|
1
|
Sha M, Wang J, Cao J, Zou ZH, Qu XY, Xi ZF, Shen C, Tong Y, Zhang JJ, Jeong S, Xia Q. Criteria and prognostic models for patients with hepatocellular carcinoma undergoing liver transplantation. Clin Mol Hepatol 2025; 31:S285-S300. [PMID: 39159949 PMCID: PMC11925443 DOI: 10.3350/cmh.2024.0323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 08/11/2024] [Accepted: 08/12/2024] [Indexed: 08/21/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-associated death globally. Liver transplantation (LT) has emerged as a key treatment for patients with HCC, and the Milan criteria have been adopted as the cornerstone of the selection policy. To allow more patients to benefit from LT, a number of expanded criteria have been proposed, many of which use radiologic morphological characteristics with larger and more tumors as surrogates to predict outcomes. Other groups developed indices incorporating biological variables and dynamic markers of response to locoregional treatment. These expanded selection criteria achieved satisfactory results with limited liver supplies. In addition, a number of prognostic models have been developed using clinicopathological characteristics, imaging radiomics features, genetic data, and advanced techniques such as artificial intelligence. These models could improve prognostic estimation, establish surveillance strategies, and bolster long-term outcomes in patients with HCC. In this study, we reviewed the latest findings and achievements regarding the selection criteria and post-transplant prognostic models for LT in patients with HCC.
Collapse
Affiliation(s)
- Meng Sha
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jun Wang
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jie Cao
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Zhi-Hui Zou
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Military Medical University, Shanghai, China
| | - Xiao-ye Qu
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Zhi-feng Xi
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Chuan Shen
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Ying Tong
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jian-jun Zhang
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Seogsong Jeong
- Department of Biomedical Informatics, Korea University College of Medicine, Seoul, Korea
| | - Qiang Xia
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| |
Collapse
|
|
2
|
Jakhete N, Majeed NA, Maluf D, Shetty K. The Role of Liver Transplantation in Hepatocellular Carcinoma. Clin Liver Dis 2025; 29:73-85. [PMID: 39608959 DOI: 10.1016/j.cld.2024.08.009] [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] [Indexed: 11/30/2024]
Abstract
Liver transplantation (LT) is the standard-of-care for early hepatocellular carcinoma (HCC). Current selection criteria depend primarily on measures of tumor burden and alpha-fetoprotein levels. Evolving strategies include the application of prognostic scores and the development of specialized molecular markers to predict recurrence. New technologies such as machine perfusion of donor organs are expected to dramatically improve the availability and access to LT in HCC.
Collapse
Affiliation(s)
- Neha Jakhete
- Division of Gastroenterology and Hepatology, Program in Transplantation, University of Maryland School of Medicine, 22 S. Greene Street, N3W50, Baltimore, MD 21201, USA
| | - Nehna Abdul Majeed
- Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, 22 S. Greene Street, N3W50, Baltimore, MD 21201, USA
| | - Daniel Maluf
- Department of Surgery, University of Maryland School of Medicine, Program in Transplantation, 22 S. Greene Street, Baltimore, MD 21201, USA
| | - Kirti Shetty
- Division of Gastroenterology and Hepatology, Program in Transplantation, University of Maryland School of Medicine, 22 S. Greene Street, N3W50, Baltimore, MD 21201, USA.
| |
Collapse
|
|
3
|
Badwei N. Molecular Clues for Prediction of Hepatocellular Carcinoma Recurrence After Liver Transplantation. J Clin Exp Hepatol 2023; 13:804-812. [PMID: 37693263 PMCID: PMC10482986 DOI: 10.1016/j.jceh.2023.02.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2022] [Accepted: 02/15/2023] [Indexed: 09/12/2023] Open
Abstract
Recurrence after liver transplantation (LT) for hepatocellular carcinoma (HCC) is one of the commonest causes of cancer-related mortality. Thus, advances in the HCC molecular features have paid researchers great attention to identifying the different risk factors that could aid in liver cancer initiation and progression for earlier prediction of post-operative HCC recurrence risk. Our review has focused on the possible molecular onco-drivers' for HCC recurrence post-LT that may represent diagnostic/prognostic tools and scoring models for the proper selection of LT candidates with HCC.
Collapse
Affiliation(s)
- Nourhan Badwei
- Tropical Medicine, Gastroenterology and Hepatology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| |
Collapse
|
|
4
|
Haque S, Bhushan Raman R, Salam M. Role of Biomarkers in Hepatocellular Carcinoma and Their Disease Progression. LIVER CANCER - GENESIS, PROGRESSION AND METASTASIS 2023. [DOI: 10.5772/intechopen.105856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the third leading and common lethal cancers worldwide. Early detection of tumorigenesis of hepatocellular carcinoma is through ultrasonography, computerized tomography (CT) scans, and magnetic resonance imaging (MRI) scans; however, these methods are not up to the mark, so a search for an efficient biomarker for early diagnosis and treatment of hepatocarcinogenesis is important. Proteomic and genomic approaches aid to develop new promising biomarkers for the diagnosis of HCC at the early stages. These biomarkers not only help in prognosis but also provide better therapeutic intervention against HCC. Among the different biomarker candidates, liquid biopsy [including circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA)] has recently emerged as a noninvasive detection technique for the characterization of circulating cells, providing a strong basis and early diagnosis for the individualized treatment of patients. This review provides the current understanding of HCC biomarkers that predict the risk of HCC recurrence.
Collapse
|
|
5
|
Kim SJ, Kim JM. Prediction models of hepatocellular carcinoma recurrence after liver transplantation: A comprehensive review. Clin Mol Hepatol 2022; 28:739-753. [PMID: 35468711 PMCID: PMC9597239 DOI: 10.3350/cmh.2022.0060] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 04/05/2022] [Accepted: 04/15/2022] [Indexed: 01/05/2023] Open
Abstract
Liver transplantation (LT) is one of the most effective treatments for hepatocellular carcinoma (HCC). Although LT eliminates HCC and greatly reduces recurrence, some patients experience recurrence after LT. Criteria and models for screening patients with a high probability of HCC recurrence after LT, starting with the Milan criteria, have been published. These models have changed over time, but a standard has not been established. We summarized HCC prediction models after LT by focusing on the application of radiologic, serologic, and pathologic factors and recent trends. This review will look at studies that are based on living donor LT and deceased donor LT, as well as studies that downstaging procedures have been performed preoperatively. This ultimately aims to help make decisions for evaluating the HCC state and selecting candidates for LT according to the circumstances of each transplantation center.
Collapse
Affiliation(s)
- Sang Jin Kim
- Department of Surgery, Korea University College of Medicine, Seoul, Korea
- Division of Hepatobiliopancreas and Transplant Surgery, Korea University Ansan Hospital, Republic of Korea, Ansan, Korea
| | - Jong Man Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| |
Collapse
|
|
6
|
Yang J, Dong W, Zhang H, Zhao H, Zeng Z, Zhang F, Li Q, Duan X, Hu Y, Xiao W. Exosomal microRNA panel as a diagnostic biomarker in patients with hepatocellular carcinoma. Front Cell Dev Biol 2022; 10:927251. [PMID: 36211468 PMCID: PMC9537616 DOI: 10.3389/fcell.2022.927251] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Accepted: 09/02/2022] [Indexed: 11/13/2022] Open
Abstract
Background: Diagnostic tools for hepatocellular carcinoma (HCC) are critical for patient treatment and prognosis. Thus, this study explored the diagnostic value of the exosomal microRNA panel for HCC.Methods: Expression profiles of microRNAs in exosomes and plasma of HCC and control groups were assessed using microRNA microarray analysis. Reverse transcription-quantitative PCR was applied to evaluate the expression of candidate microRNAs in blood samples from 50 HCC patients, 50 hepatic cirrhosis patients, and 50 healthy subjects. The area calculated the diagnostic accuracy of the microRNAs and microRNA panel under the receiver operating characteristic curve (AUC).Results: MicroRNA microarray analysis revealed that there were more differentially expressed microRNAs in the exosome HCC group than plasma HCC group. Among the 43 differentially expressed microRNAs contained in both exosomes and plasma, we finally decided to testify the expression and diagnostic significance of microRNA-26a, microRNA-29c, and microRNA-199a. The results indicated that expression of the microRNA-26a, microRNA-29c, and microRNA-199a in both exosomes and plasma was significantly lower in HCC patients compared with hepatic cirrhosis and healthy group. Interestingly, exosomal microRNAs were substantially more accurate in diagnosing HCC than microRNAs and alpha-fetoprotein in plasma. Moreover, the exosomal microRNA panel containing microRNA-26a, microRNA-29c, and microRNA-199a showed high accuracy in discriminating HCC from healthy (AUC = 0.994; sensitivity 100%; specificity 96%) and hepatic cirrhosis group (AUC = 0.965; sensitivity 92%; specificity 90%).Conclusion: This study revealed that the exosomal microRNA panel has high accuracy in diagnosing HCC and has important clinical significance.
Collapse
Affiliation(s)
- Jingwen Yang
- Senior Department of Oncology, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Weiwei Dong
- Senior Department of Oncology, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - He Zhang
- Department of Oncology, 4th Medical Center of PLA General Hospital, Beijing, China
| | - Huixia Zhao
- Department of Oncology, 4th Medical Center of PLA General Hospital, Beijing, China
| | - Zhiyan Zeng
- Department of Oncology, 4th Medical Center of PLA General Hospital, Beijing, China
| | - Fengyun Zhang
- Department of Oncology, 4th Medical Center of PLA General Hospital, Beijing, China
| | - Qiuwen Li
- Senior Department of Oncology, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Xiaohong Duan
- ChosenMed Technology (Beijing) Co., Ltd., Beijing, China
- *Correspondence: Xiaohong Duan, ; Yanyan Hu, ; Wenhua Xiao,
| | - Yanyan Hu
- Senior Department of Oncology, The Fifth Medical Center of PLA General Hospital, Beijing, China
- *Correspondence: Xiaohong Duan, ; Yanyan Hu, ; Wenhua Xiao,
| | - Wenhua Xiao
- Senior Department of Oncology, The Fifth Medical Center of PLA General Hospital, Beijing, China
- *Correspondence: Xiaohong Duan, ; Yanyan Hu, ; Wenhua Xiao,
| |
Collapse
|
|
7
|
Biomarkers for the Detection and Management of Hepatocellular Carcinoma in Patients Treated with Direct-Acting Antivirals. Cancers (Basel) 2022; 14:cancers14112700. [PMID: 35681679 PMCID: PMC9179595 DOI: 10.3390/cancers14112700] [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: 05/16/2022] [Revised: 05/24/2022] [Accepted: 05/25/2022] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Chronic Hepatitis C virus (HCV) represents the main etiological factor for hepatocellular carcinoma (HCC) in developed countries. The introduction of direct-acting antivirals (DAAs) improved the eradication of the hepatitis C virus (HCV) but not the reduction in the incidence of HCV-associated HCC. Some patients still develop HCC, even after reaching a sustained virological response (SVR). This review is a summary of pre-clinical studies that investigated predictive biomarkers for HCC occurrence and recurrence in HCV-infected patients treated with DAAs. The presented biomarkers are found dysregulated in serum or tissue at specific time points (before, during, after DAA treatment or post SVR) and correlated with HCC-predisposing conditions. Thus, this review aims to improve the management of patients developing HCV-induced HCC. Abstract Hepatocellular carcinoma (HCC) is the sixth-most common type of cancer worldwide and chronic Hepatitis C virus (HCV) represents the main etiological factor in developed countries. HCV promotes hepatocarcinogenesis through persistent liver inflammation and dysregulation of cell signaling pathways. The introduction of direct-acting antivirals (DAAs) resulted in a significant improvement in the eradication of the virus, with an expected reduction of HCC incidence. However, the risk of HCC development can persist after DAA treatment. Recent studies have investigated the potential use of molecular biomarkers that predict HCC occurrence or recurrence helping the stratification of patients under surveillance. This review aimed to summarize all pre-clinical exploration of predictive biomarkers to identify DAA-treated patients at risk for HCC development. Dysregulated microRNAs, lncRNAs, histone modifications, cytokines, proteins, and sphingolipids represent various classes of HCC risk predictors identified in two different biological sources (tissue and serum). The non-invasive serum markers can provide a more accessible means to perform clinical monitoring and predict the risk of HCC. In addition, conditions like cirrhosis, predisposing to HCC, strongly correlate with most of the molecular predictors identified, supporting the value of these molecules as possible biomarkers of HCC in DAA-treated patients.
Collapse
|
|
8
|
Mouchli M, Reddy S, Gerrard M, Boardman L, Rubio M. Usefulness of neutrophil-to-lymphocyte ratio (NLR) as a prognostic predictor after treatment of hepatocellular carcinoma." Review article. Ann Hepatol 2021; 22:100249. [PMID: 32896610 DOI: 10.1016/j.aohep.2020.08.067] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Revised: 08/07/2020] [Accepted: 08/08/2020] [Indexed: 02/06/2023]
Abstract
The neutrophil-to-lymphocyte ratio (NLR) is an inflammatory marker which has been investigated as a prognostic indicator in post-therapeutic recurrence and survival of patients with HCC. Our aim was to review all studies that assessed the prognostic value of pre-treatment NLR in predicting patient survival, cancer recurrence, and graft survival in patients undergoing various therapies for HCC. We searched the database of PubMed and Google Scholar to review all studies that have the word "NLR" and the word "HCC." We included all studies that assessed pre-treatment NLR as a prognostic factor in predicting outcomes in HCC patients. We excluded studies that assessed the correlation between post-treatment NLR or dynamic changes in NLR after treatment and HCC outcomes in an effort to minimize the confounding effect of each treatment on NLR. We reviewed 123 studies that studied the correlation between pre-treatment NLR and patient survival, 72 studies that evaluated the correlation between pre-treatment NLR and tumor recurrence, 21 studies that evaluated the correlation between NLR and tumor behavior, and 4 studies that assessed the correlation between NLR and graft survival. We found a remarkable heterogeneity between the methods of the studies, which is likely responsible for the differences in outcomes. The majority of the studies suggested a correlation between higher levels of pre-treatment NLR and poor outcomes. We concluded that NLR is a reliable and inexpensive biomarker and should be incorporated into other prognostic models to help determine outcomes following HCC treatment.
Collapse
Affiliation(s)
- Mohamad Mouchli
- Virginia Tech Carilion School of Medicine Department of Internal Medicine, Division of Gastroenterology & Hepatology, Roanoke, VA, United States; Virginia Tech Carilion School of Medicine Department of Internal Medicine, Roanoke, VA, United States; Mayo Clinic, Division of Gastroenterology & Hepatology, Rochester, MN, United States; Cleveland Clinic Foundation, Division of Gastroenterology & Hepatology, Cleveland, OH, United States.
| | - Shravani Reddy
- Virginia Tech Carilion School of Medicine Department of Internal Medicine, Roanoke, VA, United States
| | - Miranda Gerrard
- Virginia Tech Carilion School of Medicine, Roanoke, VA, United States
| | - Lisa Boardman
- Mayo Clinic, Division of Gastroenterology & Hepatology, Rochester, MN, United States
| | - Marrieth Rubio
- Virginia Tech Carilion School of Medicine Department of Internal Medicine, Division of Gastroenterology & Hepatology, Roanoke, VA, United States; Virginia Tech Carilion School of Medicine Department of Internal Medicine, Roanoke, VA, United States
| |
Collapse
|
|
9
|
Liu T, Shi Q, Yang L, Wang S, Song H, Wang Z, Xu X, Liu H, Zheng H, Shen Z. Long non-coding RNAs HERH-1 and HERH-4 facilitate cyclin A2 expression and accelerate cell cycle progression in advanced hepatocellular carcinoma. BMC Cancer 2021; 21:957. [PMID: 34445994 PMCID: PMC8390207 DOI: 10.1186/s12885-021-08714-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 08/18/2021] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND The advanced hepatocellular carcinoma (HCC), such as the recurrent tumor after liver transplantation (LT), is an obstacle of HCC treatment. The aim of this study was to discover the underlying mechanism of HCC progression caused by non-coding RNAs (ncRNAs). METHODS To this end, we investigated the selected patient cohort of matching primary and recurrent HCC after receiving LT. The recurrent tumors after LT were regarded as clinical models of the advanced HCC. Microarrays were used to profile lncRNA and mRNA expression in HCC recurrent and primary tissue samples. The mRNA profile characteristics were analyzed by bioinformatics. Two cell lines, HepG2 and QGY-7703, were used as HCC cell models. The protein-coding potential, length, and subcellular location of the interested lncRNAs were examined by bioinformatics, Northern blot, fluorescent in situ hybridization (FISH), and quantitative RT-PCR (qRT-PCR) assays. HCC cell proliferation was detected by CCK-8, doubling time and proliferation marker gene quantitation assays. DNA replication during the cell cycle was measured by EdU/PI staining and flow cytometry analyses. Promoter activity was measured using a luciferase reporter assay. Interactions between DNA, RNA, and protein were examined by immunoprecipitation and pull-down assays. The miRNA-target regulation was validated by a fluorescent reporter assay. RESULTS Both lncRNA and mRNA profiles exhibited characteristic alterations in the recurrent tumor cells compared with the primary HCC. The mRNA profile in the HCC recurrent tissues, which served as model of advanced HCC, showed an aberrant cell cycle regulation. Two lncRNAs, the highly expressed lncRNA in recurrent HCC (HERH)-1 and HERH-4, were upregulated in the advanced HCC cells. HERH-1/4 enhanced proliferation and promoted DNA replication and G1-S transition during the cell cycle in HCC cells. HERH-1 interacted with the transcription factor CREB1. CREB1 enhanced cyclin A2 (CCNA2) transcription, depending on HERH-1-CREB1 interaction. HERH-4 acted as an miR-29b/c sponge to facilitate CCNA2 protein translation through a competing endogenous RNA (ceRNA) pathway. CONCLUSIONS The oncogenic lncRNA HERH-1/4 promoted CCNA2 expression at the transcriptional and post-transcriptional levels and accelerated cell cycle progression in HCC cells. The HERH-1-CREB1-CCNA2 and HERH-4-miR-29b/c-CCNA2 axes served as molecular stimuli for HCC advance.
Collapse
Affiliation(s)
- Tao Liu
- National Health Commission's Key Laboratory of Critical Care Medicine, Tianjin First Central Hospital, School of Medicine, Nankai University, No. 24 Fukang Road, Nankai District, Tianjin, 300192, China.
- Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, 300192, China.
| | - Qiao Shi
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Lei Yang
- Department of Clinical Laboratory, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, 300192, China
| | - Shusen Wang
- National Health Commission's Key Laboratory of Critical Care Medicine, Tianjin First Central Hospital, School of Medicine, Nankai University, No. 24 Fukang Road, Nankai District, Tianjin, 300192, China
- Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, 300192, China
- Organ Transplant Center, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, 300192, China
| | - Hongli Song
- Organ Transplant Center, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, 300192, China
| | - Zhenglu Wang
- Biological Sample Resource Sharing Center (BSRSC), Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, 300192, China
| | - Xinnv Xu
- National Health Commission's Key Laboratory of Critical Care Medicine, Tianjin First Central Hospital, School of Medicine, Nankai University, No. 24 Fukang Road, Nankai District, Tianjin, 300192, China
| | - Hongsheng Liu
- National Health Commission's Key Laboratory of Critical Care Medicine, Tianjin First Central Hospital, School of Medicine, Nankai University, No. 24 Fukang Road, Nankai District, Tianjin, 300192, China
| | - Hong Zheng
- National Health Commission's Key Laboratory of Critical Care Medicine, Tianjin First Central Hospital, School of Medicine, Nankai University, No. 24 Fukang Road, Nankai District, Tianjin, 300192, China
- Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, 300192, China
- Organ Transplant Center, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, 300192, China
| | - Zhongyang Shen
- National Health Commission's Key Laboratory of Critical Care Medicine, Tianjin First Central Hospital, School of Medicine, Nankai University, No. 24 Fukang Road, Nankai District, Tianjin, 300192, China.
- Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, 300192, China.
- Organ Transplant Center, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, 300192, China.
| |
Collapse
|
|
10
|
Huang XC, Pang FX, Ou SS, Wei XJ, Xu YJ, Lai YH. Risk Score Based on Two microRNAs as a Prognostic Marker of Hepatocellular Carcinoma and the Corresponding Competitive Endogenous RNA Network. Int J Gen Med 2021; 14:3377-3385. [PMID: 34285562 PMCID: PMC8286150 DOI: 10.2147/ijgm.s318516] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Accepted: 06/28/2021] [Indexed: 12/15/2022] Open
Abstract
Purpose Liver transplantation (LT) currently yields the best outcomes for hepatocellular carcinoma (HCC). However, tumor recurrence still occurs in some patients. Identifying markers that predict HCC recurrence after LT is an unmet medical need. Methods In this study, differential expression analysis was used to identify differentially expressed microRNAs (DEmiRs) between HCC and liver tissues in the The Cancer Genome Atlas database and in data from patients with recurrent or non-recurrent HCC in the GSE64989 dataset. The expression profiles of the overlap DEmiRs were used to construct an miRNA-based risk score to predict prognosis using Cox regression analysis. The target genes of the miRNAs of interest were predicted, and they were analyzed for functional enrichment. Furthermore, we used the miRNAs of interest to construct a competitive endogenous RNA (ceRNA) network of long non-coding RNAs (lncRNAs), miRs and mRNAs. Results Four up-regulated and three down-regulated miRNAs in HCC and recurrent HCC after LT were considered as candidate miRs. MiR-3200-3p and miR-3690 were selected to construct the miR-based risk score, which was found to be associated with poor overall survival and progression-free survival. Furthermore, it proved to be an independent prognostic factor after adjusting for other clinicopathological factors. The corresponding ceRNA networks of these two miRs that we constructed may help to understand their regulatory mechanisms in HCC. Conclusion We propose a risk score based on miR-3200-3p and miR-3690 that may be useful as a prognostic marker to predict HCC recurrence after LT. We generated a ceRNA network involving these miRNAs, which may help reveal their regulatory roles in HCC.
Collapse
Affiliation(s)
- Xiao-Chun Huang
- Department of Transplantation, People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, 530021, People's Republic of China.,Guangxi Academy Of Medical Sciences, Nanning, Guangxi, 530021, People's Republic of China
| | - Fei-Xiong Pang
- Department of Transplantation, People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, 530021, People's Republic of China.,Guangxi Academy Of Medical Sciences, Nanning, Guangxi, 530021, People's Republic of China
| | - Sheng-Song Ou
- Department of Transplantation, People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, 530021, People's Republic of China.,Guangxi Academy Of Medical Sciences, Nanning, Guangxi, 530021, People's Republic of China
| | - Xiao-Jiao Wei
- Department of Transplantation, People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, 530021, People's Republic of China.,Guangxi Academy Of Medical Sciences, Nanning, Guangxi, 530021, People's Republic of China
| | - Yu-Ju Xu
- Department of Transplantation, People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, 530021, People's Republic of China.,Guangxi Academy Of Medical Sciences, Nanning, Guangxi, 530021, People's Republic of China
| | - Yan-Hua Lai
- Department of Transplantation, People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, 530021, People's Republic of China.,Guangxi Academy Of Medical Sciences, Nanning, Guangxi, 530021, People's Republic of China
| |
Collapse
|
|
11
|
Koch C, Bette T, Waidmann O, Filmann N, Schrecker C, Trojan J, Weiler N, Vermehren J, Schnitzbauer AA, Bechstein WO, Zeuzem S, Herrmann E, Welker MW. AFP ratio predicts HCC recurrence after liver transplantation. PLoS One 2020; 15:e0235576. [PMID: 32614912 PMCID: PMC7332004 DOI: 10.1371/journal.pone.0235576] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Accepted: 06/18/2020] [Indexed: 12/12/2022] Open
Abstract
Background/aims Hepatocellular carcinoma (HCC) is a leading indication for liver transplantation (LT) worldwide. Early identification of patients at risk for HCC recurrence is of paramount importance since early treatment of recurrent HCC after LT may be associated with increased survival. We evaluated incidence of and predictors for HCC recurrence, with a focus on the course of AFP levels. Methods We performed a retrospective, single-center study of 99 HCC patients who underwent LT between January 28th, 1997 and May 11th, 2016. A multi-stage proportional hazards model with three stages was used to evaluate potential predictive markers, both by univariate and multivariable analysis, for influences on 1) recurrence after transplantation, 2) mortality without HCC recurrence, and 3) mortality after recurrence. Results 19/99 HCC patients showed recurrence after LT. Waiting time was not associated with overall HCC recurrence (HR = 1, p = 0.979). Similarly, waiting time did not affect mortality in LT recipients both with (HR = 0.97, p = 0.282) or without (HR = 0.99, p = 0.685) HCC recurrence. Log10-transformed AFP values at the time of LT (HR 1.75, p = 0.023) as well as after LT (HR 2.07, p = 0.037) were significantly associated with recurrence. Median survival in patients with a ratio (AFP at recurrence divided by AFP 3 months before recurrence) of 0.5 was greater than 70 months, as compared to a median of only 8 months in patients with a ratio of 5. Conclusion A rise in AFP levels rather than an absolute threshold could help to identify patients at short-term risk for HCC recurrence post LT, which may allow intensification of the surveillance strategy on an individualized basis.
Collapse
Affiliation(s)
- Christine Koch
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt, Germany
- * E-mail:
| | - Theresa Bette
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt, Germany
| | - Oliver Waidmann
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt, Germany
| | - Natalie Filmann
- Institut für Biostatistik und Mathematische Modellierung, Universitätsklinikum Frankfurt, Frankfurt, Germany
| | | | - Jörg Trojan
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt, Germany
| | - Nina Weiler
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt, Germany
| | - Johannes Vermehren
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt, Germany
| | - Andreas A. Schnitzbauer
- Klinik für Allgemein- und Viszeralchirurgie, Universitätsklinikum Frankfurt, Frankfurt, Germany
| | - Wolf Otto Bechstein
- Klinik für Allgemein- und Viszeralchirurgie, Universitätsklinikum Frankfurt, Frankfurt, Germany
| | - Stefan Zeuzem
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt, Germany
| | - Eva Herrmann
- Institut für Biostatistik und Mathematische Modellierung, Universitätsklinikum Frankfurt, Frankfurt, Germany
| | | |
Collapse
|
|
12
|
von Felden J, Villanueva A. Role of Molecular Biomarkers in Liver Transplantation for Hepatocellular Carcinoma. Liver Transpl 2020; 26:823-831. [PMID: 32061009 DOI: 10.1002/lt.25731] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 01/23/2020] [Accepted: 02/06/2020] [Indexed: 12/13/2022]
Abstract
Patient selection and organ allocation for liver transplantation (LT) in patients with hepatocellular carcinoma (HCC) relies predominantly on clinical parameters, such as tumor burden (ie, radiological imaging). Patients transplanted within Milan criteria have outstanding outcomes with a 5- and 10-year survival of 70% and 55%, respectively. Tumor recurrence after transplantion is rare in these patients (10%); however, treatment options upon recurrence are generally limited, and outcomes are poor. There are also several studies showing how a subgroup of patients with tumors outside the Milan criteria might achieve comparable outcomes to patients within Milan criteria. In other words, the size and number of tumor nodules does not always reflect tumor biology, which could be better captured using molecular proxies for cancer aggressiveness. Over the last decade, we have significantly improved our understanding of the molecular landscape of early stage HCC. This includes the development of molecular classification, identification of prognostic and mutational signatures, and potential mechanisms of hepatocarcinogenesis. Some molecular markers have already proven useful to predict tumor-related outcomes in HCC patients after LT. Most of these analyses are limited to tissue-derived biomarkers, which limits their implementation in clinical practice because tissue biopsy is not required for HCC diagnosis. Minimally invasive alternative tools, such as liquid biopsy, are being increasingly explored and could help to individualize risk stratification for patients with HCC who will benefit from LT despite being outside the accepted clinical criteria.
Collapse
Affiliation(s)
- Johann von Felden
- Department of Internal Medicine, University Medical Center Hamburg Eppendorf, Hamburg, Germany
| | - Augusto Villanueva
- Division of Liver Diseases, Liver Cancer Program, Tisch Cancer Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.,Division of Hematology and Medical Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
| |
Collapse
|
|
13
|
Hu ZQ, Lu Y, Cui D, Ma CY, Shao S, Chen P, Tao R, Wang JJ. MicroRNAs and long non-coding RNAs in liver surgery: Diagnostic and therapeutic merits. Hepatobiliary Pancreat Dis Int 2020; 19:218-228. [PMID: 32414577 DOI: 10.1016/j.hbpd.2020.04.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Accepted: 04/09/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Hepatectomy and liver transplantation (LT) are the two most commonly performed surgical procedures for various hepatic lesions. microRNA (miRNA) and long non-coding RNA (lncRNA) have been gradually unveiled their roles as either biomarkers for early diagnosis or potentially therapeutic tools to manipulate gene expression in many disease entities. This review aimed to discuss the effects of miRNA or lncRNA in the hepatectomy and LT fields. DATA SOURCES We did a literature search from 1990 through January 2018 to summarize the currently available evidence with respect to the effects of miRNA and lncRNA in liver regeneration after partial hepatectomy, as well as their involvement in several key issues related to LT, including ischemia-reperfusion injury, allograft rejection, tolerance, recurrence of original hepatic malignancies, etc. RESULTS: Certain miRNAs and lncRNAs are actively involved in the regulation of various aspects of liver resection and transplantation. During the process of liver regeneration after hepatectomy, the expression of miRNAs and lncRNAs shows dynamic changes. CONCLUSIONS It is now clear that miRNAs and lncRNAs orchestrate in various aspects of the pathophysiological process of LT and hepatectomy. Better understanding of the underlying mechanism and future clinical trials may strengthen their positions as either biomarkers or potential therapeutic targets in the management of complications after liver surgery.
Collapse
Affiliation(s)
- Zhi-Qiu Hu
- Department of Surgery, Minhang Hospital, Fudan University, Shanghai 201199, China; Department of Hepatobiliary-Pancreatic & Minimally Invasive Surgery, Affiliated Zhejiang Provincial People's Hospital, Hangzhou Medical School, Hangzhou 310014, China
| | - Yi Lu
- Department of Hepatobiliary-Pancreatic & Minimally Invasive Surgery, Affiliated Zhejiang Provincial People's Hospital, Hangzhou Medical School, Hangzhou 310014, China; Center for Clinical Medical Research, Affiliated Zhejiang Provincial People's Hospital, Hangzhou Medical School, Hangzhou 310014, China
| | - Di Cui
- Center for Clinical Medical Research, Affiliated Zhejiang Provincial People's Hospital, Hangzhou Medical School, Hangzhou 310014, China
| | - Chen-Yang Ma
- Center for Clinical Medical Research, Affiliated Zhejiang Provincial People's Hospital, Hangzhou Medical School, Hangzhou 310014, China
| | - Su Shao
- Department of General Surgery, Chun'an 1st People's Hospital, Hangzhou 311700, China
| | - Ping Chen
- Department of Obstetrics and Gynecology, Shaoxing 2nd Hospital, Shaoxing 312000, China
| | - Ran Tao
- Department of Hepatobiliary-Pancreatic & Minimally Invasive Surgery, Affiliated Zhejiang Provincial People's Hospital, Hangzhou Medical School, Hangzhou 310014, China; Center for Clinical Medical Research, Affiliated Zhejiang Provincial People's Hospital, Hangzhou Medical School, Hangzhou 310014, China
| | - Jian-Jun Wang
- Department of General Surgery, Chun'an 1st People's Hospital, Hangzhou 311700, China.
| |
Collapse
|
|
14
|
Tohyama T, Sakamoto K, Tamura K, Nakamura T, Watanabe J, Wakisaka H, Takada Y. Pharyngeal metastasis following living-donor liver transplantation for hepatocellular carcinoma: a case report and literature review. World J Surg Oncol 2020; 18:109. [PMID: 32466780 PMCID: PMC7257203 DOI: 10.1186/s12957-020-01873-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Accepted: 05/06/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND The most common sites of recurrence after liver transplantation for hepatocellular carcinoma (HCC) have been reported to be the liver, lung, bone, and adrenal glands, but there have also been many reports of cases of multiple recurrence. The prognosis after recurrence is poor, with reported median survival after recurrence of HCC ranging from 9 to 19 months. Here, we report a case of long-term survival after recurrence of pharyngeal metastasis following living-donor liver transplantation (LDLT) for HCC within the Milan criteria, by resection of the metastatic region and cervical lymph node dissection. CASE PRESENTATION A 47-year-old man with a Model End-stage Liver Disease (MELD) score of 11 underwent LDLT for HCC within the Milan criteria for liver cirrhosis associated with hepatitis B virus infection, with his 48-year-old elder brother as the living donor. One year and 10 months after liver transplantation, he visited a nearby hospital with a chief complaint of discomfort on swallowing. A pedunculated polyp was found in the hypopharynx, and biopsy revealed HCC metastasis. We performed pharyngeal polypectomy. Two years later, cervical lymph node metastasis appeared, and neck lymph node dissection was performed. Although recurrence subsequently occurred three times in the grafted liver, the patient is still alive 12 years and 10 months after recurrence of pharyngeal metastasis. He is now a tumor-free outpatient taking sorafenib. CONCLUSION It is necessary to recognize that the nasopharyngeal region is a potential site of HCC metastasis. Prognostic improvement can be expected with close follow-up, early detection, and multidisciplinary treatment, including radical resection.
Collapse
Affiliation(s)
- Taiji Tohyama
- Department of Hepato-Biliary-Pancreatic and Breast Surgery, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan.
- Department of Surgery, Kurashiki Medical Center, Bakuro-cho, Kurashiki, Okayama, 710-8522, Japan.
| | - Katsunori Sakamoto
- Department of Hepato-Biliary-Pancreatic and Breast Surgery, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Kei Tamura
- Department of Hepato-Biliary-Pancreatic and Breast Surgery, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Taro Nakamura
- Department of Hepato-Biliary-Pancreatic and Breast Surgery, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Jota Watanabe
- Department of Hepato-Biliary-Pancreatic and Breast Surgery, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Hiroyuki Wakisaka
- Laboratory of Head and Neck Surgery, Ehime Prefectural University of Health Sciences, 543, Takoda, Tobe-cho, Iyo-gun, Ehime, 791-2101, Japan
| | - Yasutsugu Takada
- Department of Hepato-Biliary-Pancreatic and Breast Surgery, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan
| |
Collapse
|
|
15
|
Pascut D, Cavalletto L, Pratama MY, Bresolin S, Trentin L, Basso G, Bedogni G, Tiribelli C, Chemello L. Serum miRNA Are Promising Biomarkers for the Detection of Early Hepatocellular Carcinoma after Treatment with Direct-Acting Antivirals. Cancers (Basel) 2019; 11:1773. [PMID: 31717959 PMCID: PMC6895878 DOI: 10.3390/cancers11111773] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Revised: 11/01/2019] [Accepted: 11/08/2019] [Indexed: 02/07/2023] Open
Abstract
Direct antiviral agents (DAAs) have excellent efficacy against chronic hepatitis C virus (HCV) infection. Despite this strength, recent studies raised concerns about an unexpected hepatocellular carcinoma (HCC) occurrence rate after DAA therapy. In this exploratory case-control study, we evaluated the potential use of miRNAs as serum biomarkers for the detection of early HCC in DAA-treated patients. In the discovery phase, the circulating miRNome was assessed in 10 matched patients with (HCC+) or without HCC (HCC-) occurrence. Microarray analysis was performed before (T0) and after one month of the DAA therapy (T1). MiRNAs discriminating HCC+ and HCC- patients were validated in 60 samples by means of RT-qPCR. We estimated the time-averaged difference of a given miRNA between HCC+ and HCC- patients using a bootstrapped random-effect generalized least square regression model (RE-GLS). At T0, miR-1207-5p, miR-1275, miR-3197, miR-4443, miR-3178, miR-483-5p, miR-4706, miR-4793-3p and miR-1246 discriminated HCC+ from HCC- patients (p < 0.05). At T1, only miR-1180-3p, miR-1228-3p, miR-4329 and miR-4484 (p < 0.05) discriminated HCC+ from HCC- patients. The subsequent validation phase identified miR-3197 as changing with both disease and time. Our results suggest that patients might be already committed to HCC occurrence before DAA therapy. MiR-3197 shows some potential for the identification of patients at risk of HCC during DAA treatments.
Collapse
Affiliation(s)
- Devis Pascut
- Liver Research Center, Fondazione Italiana Fegato—ONLUS, AREA Science Park, Basovizza, 34149 Trieste, Italy; (M.Y.P.); (G.B.); (C.T.)
| | - Luisa Cavalletto
- Department of Internal Medicine—DIMED, University-Hospital of Padova, 35128 Padova, Italy; (L.C.); (L.C.)
| | - Muhammad Yogi Pratama
- Liver Research Center, Fondazione Italiana Fegato—ONLUS, AREA Science Park, Basovizza, 34149 Trieste, Italy; (M.Y.P.); (G.B.); (C.T.)
- Faculty of Medicine, Universitas Hasanuddin, Makassar 90245, Indonesia
| | - Silvia Bresolin
- Laboratory of Onco-Haematology, Department of Women’s and Children’s Health, University of Padova, 35128 Padova, Italy; (S.B.)
- Istituto di Ricerca Pediatrica—Città della Speranza, 35127 Padova, Italy
| | - Luca Trentin
- Laboratory of Onco-Haematology, Department of Women’s and Children’s Health, University of Padova, 35128 Padova, Italy; (S.B.)
| | - Giuseppe Basso
- IIGM Torino and Pediatric Hemato-Oncology, 10126 Torino, Italy;
| | - Giorgio Bedogni
- Liver Research Center, Fondazione Italiana Fegato—ONLUS, AREA Science Park, Basovizza, 34149 Trieste, Italy; (M.Y.P.); (G.B.); (C.T.)
| | - Claudio Tiribelli
- Liver Research Center, Fondazione Italiana Fegato—ONLUS, AREA Science Park, Basovizza, 34149 Trieste, Italy; (M.Y.P.); (G.B.); (C.T.)
| | - Liliana Chemello
- Department of Internal Medicine—DIMED, University-Hospital of Padova, 35128 Padova, Italy; (L.C.); (L.C.)
| |
Collapse
|
|
16
|
Brochado-Kith Ó, Gómez Sanz A, Real LM, Crespo García J, Ryan Murúa P, Macías J, Cabezas González J, Troya J, Pineda JA, Arias Loste MT, Díez Viñas V, Jiménez-Sousa MÁ, Medrano de Dios LM, Cuesta De la Plaza I, Monzón Fernández S, Resino García S, Fernández-Rodríguez A. MicroRNA Profile of HCV Spontaneous Clarified Individuals, Denotes Previous HCV Infection. J Clin Med 2019; 8:jcm8060849. [PMID: 31207946 PMCID: PMC6617112 DOI: 10.3390/jcm8060849] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Revised: 06/03/2019] [Accepted: 06/11/2019] [Indexed: 12/12/2022] Open
Abstract
Factors involved in the spontaneous cleareance of a hepatitis C (HCV) infection are related to both HCV and the interaction with the host immune system, but little is known about the consequences after a spontaneous resolution. The main HCV extrahepatic reservoir is the peripheral blood mononuclear cells (PBMCs), and their transcriptional profile provides us information of innate and adaptive immune responses against an HCV infection. MicroRNAs regulate the innate and adaptive immune responses, and they are actively involved in the HCV cycle. High Throughput sequencing was used to analyze the miRNA profiles from PBMCs of HCV chronic naïve patients (CHC), individuals that spontaneously clarified HCV (SC), and healthy controls (HC). We did not find any differentially expressed miRNAs between SC and CHC. However, both groups showed similar expression differences (21 miRNAs) with respect to HC. This miRNA signature correctly classifies HCV-exposed (CHC and SC) vs. HC, with the has-miR-21-3p showing the best performance. The potentially targeted molecular pathways by these 21 miRNAs mainly belong to fatty acids pathways, although hippo signaling, extracellular matrix (ECM) interaction, proteoglycans-related, and steroid biosynthesis pathways were also altered. These miRNAs target host genes involved in an HCV infection. Thus, an HCV infection promotes molecular alterations in PBMCs that can be detected after an HCV spontaneous resolution, and the 21-miRNA signature is able to identify HCV-exposed patients (either CHC or SC).
Collapse
Affiliation(s)
- Óscar Brochado-Kith
- Unit of Viral Infection and Immunity, National Center for Microbiology, Institute of Health Carlos III, Majadahonda, 28220 Madrid, Spain.
| | - Alicia Gómez Sanz
- Unit of Viral Infection and Immunity, National Center for Microbiology, Institute of Health Carlos III, Majadahonda, 28220 Madrid, Spain.
| | - Luis Miguel Real
- Unidad Clínica de Enfermedades Infecciosas, Hospital Universitario de Valme, 41014 Sevilla, Spain.
| | - Javier Crespo García
- Gastroenterology and Hepatology Department, Hospital Universitario Marques de Valdecilla, 39008 Santander, Spain.
- Institute Valdecilla (IDIVAL), School of Medicine, University of Cantabria, 39005 Santander, Spain.
| | - Pablo Ryan Murúa
- Internal Medicine Service, University Hospital Infanta Leonor, School of Medicine, Complutense University of Madrid, Gregorio Marañón Health Research Institute, 28009 Madrid, Spain.
| | - Juan Macías
- Unidad Clínica de Enfermedades Infecciosas, Hospital Universitario de Valme, 41014 Sevilla, Spain.
| | - Joaquín Cabezas González
- Gastroenterology and Hepatology Department, Hospital Universitario Marques de Valdecilla, 39008 Santander, Spain.
- Institute Valdecilla (IDIVAL), School of Medicine, University of Cantabria, 39005 Santander, Spain.
| | - Jesús Troya
- Internal Medicine Service, University Hospital Infanta Leonor, School of Medicine, Complutense University of Madrid, Gregorio Marañón Health Research Institute, 28009 Madrid, Spain.
| | - Juan Antonio Pineda
- Unidad Clínica de Enfermedades Infecciosas, Hospital Universitario de Valme, 41014 Sevilla, Spain.
| | - María Teresa Arias Loste
- Gastroenterology and Hepatology Department, Hospital Universitario Marques de Valdecilla, 39008 Santander, Spain.
- Institute Valdecilla (IDIVAL), School of Medicine, University of Cantabria, 39005 Santander, Spain.
| | - Victorino Díez Viñas
- Internal Medicine Service, University Hospital Infanta Leonor, School of Medicine, Complutense University of Madrid, Gregorio Marañón Health Research Institute, 28009 Madrid, Spain.
| | - María Ángeles Jiménez-Sousa
- Unit of Viral Infection and Immunity, National Center for Microbiology, Institute of Health Carlos III, Majadahonda, 28220 Madrid, Spain.
| | - Luz María Medrano de Dios
- Unit of Viral Infection and Immunity, National Center for Microbiology, Institute of Health Carlos III, Majadahonda, 28220 Madrid, Spain.
| | - Isabel Cuesta De la Plaza
- Bioinformatics Unit, Unidades Comunes Científico Técnicas, Institute of Health Carlos III, Majadahonda, 28220 Madrid, Spain.
| | - Sara Monzón Fernández
- Bioinformatics Unit, Unidades Comunes Científico Técnicas, Institute of Health Carlos III, Majadahonda, 28220 Madrid, Spain.
| | - Salvador Resino García
- Unit of Viral Infection and Immunity, National Center for Microbiology, Institute of Health Carlos III, Majadahonda, 28220 Madrid, Spain.
| | - Amanda Fernández-Rodríguez
- Unit of Viral Infection and Immunity, National Center for Microbiology, Institute of Health Carlos III, Majadahonda, 28220 Madrid, Spain.
| |
Collapse
|
|
17
|
Citores MJ, Lucena JL, de la Fuente S, Cuervas-Mons V. Serum biomarkers and risk of hepatocellular carcinoma recurrence after liver transplantation. World J Hepatol 2019; 11:50-64. [PMID: 30705718 PMCID: PMC6354126 DOI: 10.4254/wjh.v11.i1.50] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Revised: 11/13/2018] [Accepted: 12/05/2018] [Indexed: 02/06/2023] Open
Abstract
Liver transplantation (LT) is the only potentially curative treatment for selected patients with cirrhosis and hepatocellular carcinoma (HCC) who are not candidates for resection. When the Milan criteria are strictly applied, 75% to 85%of 3- to 4-year actuarial survival rates are achieved, but up to 20% of the patients experience HCC recurrence after transplantation. The Milan criteria are based on the preoperative tumor macromorphology, tumor size and number on computed tomography or magnetic resonance imaging that neither correlate well with posttransplant histological study of the liver explant nor accurately predict HCC recurrence after LT, since they do not include objective measures of tumor biology. Preoperative biological markers, including alpha-fetoprotein, des-gamma-carboxiprothrombin or neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio, can predict the risk for HCC recurrence after transplantation. These biomarkers have been proposed as surrogate markers of tumor differentiation and vascular invasion, with varied risk magnitudes depending on the defined cutoffs. Different studies have shown that the combination of one or several biomarkers integrated into prognostic models predict the risk of HCC recurrence after LT more accurately than Milan criteria alone. In this review, we focus on the potential utility of these serum biological markers to improve the performance of Milan criteria to identify patients at high risk of tumoral recurrence after LT.
Collapse
Affiliation(s)
- Maria J Citores
- Department of Internal Medicine, Instituto de Investigación Sanitaria Puerta de Hierro-Segovia de Arana, Majadahonda 28222, Spain.
| | - Jose L Lucena
- Liver Transplantation Unit, Hospital Universitario Puerta de Hierro-Majadahonda, Majadahonda 28222, Spain
| | - Sara de la Fuente
- Department of Internal Medicine, Hospital Universitario Puerta de Hierro-Majadahonda, Majadahonda 28222, Spain
| | - Valentin Cuervas-Mons
- Department of Internal Medicine, Hospital Universitario Puerta de Hierro-Majadahonda, Majadahonda 28222, Spain
| |
Collapse
|
|
18
|
Wen DY, Huang JC, Wang JY, Pan WY, Zeng JH, Pang YY, Yang H. Potential clinical value and putative biological function of miR-122-5p in hepatocellular carcinoma: A comprehensive study using microarray and RNA sequencing data. Oncol Lett 2018; 16:6918-6929. [PMID: 30546424 PMCID: PMC6256359 DOI: 10.3892/ol.2018.9523] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Accepted: 12/12/2017] [Indexed: 02/07/2023] Open
Abstract
In order to determine the diagnostic efficacy of microRNA (miR)-122-5p and to identify the potential molecular signaling pathways underlying the function of miR-122-5p in hepatocellular carcinoma (HCC), the expression profiles of data collected from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) and literature databases were analyzed, along with any associations between clinicopathological characteristics and the diagnostic value of miR-122-5p in HCC. The intersection of 12 online prediction databases and differentially expressed genes from TCGA and GEO were utilized in order to select the prospective target genes of miR-122-5p in HCC. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and protein-protein interaction network (PPI) analyses were subsequently performed based on the selected target genes. The average expression level of miR-122-5p was decreased in HCC patients compared with controls from TCGA database (P<0.001), and the downregulation of miR-122-5p was significantly associated with HCC tissues (P<0.001), tumor vascular invasion (P<0.001), metastasis (P=0.001), sex (P=0.006), virus infection status (P=0.001) and tissue (compared with serum; P<0.001) in cases from the GEO database. The pooled sensitivity and specificity for miR-122-5p to diagnose HCC were 0.60 [95% confidence interval (CI), 0.48–0.71] and 0.81 (95% CI, 0.70–0.89), respectively. The area under the curve (AUC) value was 0.76 (95% CI, 0.72–0.80), while in Meta-DiSc 1.4, the AUC was 0.76 (Q*=0.70). The pooled sensitivity and specificity were 0.60 (95% CI, 0.57–0.62) and 0.79 (95% CI, 0.76–0.81), respectively. A total of 198 overlapping genes were selected as the potential target genes of miR-122-5p, and 7 genes were defined as the hub genes from the PPI network. Cell division cycle 6 (CDC6), minichromosome maintenance complex component 4 (MCM4) and MCM8, which serve pivotal functions in the occurrence and development of HCC, were the most significant hub genes. The regulation of cell proliferation for cellular adhesion and the biosynthesis of amino acids was highlighted in the GO and KEGG pathway analyses. The downregulation of miR-122-5p in HCC demonstrated diagnostic value, worthy of further attention. Therefore, miR-122-5p may function as a tumor suppressor by modulating genome replication.
Collapse
Affiliation(s)
- Dong-Yue Wen
- Department of Medical Ultrasonics, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Jia-Cheng Huang
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Jie-Yu Wang
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Wen-Ya Pan
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Jiang-Hui Zeng
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Yu-Yan Pang
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Hong Yang
- Department of Medical Ultrasonics, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| |
Collapse
|
|
19
|
Pavel MC, Fuster J. Expansion of the hepatocellular carcinoma Milan criteria in liver transplantation: Future directions. World J Gastroenterol 2018; 24:3626-3636. [PMID: 30166858 PMCID: PMC6113720 DOI: 10.3748/wjg.v24.i32.3626] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2018] [Revised: 06/24/2018] [Accepted: 06/30/2018] [Indexed: 02/06/2023] Open
Abstract
Milan criteria are currently the benchmark related to liver transplantation (LT) for hepatocellular carcinoma. However, several groups have proposed different expanded criteria with acceptable results. In this article, we review the current status of LT beyond the Milan criteria in three different scenarios-expanded criteria with cadaveric LT, downstaging to Milan criteria before LT, and expansion in the context of adult living donor LT. The review focuses on three main questions: what would the impact of the expansion beyond Milan criteria be on the patients on the waiting list; whether the dichotomous criteria (yes/no) currently used are appropriate for LT or continuous survival estimations, such as the one of “Metroticket” and whether it should enter into the clinical practice; and, whether the use of living donor LT in the context of expansion beyond Milan criteria is justified.
Collapse
Affiliation(s)
- Mihai-Calin Pavel
- HepatoBilioPancreatic Surgery and Transplant Unit, Department of Surgery, Digestive and Metabolic Diseases Institute, Hospital Clínic, University of Barcelona, Barcelona, Catalonia 08036, Spain
| | - Josep Fuster
- HepatoBilioPancreatic Surgery and Transplant Unit, Department of Surgery, Digestive and Metabolic Diseases Institute, Hospital Clínic, University of Barcelona, Barcelona, Catalonia 08036, Spain
- Barcelona-Clínic Liver Cancer Group (BCLC), Liver Unit, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBEREHD, Universitat de Barcelona, Barcelona, Catalonia 08036, Spain
| |
Collapse
|
|
20
|
Fu Q, Yang F, Xiang T, Huai G, Yang X, Wei L, Yang H, Deng S. A novel microRNA signature predicts survival in liver hepatocellular carcinoma after hepatectomy. Sci Rep 2018; 8:7933. [PMID: 29785036 PMCID: PMC5962561 DOI: 10.1038/s41598-018-26374-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Accepted: 05/10/2018] [Indexed: 12/12/2022] Open
Abstract
Liver hepatocellular carcinoma (LIHC) is the most common type of primary liver cancer. In the current study, genome-wide miRNA-Seq and mRNA profiles in 318 LIHC patients derived from The Cancer Genome Atlas (TCGA) were analysed to identify miRNA-based signatures for LIHC prognosis with survival analysis and a semi-supervised principal components (SPC) method. A seven-miRNA signature was confirmed for overall survival (OS) prediction by comparing miRNA profiles in paired primary tumour and solid tumour normal tissues. Thereafter, a linear prognostic model that consisted of seven miRNAs was established and used to divide patients into high- and low-risk groups according to prognostic scores. Subsequent Kaplan-Meier analysis revealed that the seven-miRNA signature correlated with a good predictive clinical outcome for 5-year survival in LIHC patients. Additionally, this miRNA-based prognostic model could also be used for OS prognosis of LIHC patients in early stages, which could guide the future therapy of those patients and promote the OS rate. Moreover, the seven-miRNA signature was an independent prognostic factor. In conclusion, this signature may serve as a prognostic biomarker and guide LIHC therapy, and it could even be used as an LIHC therapeutic target in the future.
Collapse
Affiliation(s)
- Qiang Fu
- Organ Transplantation Center, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, Sichuan, China.,Organ Transplantation Translational Medicine Key Laboratory of Sichuan Province, Chengdu, 610072, Sichuan, China
| | - Fan Yang
- Women and Children Health Care Center of Luoyang, Luoyang, 471000, Henan, China
| | - Tengxiao Xiang
- People's Hospital of Changshou Chongqing, Chongqing, 401220, China
| | - Guoli Huai
- Organ Transplantation Center, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, Sichuan, China.,Organ Transplantation Translational Medicine Key Laboratory of Sichuan Province, Chengdu, 610072, Sichuan, China
| | - Xingxing Yang
- Organ Transplantation Center, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, Sichuan, China.,Organ Transplantation Translational Medicine Key Laboratory of Sichuan Province, Chengdu, 610072, Sichuan, China
| | - Liang Wei
- Organ Transplantation Center, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, Sichuan, China.,Organ Transplantation Translational Medicine Key Laboratory of Sichuan Province, Chengdu, 610072, Sichuan, China
| | - Hongji Yang
- Organ Transplantation Center, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, Sichuan, China. .,Organ Transplantation Translational Medicine Key Laboratory of Sichuan Province, Chengdu, 610072, Sichuan, China.
| | - Shaoping Deng
- Organ Transplantation Center, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, Sichuan, China. .,Organ Transplantation Translational Medicine Key Laboratory of Sichuan Province, Chengdu, 610072, Sichuan, China. .,Human Islet Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, 02114, MA, USA.
| |
Collapse
|
|
21
|
He RQ, Yang X, Liang L, Chen G, Ma J. MicroRNA-124-3p expression and its prospective functional pathways in hepatocellular carcinoma: A quantitative polymerase chain reaction, gene expression omnibus and bioinformatics study. Oncol Lett 2018; 15:5517-5532. [PMID: 29552191 PMCID: PMC5840674 DOI: 10.3892/ol.2018.8045] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2017] [Accepted: 12/14/2017] [Indexed: 12/24/2022] Open
Abstract
The present study aimed to explore the potential clinical significance of microRNA (miR)-124-3p expression in the hepatocarcinogenesis and development of hepatocellular carcinoma (HCC), as well as the potential target genes of functional HCC pathways. Reverse transcription-quantitative polymerase chain reaction was performed to evaluate the expression of miR-124-3p in 101 HCC and adjacent non-cancerous tissue samples. Additionally, the association between miR-124-3p expression and clinical parameters was also analyzed. Differentially expressed genes identified following miR-124-3p transfection, the prospective target genes predicted in silico and the key genes of HCC obtained from Natural Language Processing (NLP) were integrated to obtain potential target genes of miR-124-3p in HCC. Relevant signaling pathways were assessed with protein-protein interaction (PPI) networks, Gene Ontology (GO) enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) and Protein Annotation Through Evolutionary Relationships (PANTHER) pathway enrichment analysis. miR-124-3p expression was significantly reduced in HCC tissues compared with expression in adjacent non-cancerous liver tissues. In HCC, miR-124-3p was demonstrated to be associated with clinical stage. The mean survival time of the low miR-124-3p expression group was reduced compared with that of the high expression group. A total of 132 genes overlapped from differentially expressed genes, miR-124-3p predicted target genes and NLP identified genes. PPI network construction revealed a total of 109 nodes and 386 edges, and 20 key genes were identified. The major enriched terms of three GO categories included regulation of cell proliferation, positive regulation of cellular biosynthetic processes, cell leading edge, cytosol and cell projection, protein kinase activity, transcription activator activity and enzyme binding. KEGG analysis revealed pancreatic cancer, prostate cancer and non-small cell lung cancer as the top three terms. Angiogenesis, the endothelial growth factor receptor signaling pathway and the fibroblast growth factor signaling pathway were identified as the most significant terms in the PANTHER pathway analysis. The present study confirmed that miR-124-3p acts as a tumor suppressor in HCC. miR-124-3p may target multiple genes, exerting its effect spatiotemporally, or in combination with a diverse range of processes in HCC. Functional characterization of miR-124-3p targets will offer novel insight into the molecular changes that occur in HCC progression.
Collapse
Affiliation(s)
- Rong-Quan He
- Department of Medical Oncology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Xia Yang
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Liang Liang
- Department of General Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Gang Chen
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Jie Ma
- Department of Medical Oncology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| |
Collapse
|
|
22
|
Boyle M, Mann J. WITHDRAWN: Epigenetics in Chronic Liver Disease. J Hepatol 2017:S0168-8278(17)32255-9. [PMID: 28855099 DOI: 10.1016/j.jhep.2017.08.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Revised: 08/17/2017] [Accepted: 08/18/2017] [Indexed: 12/04/2022]
Abstract
This article has been withdrawn at the request of the editors. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.
Collapse
Affiliation(s)
- Marie Boyle
- Institute of Cellular Medicine, Faculty of Medical Sciences, 4(th) Floor, William Leech Building, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK
| | - Jelena Mann
- Institute of Cellular Medicine, Faculty of Medical Sciences, 4(th) Floor, William Leech Building, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
| |
Collapse
|
|
23
|
Dysfunction of IKZF1/MYC/MDIG axis contributes to liver cancer progression through regulating H3K9me3/p21 activity. Cell Death Dis 2017; 8:e2766. [PMID: 28471446 PMCID: PMC6258834 DOI: 10.1038/cddis.2017.165] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2017] [Revised: 03/15/2017] [Accepted: 03/16/2017] [Indexed: 12/20/2022]
Abstract
MDIG is known to be overexpressed in many types of human cancers and has demonstrated predictive power in the prognosis of cancer, although the functions and mechanisms of MDIG in liver cancer, especially in hepatocellular carcinoma (HCC), are still unknown. In this study, we report that MDIG and MYC were negatively regulated by IKZF1. MDIG overexpression substantially promoted HCC cell proliferation, cell migration and spreading, whereas knockdown of MDIG would reverse above-mentioned effect. MDIG effects on tumour cell growth were further demonstrated in a tumour xenograft model. Moreover, MDIG had effects on the level of p21(CIP1/WAF1) via H3K9me3 expression in HCC. MDIG was also found to be closely related to the sorafenib resistance of HCC cells in vitro. Clinically, we found that MDIG was frequently overexpressed in human HCCs (69.7% n=155) and was significantly associated with histological grade and hepatitis B virus infection. Our findings indicate that MDIG plays an important role in HCC progression via MDIG/H3K9me3/p21(CIP1/WAF1) signalling and serves as a potential therapeutic target.
Collapse
|
|
24
|
Tunissiolli NM, Castanhole-Nunes MMU, Biselli-Chicote PM, Pavarino ÉC, da Silva RF, da Silva RDCMA, Goloni-Bertollo EM. Hepatocellular Carcinoma: a Comprehensive Review of
Biomarkers, Clinical Aspects, and Therapy. Asian Pac J Cancer Prev 2017; 18:863-872. [PMID: 28545181 PMCID: PMC5494234 DOI: 10.22034/apjcp.2017.18.4.863] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a cause of several deaths related to cancer worldwidely. In early stage, curative treatments such as surgical resection, liver transplant and local ablation can improve the patient ´s survival. However, the disease is detected in advanced stage; moreover some available therapies are restricted to palliative care and local treatment. Early detections of HCC and adequate therapy are crucial to increase survival as well as to improve the patient´s quality of life. Therefore, researchers have been investigating molecular biomarkers with high sensibility and reliability as Golgi 73 protein (GP73), Glypican-3 (GPC3), Osteopontin (OPN), microRNAs and others. MicroRNAs can regulate important pathways on carcinogenesis, as tumor angiogenesis and progression. So, they can be considered as possible markers of prognosis in HCC, and therapeutic target for this tumor type. In this review, we discuss the recent advances related to the cause (highlighting the main risk factors), treatment, biomarkers, clinic aspects, and outcome in hepatocellular carcinoma.
Collapse
Affiliation(s)
- Nathalia Martines Tunissiolli
- Research Unit of Genetics and Molecular Biology (UPGEM), São José do Rio Preto Medical School (FAMERP), São José do Rio Preto- SP, Brazil
- Liver Tumors Study Group (GETF),São Jose do Rio Preto Medical
School (FAMERP), Sao Jose do Rio Preto- SP, Brazil.
| | | | | | | | | | | | | |
Collapse
|
|
25
|
von Felden J, Heim D, Schulze K, Krech T, Ewald F, Nashan B, Lohse AW, Wege H. High expression of micro RNA-135A in hepatocellular carcinoma is associated with recurrence within 12 months after resection. BMC Cancer 2017; 17:60. [PMID: 28100188 PMCID: PMC5242004 DOI: 10.1186/s12885-017-3053-7] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2016] [Accepted: 01/10/2017] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Hepatocellular carcinoma has a dismal prognosis due to recurrence rates of up to 70% after curative resection. Early recurrence is driven by synchronous microscopic intrahepatic metastases. The predictive value of histological parameters is discussed controversially and adjuvant therapy is not established. The aim of this study was to identify patients at high risk for early intrahepatic recurrence by expression profiling of selected micro RNAs. METHODS In 52 patients undergoing HCC resection between 2011 and 2014, liver and tumor tissue was collected during surgery. Twelve patients with incomplete data regarding HCC recurrence, secondary liver transplantation, or perioperative death were excluded, leaving 40 patients with early recurrence <12 months (R+) or without recurrence for >24 months (R-) to compare grading, T, L, V, and R status. If tissue quality permitted, micro RNAs were measured in HCC and liver tissue. RESULTS Ten women and 30 men (64.0 ± 10.2 years) were analyzed. R+ occurred in 29 patients 6.2 ± 4.5 months after resection. Surveillance of R- was 26.2 ± 5.2 months. High intratumoral expression of miR-135a was associated with high risk of recurrence (HR = 4.2, p = 0.024, time to recurrence 8.8 ± 2.0 vs. 24.8 ± 4.4 months in patients with low miR-135a expression). As expected, T3 status was correlated with early recurrence, while other histological parameters and expression of miR-21, miR-122, and miR-125a did not. CONCLUSIONS We show a significant association between high expression of miR-135a and early HCC recurrence. Therefore, high intratumoral miR-135a expression might serve as a novel biomarker to identify patients urgently requiring adjuvant therapy post resection.
Collapse
Affiliation(s)
- Johann von Felden
- I. Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.
| | - Denise Heim
- I. Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Kornelius Schulze
- I. Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Till Krech
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Florian Ewald
- Department for Hepatobiliary and Transplant Surgery, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Björn Nashan
- Department for Hepatobiliary and Transplant Surgery, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Ansgar W Lohse
- I. Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Henning Wege
- I. Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| |
Collapse
|
|
26
|
Picascia A, Grimaldi V, Napoli C. From HLA typing to anti-HLA antibody detection and beyond: The road ahead. Transplant Rev (Orlando) 2016; 30:187-94. [DOI: 10.1016/j.trre.2016.07.007] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2016] [Revised: 07/07/2016] [Accepted: 07/22/2016] [Indexed: 01/27/2023]
|
|
27
|
Elshamy M, Aucejo F, Menon KVN, Eghtesad B. Hepatocellular carcinoma beyond Milan criteria: Management and transplant selection criteria. World J Hepatol 2016; 8:874-880. [PMID: 27478537 PMCID: PMC4958697 DOI: 10.4254/wjh.v8.i21.874] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Revised: 06/17/2016] [Accepted: 07/13/2016] [Indexed: 02/06/2023] Open
Abstract
Liver transplantation (LT) for hepatocellular carcinoma (HCC) has been established as a standard treatment in selected patients for the last two and a half decades. After initially dismal outcomes, the Milan criteria (MC) (single HCC ≤ 5 cm or up to 3 HCCs ≤ 3 cm) have been adopted worldwide to select HCC patients for LT, however cumulative experience has shown that MC can be too strict. This has led to the development of numerous expanded criteria worldwide. Morphometric expansions on MC as well as various criteria which incorporate biomarkers as surrogates of tumor biology have been described. HCC that presents beyond MC initially can be downstaged with locoregional therapy (LRT). Post-LRT monitoring aims to identify candidates with favorable tumor behavior. Similarly, tumor marker levels as response to LRT has been utilized as surrogate of tumor biology. Molecular signatures of HCC have also been correlated to outcomes; these have yet to be incorporated into HCC-LT selection criteria formally. The ongoing discrepancy between organ demand and supply makes patient selection the most challenging element of organ allocation. Further validation of extended HCC-LT criteria models and pre-LT treatment strategies are required.
Collapse
|
|
28
|
Mahgoub A, Steer CJ. MicroRNAs in the Evaluation and Potential Treatment of Liver Diseases. J Clin Med 2016; 5:E52. [PMID: 27171116 PMCID: PMC4882481 DOI: 10.3390/jcm5050052] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2016] [Revised: 04/18/2016] [Accepted: 04/25/2016] [Indexed: 02/07/2023] Open
Abstract
Acute and chronic liver disease continue to result in significant morbidity and mortality of patients, along with increasing burden on their families, society and the health care system. This in part is due to increased incidence of liver disease associated factors such as metabolic syndrome; improved survival of patients with chronic predisposing conditions such as HIV; as well as advances in the field of transplantation and associated care leading to improved survival. The fact that one disease can result in different manifestations and outcomes highlights the need for improved understanding of not just genetic phenomenon predisposing to a condition, but additionally the role of epigenetic and environmental factors leading to the phenotype of the disease. It is not surprising that providers continue to face daily challenges pertaining to diagnostic accuracy, prognostication of disease severity, progression, and response to therapies. A number of these challenges can be addressed by incorporating a personalized approach of management to the current paradigm of care. Recent advances in the fields of molecular biology and genetics have paved the way to more accurate, individualized and precise approach to caring for liver disease. The study of microRNAs and their role in both healthy and diseased livers is one example of such advances. As these small, non-coding RNAs work on fine-tuning of cellular activities and organ function in a dynamic and precise fashion, they provide us a golden opportunity to advance the field of hepatology. The study of microRNAs in liver disease promises tremendous improvement in hepatology and is likely to lay the foundation towards a personalized approach in liver disease.
Collapse
Affiliation(s)
- Amar Mahgoub
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Minnesota Medical School, Veterans of Foreign Wars Cancer Research Center, 406 Harvard Street, S.E., Minneapolis, MN 55455, USA.
| | - Clifford J Steer
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Minnesota Medical School, Veterans of Foreign Wars Cancer Research Center, 406 Harvard Street, S.E., Minneapolis, MN 55455, USA.
- Department of Genetics, Cell Biology and Development, University of Minnesota Medical School, Veterans of Foreign Wars Cancer Research Center, 406 Harvard Street, S.E., Minneapolis, MN 55455, USA.
| |
Collapse
|