasive) surveillance and diagnostic tools that may facilitate earlier diagnosis of CCA and potential disease cure.
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Affiliation(s)
- Brian M Fung
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Arizona College of Medicine - Phoenix, Phoenix, AZ, USA
| | - James H Tabibian
- Division of Gastroenterology, Department of Medicine, Olive View-UCLA Medical Center, Sylmar, CA, USA
- David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
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Kim SY, Lee HS, Bang SM, Han DH, Hwang HK, Choi GH, Chung MJ, Kim SU. Serum Dickkopf-1 in Combined with CA 19-9 as a Biomarker of Intrahepatic Cholangiocarcinoma. Cancers (Basel) 2021; 13:1828. [PMID: 33921232 PMCID: PMC8069292 DOI: 10.3390/cancers13081828] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 04/06/2021] [Accepted: 04/08/2021] [Indexed: 02/06/2023] Open
Abstract
Dickkopf-related protein 1 (DKK-1) has a diagnostic and prognostic value in various malignant tumors. We investigated the diagnostic and prognostic performance of DKK-1 in combination with carbohydrate antigen 19-9 (CA 19-9) in cholangiocarcinoma (CCC) patients. Serum DKK-1 levels were measured using enzyme-linked immunosorbent assay. The receiver operating characteristic (ROC) curve, area under ROC (AUROC) analyses, Kaplan-Meier method, and Cox proportional hazard model were used to evaluate the diagnostic and prognostic performance of DKK-1 in combination with CA 19-9. We checked DKK-1 levels in 356 CCC patients and found that DKK-1 was significantly elevated only in 79 intrahepatic CCC (ICC) patients compared to controls (340.5 vs. 249.8 pg/mL, p = 0.002). The optimal cutoff level of DKK-1 used to identify ICC patients was 258.0 pg/mL (AUROC = 0.637, sensitivity = 59.5%, specificity = 56.9%, positive predictive value (PPV) = 40.5%, negative predictive value (NPV) = 74.0%, positive likelihood ratio (LR) = 1.38, and negative LR = 0.71). Using this cutoff, 47 (59.5%) patients were correctly diagnosed with ICC. DKK-1 in combination with CA 19-9 showed a better diagnostic performance (AUROC = 0.793, sensitivity = 74.7%, specificity = 56.3%, PPV = 45.7, NPV = 81.8, positive LR = 1.71, and negative LR = 0.45) than CA 19-9 alone. The low DKK-1 and CA 19-9 expression group had a significantly longer overall survival (OS) than the high expression group (p = 0.006). The higher level of DKK-1 and CA 19-9 was independently associated with shorter OS (hazard ratio = 3.077, 95% confidence interval 1.389-6.819, p = 0.006). The diagnostic and prognostic performance of DKK-1 in combination with CA 19-9 might be better than those of CA 19-9 alone in ICC patients.
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Affiliation(s)
- Si-Young Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 120-752, Korea; (S.-Y.K.); (H.-S.L.); (S.-M.B.)
| | - Hee-Seung Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 120-752, Korea; (S.-Y.K.); (H.-S.L.); (S.-M.B.)
| | - Seung-Min Bang
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 120-752, Korea; (S.-Y.K.); (H.-S.L.); (S.-M.B.)
| | - Dai-Hoon Han
- Department of Hepatobiliary and Pancreatic Surgery, Yonsei University College of Medicine, Seoul 120-752, Korea; (D.-H.H.); (H.-K.H.); (G.-H.C.)
| | - Ho-Kyoung Hwang
- Department of Hepatobiliary and Pancreatic Surgery, Yonsei University College of Medicine, Seoul 120-752, Korea; (D.-H.H.); (H.-K.H.); (G.-H.C.)
| | - Gi-Hong Choi
- Department of Hepatobiliary and Pancreatic Surgery, Yonsei University College of Medicine, Seoul 120-752, Korea; (D.-H.H.); (H.-K.H.); (G.-H.C.)
| | - Moon-Jae Chung
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 120-752, Korea; (S.-Y.K.); (H.-S.L.); (S.-M.B.)
| | - Seung-Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 120-752, Korea; (S.-Y.K.); (H.-S.L.); (S.-M.B.)
- Yonsei Liver Center, Severance Hospital, Seoul 120-752, Korea
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A High-Accuracy Model Based on Plasma miRNAs Diagnoses Intrahepatic Cholangiocarcinoma: A Single Center with 1001 Samples. Diagnostics (Basel) 2021; 11:diagnostics11040610. [PMID: 33805513 PMCID: PMC8066692 DOI: 10.3390/diagnostics11040610] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 03/20/2021] [Accepted: 03/26/2021] [Indexed: 12/13/2022] Open
Abstract
Objectives: Intrahepatic cholangiocarcinoma (iCCA) is a highly malignant cancer. More than 70% of patients are diagnosed at an advanced stage. The aim of this study was to evaluate the diagnostic value of plasma miR-21, miR-122, and CA19-9, hoping to establish a novel model to improve the accuracy for diagnosing iCCA. Materials and methods: Plasma miR-21 and miR-122 were detected in 359 iCCA patients and 642 controls (healthy, benign liver lesions, other malignant liver tumors). All 1001 samples were allocated to training cohort (n = 668) and validation cohort (n = 333) in a chronological order. A logistic regression model was applied to combine these markers. Area under the receiver operating characteristic curve (AUC) was used as an accuracy index to evaluate the diagnostic performance. Results: Plasma miR-21 and miR-122 were significantly higher in iCCA patients than those in controls. Higher plasma miR-21 level was significantly correlated with larger tumor size (p = 0.030). A three-marker model was constructed by using miR-21, miR-122 and CA19-9, which showed an AUC of 0.853 (95% CI: 0.824–0.879; sensitivity: 73.0%, specificity: 87.4%) to differentiate iCCA from controls. These results were subsequently confirmed in the validation cohort with an AUC of 0.866 (0.825–0.901). The results were similar for diagnosing early (stages 0–I) iCCA patients (AUC: 0.848) and CA19-9negative iCCA patients (AUC: 0.795). Conclusions: We established a novel three-marker model with a high accuracy based on a large number of participants to differentiate iCCA from controls. This model showed a great clinical value especially for the diagnosis of early iCCA and CA19-9negative iCCA.
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Adam-Artigues A, Garrido-Cano I, Simón S, Ortega B, Moragón S, Lameirinhas A, Constâncio V, Salta S, Burgués O, Bermejo B, Henrique R, Lluch A, Jerónimo C, Eroles P, Cejalvo JM. Circulating miR-30b-5p levels in plasma as a novel potential biomarker for early detection of breast cancer. ESMO Open 2021; 6:100039. [PMID: 33477007 PMCID: PMC7820029 DOI: 10.1016/j.esmoop.2020.100039] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2020] [Revised: 12/13/2020] [Accepted: 12/17/2020] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Recently, microRNAs have been demonstrated to be potential non-invasive biomarkers for diagnosis, prognosis assessment or prediction of response to treatment in cancer. In this study, we evaluate the potential of miR-30b-5p as a biomarker for early diagnosis of breast cancer (BC) in tissue and plasma. METHODS Expression of miR-30b-5p was determined in a series of 112 BC and 40 normal breast tissues. Circulating miR-30b-5p levels in plasma samples were determined in a discovery cohort of 38 BC patients and 40 healthy donors and in a validation cohort of 83 BC patients and 83 healthy volunteers. miR-30b-5p expression was measured by quantitative real-time PCR and receiver operating characteristics curve analysis was carried out. RESULTS The miR-30b-5p expression was significantly lower in BC tissue than in healthy breast samples. In contrast, circulating miR-30b-5p levels were significantly higher in BC patients compared with healthy donors. Furthermore, circulating miR-30b-5p levels were significantly higher in patients with positive axillary lymph node and de novo metastatic patients. Receiver operating characteristics curve analysis demonstrated a good diagnostic potential of miR-30b-5p to detect BC even at an early stage of the disease. CONCLUSION Thus, we highlight the potential of miR-30b-5p as a non-invasive, fast, reproducible and cost-effective diagnostic biomarker of BC.
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Affiliation(s)
| | | | - S Simón
- Biomedical Research Institute INCLIVA, Valencia, Spain; Clinical Oncology Department, Hospital Clínico Universitario de Valencia, Valencia, Spain
| | - B Ortega
- Biomedical Research Institute INCLIVA, Valencia, Spain; Clinical Oncology Department, Hospital Clínico Universitario de Valencia, Valencia, Spain
| | - S Moragón
- Biomedical Research Institute INCLIVA, Valencia, Spain; Clinical Oncology Department, Hospital Clínico Universitario de Valencia, Valencia, Spain
| | - A Lameirinhas
- Biomedical Research Institute INCLIVA, Valencia, Spain
| | - V Constâncio
- Cancer Biology and Epigenetics Group Research Center, Portuguese Oncology Institute of Porto (CI-IPOP), Porto, Portugal
| | - S Salta
- Cancer Biology and Epigenetics Group Research Center, Portuguese Oncology Institute of Porto (CI-IPOP), Porto, Portugal
| | - O Burgués
- Biomedical Research Institute INCLIVA, Valencia, Spain; Clinical Oncology Department, Hospital Clínico Universitario de Valencia, Valencia, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - B Bermejo
- Biomedical Research Institute INCLIVA, Valencia, Spain; Clinical Oncology Department, Hospital Clínico Universitario de Valencia, Valencia, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - R Henrique
- Cancer Biology and Epigenetics Group Research Center, Portuguese Oncology Institute of Porto (CI-IPOP), Porto, Portugal; Department of Pathology, Portuguese Oncology Institute of Porto, Porto, Portugal; Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar University of Porto (ICBAS-UP), Porto, Portugal
| | - A Lluch
- Clinical Oncology Department, Hospital Clínico Universitario de Valencia, Valencia, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain; Department of Medicine, Universitat de València, Valencia, Spain
| | - C Jerónimo
- Cancer Biology and Epigenetics Group Research Center, Portuguese Oncology Institute of Porto (CI-IPOP), Porto, Portugal; Department of Pathology, Portuguese Oncology Institute of Porto, Porto, Portugal; Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar University of Porto (ICBAS-UP), Porto, Portugal
| | - P Eroles
- Biomedical Research Institute INCLIVA, Valencia, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain; Department of Physiology, Universitat de València, València, Spain.
| | - J M Cejalvo
- Biomedical Research Institute INCLIVA, Valencia, Spain; Clinical Oncology Department, Hospital Clínico Universitario de Valencia, Valencia, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
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Mokhtari F, Mohebbi SR, Sharifian A, Ramandi M, Razzaghi MR. Circulating non-coding RNAs as potential diagnostic biomarkers in liver diseases. GASTROENTEROLOGY AND HEPATOLOGY FROM BED TO BENCH 2021; 14:S10-S23. [PMID: 35154598 PMCID: PMC8817748] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Accepted: 08/23/2021] [Indexed: 11/07/2022]
Abstract
The liver plays a principal role in the human body as a metabolic and detoxifying unit. Liver diseases are the world's major health problems and affect millions of people worldwide. Early detection of liver diseases is certainly effective in timely treatment and prevention of their progression. Liver injury is associated with significant alterations in immune responses and pattern changes in various tissue-related gene expressions and cytokine production. Increasing or decreasing the specific spectrum of non-coding RNAs in different phases of liver disease can be a criterion for diagnosis. Novel diagnostic biomarkers are needed for liver diseases. Currently, micro-RNAs (miRNAs) are known to play important roles in the diagnosis of liver diseases. Circulating biomarkers such as miRNA-assisted diagnosis can conceivably be helpful for the early treatment of liver diseases. In this review, we look at miRNAs and their potential applications in liver diseases as diagnostic biomarkers were investigated.
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Affiliation(s)
- Fedra Mokhtari
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Seyed Reza Mohebbi
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Afsaneh Sharifian
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Marzieh Ramandi
- Proteomics Research Center, Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Razzaghi
- Laser Application in Medical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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43
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Nault JC, Villanueva A. Biomarkers for Hepatobiliary Cancers. Hepatology 2021; 73 Suppl 1:115-127. [PMID: 32045030 DOI: 10.1002/hep.31175] [Citation(s) in RCA: 106] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Accepted: 01/28/2020] [Indexed: 12/25/2022]
Abstract
The clinical management of primary liver cancers such as hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) has significantly changed in the last 3 years. The introduction of systemic therapies, including immune-based therapies and biomarker-driven therapies, has significantly improved survival, particularly in patients at advanced stages of disease. Survival is still poor, and projections from the World Health Organization underscore the need to improve outcomes in these patients. Biomarkers have emerged as powerful tools for the diagnosis, prognosis, and prediction of treatment responses to improve patient stratification and maximize clinical benefits. Recent advances in understanding the molecular alterations of HCC have not yet translated into biomarkers. Some reasons for the lack of progress are the absence of druggable mutations in the majority of liver cancers and the significant heterogeneity of the disease. In contrast, several therapeutic targets have been identified in CCA, and biomarker-driven therapies are currently under evaluation in phase 2/3 clinical trials. Here, we summarize the status on biomarker development for HCC and CCA.
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Affiliation(s)
- Jean-Charles Nault
- Centre de Recherche des Cordeliers, Functional Genomics of Solid Tumors Laboratory, Sorbonne Université, Inserm, USPC, Université Paris Descartes, Université Paris Diderot, Université Paris 13, Paris, France.,Liver Unit, Hôpital Jean Verdier, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hôpitaux de Paris, Bondy, France.,Unité de Formation et de Recherche Santé Médecine et Biologie Humaine, Université Paris 13, Paris, France
| | - Augusto Villanueva
- Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, Liver Cancer Program, Tisch Cancer Institute, New York, NY.,Division of Hematology and Medical Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
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44
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Ofoeyeno N, Ekpenyong E, Braconi C. Pathogenetic Role and Clinical Implications of Regulatory RNAs in Biliary Tract Cancer. Cancers (Basel) 2020; 13:E12. [PMID: 33375055 PMCID: PMC7792779 DOI: 10.3390/cancers13010012] [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: 11/17/2020] [Revised: 12/18/2020] [Accepted: 12/19/2020] [Indexed: 02/07/2023] Open
Abstract
Biliary tract cancer (BTC) is characterised by poor prognosis and low overall survival in patients. This is generally due to minimal understanding of its pathogenesis, late diagnosis and limited therapeutics in preventing or treating BTC patients. Non-coding RNA (ncRNA) are small RNAs (mRNA) that are not translated to proteins. ncRNAs were considered to be of no importance in the genome, but recent studies have shown they play essential roles in biology and oncology such as transcriptional repression and degradation, thus regulating mRNA transcriptomes. This has led to investigations into the role of ncRNAs in the pathogenesis of BTC, and their clinical implications. In this review, the mechanisms of action of ncRNA are discussed and the role of microRNAs in BTC is summarised. The scope of this review will be limited to miRNA as they have been shown to play the most significant roles in BTC progression. There is huge potential in miRNA-based biomarkers and therapeutics in BTC, but more studies, research and technological advancements are required before it can be translated into clinical practice for patients.
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Affiliation(s)
- Nduka Ofoeyeno
- The Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK;
| | | | - Chiara Braconi
- The Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK;
- Beatson West of Scotland Cancer Centre, Glasgow G12 Y0N, UK
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45
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Song J, Li Y, Bowlus CL, Yang G, Leung PSC, Gershwin ME. Cholangiocarcinoma in Patients with Primary Sclerosing Cholangitis (PSC): a Comprehensive Review. Clin Rev Allergy Immunol 2020; 58:134-149. [PMID: 31463807 DOI: 10.1007/s12016-019-08764-7] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Cholangiocarcinoma (CCA) is the most common malignancy in patients with primary sclerosing cholangitis (PSC) and carries a high rate of mortality. Although the pathogenesis of CCA in PSC is largely unknown, inflammation-driven carcinogenesis concomitant with various genetic and epigenetic abnormalities are underlying factors. The majority of CCA cases develop from a dominant stricture (DS), which is defined as a stricture with a diameter < 1.5 mm in the common bile duct or < 1.0 mm in the hepatic duct. In PSC patients presenting with an abrupt aggravation of jaundice, pain, fatigue, pruritus, weight loss, or worsening liver biochemistries, CCA should be suspected and evaluated utilizing a variety of diagnostic modalities. However, early recognition of CCA in PSC remains a major challenge. Importantly, 30-50% of CCA in PSC patients are observed within the first year following the diagnosis of PSC followed by an annual incidence ranging from 0.5 to 1.5 per 100 persons, which is nearly 10 to 1000 times higher than that in the general population. Cumulative 5-year, 10-year, and lifetime incidences are 7%, 8-11%, and 9-20%, respectively. When PSC-associated CCA is diagnosed, most tumors are unresectable, and no effective medications are available. Given the poor therapeutic outcome, the surveillance and management of PSC patients who are at an increased risk of developing CCA are of importance. Such patients include older males with large-duct PSC and possibly concurrent ulcerative colitis. Thus, more attention should be paid to patients with these clinical features, in particular within the first year after PSC diagnosis. In contrast, CCA is less frequently observed in pediatric or female PSC patients or in those with small-duct PSC or concurrent Crohn's disease. Recently, new biomarkers such as antibodies to glycoprotein 2 have been found to be associated with an increased risk of developing CCA in PSC. Herein, we review the literature on the pathogenesis, incidence, clinical features, and risk factors, with a focus on various diagnostic modalities of PSC-associated CCA.
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Affiliation(s)
- Junmin Song
- Department of Gastroenterology, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004, Liaoning, People's Republic of China.,Division of Rheumatology, Allergy and Clinical Immunology, University of California, 451 Health Science Drive, Suite 6510, Davis, CA, 95616, USA
| | - Yang Li
- Department of Intensive Care Unit (ICU), Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, Liaoning, 110004, People's Republic of China
| | - Christopher L Bowlus
- Division of Gastroenterology and Hepatology, University of California, 451 Health Sciences Drive, Suite 6510, Davis, CA, 95616, USA
| | - GuoXiang Yang
- Division of Rheumatology, Allergy and Clinical Immunology, University of California, 451 Health Science Drive, Suite 6510, Davis, CA, 95616, USA
| | - Patrick S C Leung
- Division of Rheumatology, Allergy and Clinical Immunology, University of California, 451 Health Science Drive, Suite 6510, Davis, CA, 95616, USA.
| | - M Eric Gershwin
- Division of Rheumatology, Allergy and Clinical Immunology, University of California, 451 Health Science Drive, Suite 6510, Davis, CA, 95616, USA.
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Banales JM, Marin JJG, Lamarca A, Rodrigues PM, Khan SA, Roberts LR, Cardinale V, Carpino G, Andersen JB, Braconi C, Calvisi DF, Perugorria MJ, Fabris L, Boulter L, Macias RIR, Gaudio E, Alvaro D, Gradilone SA, Strazzabosco M, Marzioni M, Coulouarn C, Fouassier L, Raggi C, Invernizzi P, Mertens JC, Moncsek A, Ilyas SI, Heimbach J, Koerkamp BG, Bruix J, Forner A, Bridgewater J, Valle JW, Gores GJ. Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nat Rev Gastroenterol Hepatol 2020; 17:557-588. [PMID: 32606456 PMCID: PMC7447603 DOI: 10.1038/s41575-020-0310-z] [Citation(s) in RCA: 1489] [Impact Index Per Article: 297.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/29/2020] [Indexed: 02/07/2023]
Abstract
Cholangiocarcinoma (CCA) includes a cluster of highly heterogeneous biliary malignant tumours that can arise at any point of the biliary tree. Their incidence is increasing globally, currently accounting for ~15% of all primary liver cancers and ~3% of gastrointestinal malignancies. The silent presentation of these tumours combined with their highly aggressive nature and refractoriness to chemotherapy contribute to their alarming mortality, representing ~2% of all cancer-related deaths worldwide yearly. The current diagnosis of CCA by non-invasive approaches is not accurate enough, and histological confirmation is necessary. Furthermore, the high heterogeneity of CCAs at the genomic, epigenetic and molecular levels severely compromises the efficacy of the available therapies. In the past decade, increasing efforts have been made to understand the complexity of these tumours and to develop new diagnostic tools and therapies that might help to improve patient outcomes. In this expert Consensus Statement, which is endorsed by the European Network for the Study of Cholangiocarcinoma, we aim to summarize and critically discuss the latest advances in CCA, mostly focusing on classification, cells of origin, genetic and epigenetic abnormalities, molecular alterations, biomarker discovery and treatments. Furthermore, the horizon of CCA for the next decade from 2020 onwards is highlighted.
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Affiliation(s)
- Jesus M Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain.
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, "Instituto de Salud Carlos III"), San Sebastian, Spain.
- Ikerbasque, Basque Foundation for Science, Bilbao, Spain.
| | - Jose J G Marin
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, "Instituto de Salud Carlos III"), San Sebastian, Spain
- Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, University of Salamanca, Salamanca, Spain
| | - Angela Lamarca
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
- Division of Cancer Sciences, University of Manchester, Manchester, UK
| | - Pedro M Rodrigues
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
| | - Shahid A Khan
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK
| | - Lewis R Roberts
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
| | - Vincenzo Cardinale
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Guido Carpino
- Department of Movement, Human and Health Sciences, Division of Health Sciences, University of Rome "Foro Italico", Rome, Italy
| | - Jesper B Andersen
- Biotech Research and Innovation Centre (BRIC), Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Chiara Braconi
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Diego F Calvisi
- Institute of Pathology, University of Regensburg, Regensburg, Germany
| | - Maria J Perugorria
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, "Instituto de Salud Carlos III"), San Sebastian, Spain
| | - Luca Fabris
- Department of Molecular Medicine, University of Padua School of Medicine, Padua, Italy
- Digestive Disease Section, Yale University School of Medicine, New Haven, CT, USA
| | - Luke Boulter
- MRC-Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK
| | - Rocio I R Macias
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, "Instituto de Salud Carlos III"), San Sebastian, Spain
- Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, University of Salamanca, Salamanca, Spain
| | - Eugenio Gaudio
- Division of Human Anatomy, Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Domenico Alvaro
- Department of Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy
| | | | - Mario Strazzabosco
- Department of Molecular Medicine, University of Padua School of Medicine, Padua, Italy
- Digestive Disease Section, Yale University School of Medicine, New Haven, CT, USA
| | - Marco Marzioni
- Clinic of Gastroenterology and Hepatology, Universita Politecnica delle Marche, Ancona, Italy
| | | | - Laura Fouassier
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine (CRSA), Paris, France
| | - Chiara Raggi
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Pietro Invernizzi
- Division of Gastroenterology and Center of Autoimmune Liver Diseases, Department of Medicine and Surgery, San Gerardo Hospital, University of Milano, Bicocca, Italy
| | - Joachim C Mertens
- Department of Gastroenterology and Hepatology, University Hospital Zurich and University of Zurich, Zürich, Switzerland
| | - Anja Moncsek
- Department of Gastroenterology and Hepatology, University Hospital Zurich and University of Zurich, Zürich, Switzerland
| | - Sumera I. Ilyas
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
| | | | | | - Jordi Bruix
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, "Instituto de Salud Carlos III"), San Sebastian, Spain
- Barcelona Clinic Liver Cancer (BCLC) group, Liver Unit, Hospital Clínic of Barcelona, Fundació Clínic per a la Recerca Biomédica (FCRB), IDIBAPS, University of Barcelona, Barcelona, Spain
| | - Alejandro Forner
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, "Instituto de Salud Carlos III"), San Sebastian, Spain
- Barcelona Clinic Liver Cancer (BCLC) group, Liver Unit, Hospital Clínic of Barcelona, Fundació Clínic per a la Recerca Biomédica (FCRB), IDIBAPS, University of Barcelona, Barcelona, Spain
| | - John Bridgewater
- Department of Medical Oncology, UCL Cancer Institute, London, UK
| | - Juan W Valle
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
- Division of Cancer Sciences, University of Manchester, Manchester, UK
| | - Gregory J Gores
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
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Huang C, Xing X, Xiang X, Fan X, Men R, Ye T, Yang L. MicroRNAs in autoimmune liver diseases: from diagnosis to potential therapeutic targets. Biomed Pharmacother 2020; 130:110558. [PMID: 32781357 DOI: 10.1016/j.biopha.2020.110558] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 07/21/2020] [Accepted: 07/26/2020] [Indexed: 02/08/2023] Open
Abstract
Autoimmune liver diseases (AILDs) are a group of liver disorders composed of autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC) characterized by chronic hepatic and biliary inflammation. Although several genetic factors, such as HLA alleles, TNFA, and CTLA-4, have been reported in the pathogenesis of AILDs, many details remain unknown. In recent years, microRNAs (miRNAs) have emerged as crucial components in the diagnosis and therapeutic applications of various autoimmune diseases, including systemic lupus erythematosus (SLE), glomerulonephritis, and AILDs. MiRNAs comprise a class of small, noncoding molecules of 19--25 nucleotides that modulate multiple genes by suppressing or degrading target mRNAs. Altered miRNA profiles have been identified in serum, immune cells, and live tissues from AILD patients. Elevated serum miR-21 and miR-122 levels in AIH patients as well as decreased miR-200c levels in PSC patients indicate their diagnostic utility. Highly expressed miR-122 and miR-378f as well as downregulated miR-4311 and miR-4714-3p in serum samples from refractory PBC patients suggest their potential to evaluate treatment efficacy. Moreover, miRNAs have been reported to participate in AILD development. Increased miR-506 levels may impair bile secretion in PBC by inhibiting Cl-/HCO3-anion exchanger 2 (AE2) and type III inositol 1,4,5-trisphosphate receptor-3 (InsP3R3). Additionally, different miRNA mimics or antagonists, such as atagomiR-155 and miR-223 mimics, have been widely applied in experimental AILD murine models with great efficacy. Here, we provide an overview of miRNAs in AILDs, aiming to summarize their potential roles in diagnosis and therapeutic interventions, and we discuss the challenges and future applications of miRNAs in clinical practice.
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Affiliation(s)
- Chen Huang
- Department of Gastroenterology and Hepatology, Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, West China Hospital, Sichuan University, Chengdu, China
| | - Xian Xing
- Department of Gastroenterology and Hepatology, Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, West China Hospital, Sichuan University, Chengdu, China
| | - Xinyu Xiang
- Department of Gastroenterology and Hepatology, Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, West China Hospital, Sichuan University, Chengdu, China
| | - Xiaoli Fan
- Department of Gastroenterology and Hepatology, Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, West China Hospital, Sichuan University, Chengdu, China
| | - Ruoting Men
- Department of Gastroenterology and Hepatology, Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, West China Hospital, Sichuan University, Chengdu, China
| | - Tinghong Ye
- Laboratory of Liver Surgery, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
| | - Li Yang
- Department of Gastroenterology and Hepatology, Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, West China Hospital, Sichuan University, Chengdu, China.
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48
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Vedeld HM, Folseraas T, Lind GE. Detecting cholangiocarcinoma in patients with primary sclerosing cholangitis - The promise of DNA methylation and molecular biomarkers. JHEP Rep 2020; 2:100143. [PMID: 32939446 PMCID: PMC7479288 DOI: 10.1016/j.jhepr.2020.100143] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 06/25/2020] [Accepted: 06/30/2020] [Indexed: 02/07/2023] Open
Abstract
Cholangiocarcinoma (CCA) is a highly fatal malignancy of the bile ducts that arises in up to 20% of patients with primary sclerosing cholangitis (PSC). Current detection methods for CCA display suboptimal sensitivity and/or specificity, and there is no evidence-based screening strategy for CCA in patients with PSC. Consequently, CCA is often detected too late for surgical resection, contributing to the high mortality associated with this malignancy. Recently, biomarkers have emerged with potential to complement current detection methods, and/or be used for cancer surveillance in high-risk patient groups, including patients with PSC. Aberrant DNA methylation patterns represent promising biomarkers with great potential for CCA detection. Such aberrations are frequent in CCA, often occur early, and can be detected in liquid biopsies, including blood, bile and urine. This review summarises and highlights the most promising DNA methylation biomarkers identified for CCA detection so far, focusing on patients with PSC. Other promising molecular biomarkers for detection of PSC-associated CCA in liquid biopsies will also be briefly covered.
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Affiliation(s)
- Hege Marie Vedeld
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital - Norwegian Radium Hospital, Oslo, Norway.,K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway
| | - Trine Folseraas
- Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway.,Section of Gastroenterology, Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Guro Elisabeth Lind
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital - Norwegian Radium Hospital, Oslo, Norway.,K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway
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49
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Roles of miR-640 and Zinc Finger Protein 91 (ZFP91) in Angiopoietin-1-Induced In Vitro Angiogenesis. Cells 2020; 9:cells9071602. [PMID: 32630670 PMCID: PMC7408170 DOI: 10.3390/cells9071602] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 06/26/2020] [Accepted: 06/30/2020] [Indexed: 12/12/2022] Open
Abstract
Angiopoietin-1 (Ang-1) is a ligand of Tie-2 receptors that promotes angiogenesis. It has been established that regulatory loops exist between angiogenic growth factors and distinct pro or anti-angiogenic miRNAs, but the nature and the roles of Ang-1-regulated miRNAs remain unclear. In this study, we assessed the role of miR-640 in Ang-1-induced angiogenesis in human umbilical vein endothelial cells (HUVECs). Exposure to Ang-1 (300 ng/mL) from 6 to 72 h significantly decreased expression of mature miR-640, a response that was mediated by Tie-2 receptors and was also observed in response to Ang-2, the vascular endothelial growth factor, and transforming growth factor β. Increasing miR-640 levels using a mimic inhibited Ang-1-induced cell migration and capillary-like tube formation whereas inhibition of miR-640 enhanced these responses. Pull down assays of biotinylated miR-640 revealed that miR-640 directly targets Zinc Finger Protein 91 (ZFP91), an atypical E3-ubiquitin ligase. Ang-1 exposure induced ZFP91 expression through down-regulation of miR-640. Silencing of ZFP91 significantly inhibited Ang-1-induced cell migration and tube formation. We conclude that Ang-1 upregulates ZFP91 expression through transcriptional down-regulation of miR-640 and that ZFP91 plays important roles in the promotion of Ang-1-induced endothelial cell migration and differentiation.
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50
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Qin X, Song Y. Bioinformatics Analysis Identifies the Estrogen Receptor 1 (ESR1) Gene and hsa-miR-26a-5p as Potential Prognostic Biomarkers in Patients with Intrahepatic Cholangiocarcinoma. Med Sci Monit 2020; 26:e921815. [PMID: 32435051 PMCID: PMC7257878 DOI: 10.12659/msm.921815] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Background Intrahepatic cholangiocarcinoma arises from the epithelial cells of the bile ducts and is associated with poor prognosis. This study aimed to use bioinformatics analysis to identify molecular biomarkers of intrahepatic cholangiocarcinoma and their potential mechanisms. Material/Methods MicroRNA (miRNA) and mRNA microarrays from GSE53870 and GSE32879 were downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed miRNAs (DEMs) associated with prognosis were identified using limma software and Kaplan-Meier survival analysis. Predictive target genes of the DEMs were identified using miRWalk, miRTarBase, miRDB, and TargetScan databases of miRNA-binding sites and targets. Target genes underwent Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Hub genes were analyzed by constructing the protein-protein interaction (PPI) network using Cytoscape. DEMs validated the hub genes, followed by construction of the miRNA-gene regulatory network. Results Twenty-five DEMs were identified. Fifteen DEMs were upregulated, and ten were down-regulated. Kaplan-Meier survival analysis identified seven upregulated DEMs and nine down-regulated DEMs that were associated with the overall survival (OS), and 130 target genes were selected. GO analysis showed that target genes were mainly enriched for metabolism and development processes. KEGG analysis showed that target genes were mainly enriched for cancer processes and some signaling pathways. Fourteen hub genes identified from the PPI network were associated with the regulation of cell proliferation. The overlap between hub genes and DEMs identified the estrogen receptor 1 (ESR1) gene and hsa-miR-26a-5p. Conclusions Bioinformatics analysis identified ESR1 and hsa-miR-26a-5p as potential prognostic biomarkers for intrahepatic cholangiocarcinoma.
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Affiliation(s)
- Xianzheng Qin
- Queen Mary School of Nanchang University, Nanchang, Jiangxi, China (mainland)
| | - Yuning Song
- Queen Mary School of Nanchang University, Nanchang, Jiangxi, China (mainland)
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