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Jiang Y, Qi S, Zhang R, Zhao R, Fu Y, Fang Y, Shao M. Diagnosis of hepatocellular carcinoma using liquid biopsy-based biomarkers: a systematic review and network meta-analysis. Front Oncol 2025; 14:1483521. [PMID: 39935848 PMCID: PMC11810725 DOI: 10.3389/fonc.2024.1483521] [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: 08/20/2024] [Accepted: 12/31/2024] [Indexed: 02/13/2025] Open
Abstract
Introduction The diagnostic performance of liquid biopsy-based biomarkers for HCC was comprehensively compared in this network meta-analysis (NMA). Methods A thorough literature search was conducted to identify all comparative studies from January 1, 2000, to January 11, 2024. The QUADAS-2 tool was utilized to appraise the quality of studies involving diagnostic performance. R (v4.3.3) and an ANOVA model-based NMA were used to assess the diagnostic accuracy of each biomarker. Results This study included 82 studies comprising a total of 15,024 patients.CircRNA demonstrated significantly superior performance in distinguishing HCC from healthy populations (superiority index: 3.550 (95% CI [0.143-3])) compared to other diagnostic biomarkers for HCC. "mRNA exhibited significantly superior performance in distinguishing HCC from liver disease patients (superiority index:10.621 (95% CI [7-11])) compared to other diagnostic biomarkers for HCC. Further subgroup analysis of the top-ranking liquid biopsy-based diagnostic biomarkers revealed that hsa_circ_000224 (superiority index: 3.091 (95% CI[0.143-9]) ranked remarkably higher in distinguishing HCC from both healthy populations and liver disease patients. Subgroup analysis of mRNA demonstrated that KIAA0101 mRNA (superiority index: 2.434 (95% CI [0.2-5]) ranked remarkably higher in distinguishing HCC from healthy populations and liver disease patients, respectively. Discussion The results of this meta-analysis show that circRNA and mRNA are the first choice for HCC diagnosis. Subsequent analysis of circRNA and mRNA highlighted hsa_circ_000224, hsa_circ_0003998, KIAA0101 mRNA and GPC-3mRNA as the optimal diagnostic biomarkers for distinguishing HCC from healthy populations and liver disease patients, respectively. Well-structured prospective studies are crucial to comprehensively validate these findings. Systematic Review Registration https://www.crd.york.ac.uk/PROSPERO/,identifier CRD42024521299.
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Affiliation(s)
- Yutong Jiang
- The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
- The First Clinical Medical College of Henan University of Chinese Medicine, Zhengzhou, China
| | - Shangwen Qi
- The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
- The First Clinical Medical College of Henan University of Chinese Medicine, Zhengzhou, China
| | - Rongrong Zhang
- The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
- The First Clinical Medical College of Henan University of Chinese Medicine, Zhengzhou, China
| | - Ruixia Zhao
- The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Yu Fu
- The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Yuxuan Fang
- The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
- The First Clinical Medical College of Henan University of Chinese Medicine, Zhengzhou, China
| | - Mingyi Shao
- The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
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Szternel Ł, Sobucki B, Wieprzycka L, Krintus M, Panteghini M. Golgi protein 73 in liver fibrosis. Clin Chim Acta 2025; 565:119999. [PMID: 39401651 DOI: 10.1016/j.cca.2024.119999] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Revised: 10/10/2024] [Accepted: 10/10/2024] [Indexed: 10/17/2024]
Abstract
Golgi protein 73 (GP73) is implicated in key pathogenic processes, particularly those related to inflammation and fibrogenesis. In the last years, its measurement has emerged as a promising biomarker for detection of liver fibrosis (LF), a common consequence of chronic liver disease that can progress to cirrhosis and eventually hepatocellular carcinoma. GP73 concentrations in blood appear significantly increased in LF patients, correlating with disease severity, making this biomarker a possible non-invasive alternative for detecting and monitoring this condition regardless of etiology. Understanding the molecular mechanisms involving GP73 expression could also lead to new therapeutic strategies aimed at modulating its synthesis or function to prevent or reverse LF. Despite its clinical potential, GP73 as a LF biomarker faces several challenges. The lack of demonstrated comparability among different assays as well as the lack of knowledge of individual variability can make difficult the result interpretation. Further research is therefore needed focusing on robust clinical validation of GP73 as a LF biomarker. Addressing analytical, biological, and clinical limitations will be critical to exploiting its potential for improving detection and monitoring of advanced LF.
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Affiliation(s)
- Łukasz Szternel
- Department of Laboratory Medicine, Nicolaus Copernicus University in Torun, Collegium Medicum in Bydgoszcz, Poland
| | - Bartłomiej Sobucki
- Department of Laboratory Medicine, Nicolaus Copernicus University in Torun, Collegium Medicum in Bydgoszcz, Poland
| | - Laura Wieprzycka
- Department of Laboratory Medicine, Nicolaus Copernicus University in Torun, Collegium Medicum in Bydgoszcz, Poland
| | - Magdalena Krintus
- Department of Laboratory Medicine, Nicolaus Copernicus University in Torun, Collegium Medicum in Bydgoszcz, Poland.
| | - Mauro Panteghini
- Department of Laboratory Medicine, Nicolaus Copernicus University in Torun, Collegium Medicum in Bydgoszcz, Poland
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Feng P, Hu X, Zhou S, Liu X, Zeng L, Liu Y. Golgi protein 73: the driver of inflammation in the immune and tumor microenvironment. Front Immunol 2025; 15:1508034. [PMID: 39845976 PMCID: PMC11750648 DOI: 10.3389/fimmu.2024.1508034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Accepted: 12/18/2024] [Indexed: 01/24/2025] Open
Abstract
Golgi Protein 73 (GP73) is a Golgi-resident protein that is highly expressed in primary tumor tissues. Initially identified as an oncoprotein, GP73 has been shown to promote tumor development, particularly by mediating the transport of proteins related to epithelial-mesenchymal transition (EMT), thus facilitating tumor cell EMT. Though our previous review has summarized the functional roles of GP73 in intracellular signal transduction and its various mechanisms in promoting EMT, recent studies have revealed that GP73 plays a crucial role in regulating the tumor and immune microenvironment. GP73 can modulate intracellular signaling pathways to influence cytokine and chemokine networks, resulting in inflammation caused by viral and bacterial infection or immune diseases, and leading tumor microenvironment deteriorated. Additionally, extracellular GP73 can also regulate signaling pathways of target cells by binding to their cell-surface receptors or entering the acceptor cells, thereby facilitating inflammation or promoting tumor development. In this review, we aim to summarize the findings, providing insights for future investigations on GP73 and its potential as a therapeutic target in ameliorating chronic inflammation in the immune and tumor microenvironment.
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Affiliation(s)
- Pingping Feng
- Hangzhou Lin’an Traditional Chinese Medicine Hospital, Affiliated Hospital, Hangzhou City University, Hangzhou, China
- Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, Hangzhou City University School of Medicine, Hangzhou, China
| | - Xinyang Hu
- Laboratory of Cancer Biology, Key Laboratory of Biotherapy of Zhejiang Province, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Cancer Center, Zhejiang University, Hangzhou, China
| | - Sining Zhou
- Life Sciences Institute, Zhejiang University, Hangzhou, China
| | - Xianyong Liu
- Hangzhou Lin’an Traditional Chinese Medicine Hospital, Affiliated Hospital, Hangzhou City University, Hangzhou, China
| | - Linghui Zeng
- Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, Hangzhou City University School of Medicine, Hangzhou, China
| | - Yiming Liu
- Hangzhou Lin’an Traditional Chinese Medicine Hospital, Affiliated Hospital, Hangzhou City University, Hangzhou, China
- Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, Hangzhou City University School of Medicine, Hangzhou, China
- Laboratory of Cancer Biology, Key Laboratory of Biotherapy of Zhejiang Province, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Cancer Center, Zhejiang University, Hangzhou, China
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Bai W, Li B, Wu P, Li X, Huang X, Shi N, Yang C, Hu F, Xie X. The first structure of human Golm1 coiled coil domain reveals an unexpected tetramer and highlights its structural diversity. Int J Biol Macromol 2024; 275:133624. [PMID: 38964685 DOI: 10.1016/j.ijbiomac.2024.133624] [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: 02/22/2024] [Revised: 06/23/2024] [Accepted: 07/01/2024] [Indexed: 07/06/2024]
Abstract
Golgi membrane protein 1 (Golm1), a transmembrane protein with diverse subcellular localizations, has garnered significant attention in recent years due to its strong association with the development and progression of liver diseases and numerous cancers. Interestingly, although Golm1 is a membrane protein, the C-terminal of Golm1, which contains a coiled coil domain and a flexible acid region, can also be detected in the plasma of patients with various liver diseases. Notably, the coiled coil domain of serum Golm1 is postulated to play a pivotal role in physiological and pathological functions. However, little is currently known about the structure of this coiled coil domain and the full-length protein, which may limit our understanding of Golm1. Therefore, this study aims to address this gap in knowledge and reports the first crystal structure of the coiled coil domain of Golm1 at a resolution of 2.28 Å. Meanwhile, we have also confirmed that the Golm1 coiled coil domain in solution can form tetramer. Our results reveal that Golm1 can form a novel tetrameric structure that differs from the previous reported dimeric structure Golm1 could assemble, which may provide novel insights into the diversity of physiological functions and pathological roles.
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Affiliation(s)
- Wenfeng Bai
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China
| | - Bowen Li
- State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou 350002, China
| | - Pei Wu
- State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou 350002, China
| | - Xinzhu Li
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Xiaochen Huang
- State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou 350002, China
| | - Ning Shi
- State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou 350002, China; Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China
| | - Congcong Yang
- Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China.
| | - Fen Hu
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Department of Etiology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350002, China.
| | - Xi Xie
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou 350002, China.
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Woo J, Choi Y. Biomarkers in Detection of Hepatitis C Virus Infection. Pathogens 2024; 13:331. [PMID: 38668286 PMCID: PMC11054098 DOI: 10.3390/pathogens13040331] [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: 04/01/2024] [Revised: 04/10/2024] [Accepted: 04/12/2024] [Indexed: 04/29/2024] Open
Abstract
The hepatitis C virus (HCV) infection affects 58 million people worldwide. In the United States, the incidence rate of acute hepatitis C has doubled since 2014; during 2021, this increased to 5% from 2020. Acute hepatitis C is defined by any symptom of acute viral hepatitis plus either jaundice or elevated serum alanine aminotransferase (ALT) activity with the detection of HCV RNA, the anti-HCV antibody, or hepatitis C virus antigen(s). However, most patients with acute infection are asymptomatic. In addition, ALT activity and HCV RNA levels can fluctuate, and a delayed detection of the anti-HCV antibody can occur among some immunocompromised persons with HCV infection. The detection of specific biomarkers can be of great value in the early detection of HCV infection at an asymptomatic stage. The high rate of HCV replication (which is approximately 1010 to 1012 virions per day) and the lack of proofreading by the viral RNA polymerase leads to enormous genetic diversity, creating a major challenge for the host immune response. This broad genetic diversity contributes to the likelihood of developing chronic infection, thus leading to the development of cirrhosis and liver cancer. Direct-acting antiviral (DAA) therapies for HCV infection are highly effective with a cure rate of up to 99%. At the same time, many patients with HCV infection are unaware of their infection status because of the mostly asymptomatic nature of hepatitis C, so they remain undiagnosed until the liver damage has advanced. Molecular mechanisms induced by HCV have been intensely investigated to find biomarkers for diagnosing the acute and chronic phases of the infection. However, there are no clinically verified biomarkers for patients with hepatitis C. In this review, we discuss the biomarkers that can differentiate acute from chronic hepatitis C, and we summarize the current state of the literature on the useful biomarkers that are detectable during acute and chronic HCV infection, liver fibrosis/cirrhosis, and hepatocellular carcinoma (HCC).
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Affiliation(s)
| | - Youkyung Choi
- Division of Viral Hepatitis, National Center for HIV, Viral Hepatitis, STD and TB Prevention, US Centers for Disease Control and Prevention (CDC), Atlanta, GA 30329-4018, USA;
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Yu WM, Li GW, Lou MG, Wu ZY. A meta-analysis of the prognostic impact of tissue golgi protein 73 (tGP73) in hepatocellular carcinoma. BMC Gastroenterol 2023; 23:401. [PMID: 37978447 PMCID: PMC10656938 DOI: 10.1186/s12876-023-03050-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Accepted: 11/09/2023] [Indexed: 11/19/2023] Open
Abstract
INTRODUCTION To date, an increasing number of studies have revealed that GP73 may have prognostic value in liver cancer. However, most of the studies evaluated serum GP73, and the results regarding the prognostic value of tGP73 in liver cancer are still controversial. Therefore, in this meta-analysis, we aimed to determine whether tGP73 has any prognostic value in patients with HCC. MATERIALS AND METHODS Relevant publications were searched for in PubMed, EMBASE, OVID, the Cochrane Library, and the Web of Science databases up to March 2023. The hazard ratio (HR) or odds ratio (OR) with corresponding 95% confidence intervals (95% CIs) of eligible studies were assessed by fixed-effects or random-effects models. In addition, subgroup analyses were conducted to investigate the possible causes of heterogeneity, and publication bias analysis was also performed to assess the reliability of the meta-analysis results. RESULTS A total of 10 studies were included. These studies included 1569 HCC patients, and a meta-analysis was performed. The results of our meta-analysis showed that higher GP73 expression levels were significantly associated with poorer OS (HR = 1.87, 95% CI: 1.41-2.48, P < 0.0001, I2 = 58%). However, there was no significant correlation between high GP73 expression and disease-free survival (DFS) (HR: 1.43, 95% CI: 0.93-2.33, P = 0.100). In addition, abnormal GP73 expression was also related to higher tumour tissue differentiation grade (OR = 3.03, 95% CI = 2.01-4.57, P < 0.0001, I2 = 89%), later tumour stage (OR = 5.89, 95% CI = 2.31-14.99, P < 0.0001, I2 = 0%), vascular invasion (OR = 1.72, 95% CI = 1.12-2.64, P = 0.010, I2 = 0%), multiple tumours (OR = 2.44, 95% CI = 1.37-3.68, P = 0.001, I2 = 44%) and early postoperative tumour recurrence (OR = 1.92, 95% CI = 1.10-3.28, P = 0.020, I2 = 62%). CONCLUSIONS The meta-analysis showed that the overexpression of GP73 may be related to a poor prognosis of HCC, and it may also have a predictive effect on the invasion and metastasis of HCC.
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Affiliation(s)
- Wei-Ming Yu
- Department of Hepatobiliary and pancreatic surgery, The First People's Hospital of Fuyang District, Fuyang First Hospital Affiliated to Binjiang College of Zhejiang Chinese Medicine University, Hangzhou, China.
| | - Guo-Wei Li
- Department of Hepatobiliary and pancreatic surgery, The First People's Hospital of Fuyang District, Fuyang First Hospital Affiliated to Binjiang College of Zhejiang Chinese Medicine University, Hangzhou, China
| | - Ming-Geng Lou
- Department of Hepatobiliary and pancreatic surgery, The First People's Hospital of Fuyang District, Fuyang First Hospital Affiliated to Binjiang College of Zhejiang Chinese Medicine University, Hangzhou, China
| | - Zheng-Yu Wu
- Department of Hepatobiliary and pancreatic surgery, The First People's Hospital of Fuyang District, Fuyang First Hospital Affiliated to Binjiang College of Zhejiang Chinese Medicine University, Hangzhou, China
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Ma X, Yan H, Zhang J, Zhang C, Duan C, Li S, Ding W, Li Y, Lu W, Wang Y, Yang X. GP73 is a promising indicator in HIV diagnosis and treatment: a one-year follow-up study. Diagn Microbiol Infect Dis 2023; 105:115890. [PMID: 36739792 DOI: 10.1016/j.diagmicrobio.2022.115890] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 12/28/2022] [Accepted: 12/31/2022] [Indexed: 01/05/2023]
Abstract
Golgi protein 73 (GP73) has been recognized as a biomarker for evaluating liver diseases, although the serum profile of patients with HIV remains unclear. This study was designed to investigate the diagnostic values of serum GP73 in patients with HIV. A total of 92 patients with HIV and 60 healthy participants were selected, and serum samples were collected; 51 of 92 patients were followed up and all indicators were re-tested after 1 year. Patients with HIV had significantly lower GP73 concentration, lower viral load, and higher CD4+ T cell counts after antiretroviral treatment. A significant correlation between the changes of GP73 level and CD4+ T cell count was observed. The CD4+ T cell count was significantly correlated with the glycosylated GP73 level. The area under the ROC curve (AUC) of GP73 to predict negative viral load-negative conversion alone was 0.705. When the cut-off value was set at 146.7 ng/mL, the sensitivity and specificity were 73% and 70% respectively. These results indicate that serum GP73 may have predictive ability for negative viral load-negative conversion.
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Affiliation(s)
- Xueping Ma
- Department of laboratory medicine, The Third Medical Center, General Hospital of the Chinese People's Liberation Army, Beijing, China
| | - Haozhen Yan
- NMPA Key Laboratory for Quality Monitoring and Evaluation of Vaccines and Biological Products, Key Laboratory of Tropical Diseases Control, Sun Yat-Sen University, Ministry of Education, Guangzhou, China
| | - Jing Zhang
- Department of laboratory medicine, The Third Medical Center, General Hospital of the Chinese People's Liberation Army, Beijing, China
| | - Cui Zhang
- Department of laboratory medicine, The Third Medical Center, General Hospital of the Chinese People's Liberation Army, Beijing, China
| | - Cuijuan Duan
- Department of laboratory medicine, The Third Medical Center, General Hospital of the Chinese People's Liberation Army, Beijing, China
| | - Shulei Li
- Department of laboratory medicine, The Third Medical Center, General Hospital of the Chinese People's Liberation Army, Beijing, China
| | - Wenfeng Ding
- Department of laboratory medicine, The Third Medical Center, General Hospital of the Chinese People's Liberation Army, Beijing, China
| | - Yingli Li
- Department of laboratory medicine, The Third Medical Center, General Hospital of the Chinese People's Liberation Army, Beijing, China
| | - Wenjing Lu
- Department of laboratory medicine, The Third Medical Center, General Hospital of the Chinese People's Liberation Army, Beijing, China
| | - Yufei Wang
- Department of laboratory medicine, The Third Medical Center, General Hospital of the Chinese People's Liberation Army, Beijing, China.
| | - Xiaoli Yang
- Department of laboratory medicine, The Third Medical Center, General Hospital of the Chinese People's Liberation Army, Beijing, China.
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Loosen SH, Halpaap J, Labuhn S, Bednarsch J, Alizai PH, Roeth AA, Lang SA, Vucur M, Kather JN, Knoefel WT, Ulmer TF, Neumann UP, Roderburg C, Luedde T. Golgi Protein 73 (GP73) Serum Levels Predict Outcome after Resection of Biliary Tract Cancer. Cancers (Basel) 2022; 14:cancers14184428. [PMID: 36139589 PMCID: PMC9497317 DOI: 10.3390/cancers14184428] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 09/05/2022] [Accepted: 09/08/2022] [Indexed: 11/24/2022] Open
Abstract
Simple Summary Biliary tract cancer (BTC) represents a rare liver malignancy with unfavorable outcome. It is often challenging to identify the ideal surgical candidates and present stratification algorithms are rarely based on the individual tumor biology. In the present manuscript, we evaluated a role of serum Golgi protein 73 (GP73) in patients with resectable BTC. We could show that elevated levels of GP73 before surgery identified a subgroup of BTC patients with a significantly reduced overall survival after tumor resection. Therefore, measurement of GP73 serum levels might become a novel tool in the challenging preoperative stratification process of patients with resectable BTC. Abstract Background: Tumor resection represents the only potentially curative therapy for patients with biliary tract cancer. Nevertheless, disease recurrence is observed in about 50% of patients, leading to a 5-years survival rate of less than 50%. The Golgi protein 73 (GP73), a type II Golgi transmembrane protein, exerts important functions of intracellular protein processing and transportation. Circulating GP73 has recently been suggested as a prognostic marker following resection of hepatocellular carcinoma (HCC) but its role in the context of BTC has remained unknown. In this study, we evaluate a potential role of circulating GP73 as a novel biomarker in patients with resectable BTC. Methods: GP73 serum levels were measured by immunoassay in n = 97 BTC and n = 40 HCC patients as well as n = 31 healthy controls. Results were correlated with clinical data. Results: Serum GP73 levels were significantly elevated in BTC patients compared to healthy controls but lower compared to HCC patients. The combination of GP73/CA19-9 showed a sensitivity and specificity of 83.5% and 90.3% regarding the differentiation of BTC patients and healthy controls. BTC patients with baseline GP73 levels above the ideal cut-off value (42.47 ng/mL) showed a significantly reduced median overall survival (193 days) compared to patients with preoperative GP73 levels below this cut-off (882 days). These results were confirmed in uni- and multivariate Cox-regression analysis including several clinicopathological parameters such as age, ECOG performance status, tumor stage as well as established tumor markers and parameters of liver and kidney function. Conclusions: GP73 represents a previously unrecognized biomarker in the patients with resectable BTC that identifies patients with an impaired postoperative outcome. If larger clinical trials confirmed these findings, measurement of GP73 serum levels might become a novel tool in the challenging preoperative stratification process of patients with resectable BTC.
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Affiliation(s)
- Sven H. Loosen
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
- Correspondence: (S.H.L.); (T.L.); Tel.: +49-211-81-16630 (S.H.L. & T.L.); Fax: +49-211-81-04489 (S.H.L. & T.L.)
| | - Justus Halpaap
- Department of Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany
| | - Simon Labuhn
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
| | - Jan Bednarsch
- Department of Visceral and Transplantation Surgery, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany
| | - Patrick H. Alizai
- Department of Visceral and Transplantation Surgery, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany
| | - Anjali A. Roeth
- Department of Visceral and Transplantation Surgery, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany
| | - Sven A. Lang
- Department of Visceral and Transplantation Surgery, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany
| | - Mihael Vucur
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
| | - Jakob N. Kather
- Else Kroener Fresenius Center for Digital Health, Medical Faculty Carl Gustav Carus, Technical University Dresden, 01069 Dresden, Germany
| | - Wolfram T. Knoefel
- Department of General, Visceral and Pediatric Surgery, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
| | - Tom F. Ulmer
- Department of Visceral and Transplantation Surgery, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany
| | - Ulf P. Neumann
- Department of Visceral and Transplantation Surgery, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany
| | - Christoph Roderburg
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
| | - Tom Luedde
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
- Correspondence: (S.H.L.); (T.L.); Tel.: +49-211-81-16630 (S.H.L. & T.L.); Fax: +49-211-81-04489 (S.H.L. & T.L.)
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Shao WQ, Zhu WW, Luo MJ, Fan MH, Li Q, Wang SH, Lin ZF, Zhao J, Zheng Y, Dong QZ, Lu L, Jia HL, Zhang JB, Lu M, Chen JH, Qin LX. Cholesterol suppresses GOLM1-dependent selective autophagy of RTKs in hepatocellular carcinoma. Cell Rep 2022; 39:110712. [PMID: 35443161 DOI: 10.1016/j.celrep.2022.110712] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 01/21/2022] [Accepted: 03/29/2022] [Indexed: 01/03/2023] Open
Abstract
Aberrant activation of receptor tyrosine kinases (RTKs) and the subsequent metabolic reprogramming play critical roles in cancer progression. Our previous study has shown that Golgi membrane protein 1 (GOLM1) promotes hepatocellular carcinoma (HCC) metastasis by enhancing the recycling of RTKs. However, how this RTK recycling process is regulated and coupled with RTK degradation remains poorly defined. Here, we demonstrate that cholesterol suppresses the autophagic degradation of RTKs in a GOLM1-dependent manner. Further mechanistic studies reveal that GOLM1 mediates the selective autophagy of RTKs by interacting with LC3 through an LC3-interacting region (LIR), which is regulated by a cholesterol-mTORC1 axis. Lowering cholesterol by statins improves the efficacy of multiple tyrosine kinase inhibitors (TKIs) in vivo. Our findings indicate that cholesterol serves as a signal to switch GOLM1-RTK degradation to GOLM1-RTK recycling and suggest that lowering cholesterol by statin may be a promising combination strategy to improve the TKI efficiency in HCC.
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Affiliation(s)
- Wei-Qing Shao
- General Surgery Department of Huashan Hospital & Cancer Metastasis Institute, Fudan University, Shanghai 200040, China
| | - Wen-Wei Zhu
- General Surgery Department of Huashan Hospital & Cancer Metastasis Institute, Fudan University, Shanghai 200040, China
| | - Meng-Jun Luo
- Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Ming-Hao Fan
- General Surgery Department of Huashan Hospital & Cancer Metastasis Institute, Fudan University, Shanghai 200040, China
| | - Qin Li
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai 200031, China
| | - Sheng-Hao Wang
- General Surgery Department of Huashan Hospital & Cancer Metastasis Institute, Fudan University, Shanghai 200040, China
| | - Zhi-Fei Lin
- General Surgery Department of Huashan Hospital & Cancer Metastasis Institute, Fudan University, Shanghai 200040, China
| | - Jing Zhao
- General Surgery Department of Huashan Hospital & Cancer Metastasis Institute, Fudan University, Shanghai 200040, China
| | - Yan Zheng
- General Surgery Department of Huashan Hospital & Cancer Metastasis Institute, Fudan University, Shanghai 200040, China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
| | - Qiong-Zhu Dong
- General Surgery Department of Huashan Hospital & Cancer Metastasis Institute, Fudan University, Shanghai 200040, China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
| | - Lu Lu
- General Surgery Department of Huashan Hospital & Cancer Metastasis Institute, Fudan University, Shanghai 200040, China
| | - Hu-Liang Jia
- General Surgery Department of Huashan Hospital & Cancer Metastasis Institute, Fudan University, Shanghai 200040, China
| | - Ju-Bo Zhang
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Ming Lu
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai 200031, China.
| | - Jin-Hong Chen
- General Surgery Department of Huashan Hospital & Cancer Metastasis Institute, Fudan University, Shanghai 200040, China.
| | - Lun-Xiu Qin
- General Surgery Department of Huashan Hospital & Cancer Metastasis Institute, Fudan University, Shanghai 200040, China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
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10
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Yan Q, Sun YS, An R, Liu F, Fang Q, Wang Z, Xu T, Chen L, Du J. Application and progress of the detection technologies in hepatocellular carcinoma. Genes Dis 2022. [PMID: 37492708 PMCID: PMC10363596 DOI: 10.1016/j.gendis.2022.04.003] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) has a very high incidence and fatality rate, and in most cases, it is already at an advanced stage when diagnosed. Therefore, early prevention and detection of HCC are two of the most effective strategies. However, the methods recommended in the practice guidelines for the detection of HCC cannot guarantee high sensitivity and specificity except for the liver biopsy, which is known as the "gold standard". In this review, we divided the detection of HCC into pre-treatment diagnosis and post-treatment monitoring, and found that in addition to the traditional imaging detection and liver biopsy, alpha fetoprotein (AFP), lens culinaris-agglutinin-reactive fraction of AFP (AFP-L3), protein induced by vitamin K absence or antagonist-II (PIVKA-II) and other biomarkers are excellent biomarkers for HCC, especially when they are combined together. Most notably, the emerging liquid biopsy shows great promise in detecting HCC. In addition, lactic dehydrogenase (LDH), suppressor of cytokine signaling (SOCS) and other relevant biomarkers may become promising biomarkers for HCC post-treatment monitoring. Through the detailed introduction of the diagnostic technology of HCC, we can have a detailed understanding of its development process and then obtain some enlightenment from the diagnosis, to improve the diagnostic rate of HCC and reduce its mortality.
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11
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Li S, Huang P, Jeyarajan AJ, Ma C, Zhu K, Zhu C, Jiang N, Li M, Shao T, Han M, Tan L, Lin W. Assessment of Non-invasive Markers for the Prediction of Esophageal Variceal Hemorrhage. Front Med (Lausanne) 2021; 8:770836. [PMID: 34926512 PMCID: PMC8672133 DOI: 10.3389/fmed.2021.770836] [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: 09/05/2021] [Accepted: 11/09/2021] [Indexed: 12/12/2022] Open
Abstract
Background: Esophageal variceal (EV) hemorrhage is a life-threatening consequence of portal hypertension in cirrhotic patients. Screening upper endoscopy and endoscopic variceal ligation to identify and treat EVs have contraindications, complications, and high costs. We sought to identify non-invasive tests (NITs) as alternatives to endoscopic EV screening. Methods: In this case-control study, we retrospectively analyzed 286 cirrhotic patients treated for EVs at the Second People's Hospital of Fuyang City, China from January to December 2019. We applied ROC curve analysis to assess the accuracy of various NITs in predicting EV hemorrhage. Results: There were significant differences between the hemorrhage and non-hemorrhage groups in median serum albumin (ALB) (p < 0.001), median bilirubin (TBIL) (p < 0.046), prothrombin (PT) time (p < 0.001), Golgi protein 73 (GP73; p = 0.012) and Child-Pugh (C-P) scores (p < 0.001). For ALB (cutoff <33.2g/L), PT time (cutoff > 14.2 seconds), GP73 (cutoff > 126.4 ng/ml), and C-P scores, the areas under the ROC curves (AUCs) were 73.4% (95% CI: 67.5-79.2), 68.6% (95% CI: 62.4-74.8), 62.2% (95% CI: 52.8-71.5) and 69.8% (95%CI: 63.8-75.8), respectively, with corresponding sensitives of 71.5, 59.8, 69.8, and 92.2% and specificities of 65.6%, 70.1%, 56.5%, and 38.6%. When ALB was combined with GP73, the AUC was 74.3% (95% CI: 66.1-82.5) with a sensitivity of 65.1% and specificity of 76.5%. When ALB, PT, and C-P scores were combined, the AUC was 76.5% (95% CI: 70.9-82.1) with a sensitivity of 79.5% and specificity of 64.3%. When ALB, PT, GP73, and C-P scores were combined, the AUC was 75.2% (95% CI: 67.3-83.1) with a sensitivity of 54.0% and specificity of 86.9%. Conclusion: ALB, TBIL, GP73, and C-P scores, may be used to predict EV hemorrhage in cirrhotic patients. The combination of multiple NITs is better than a single index and can increase diagnostic performance.
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Affiliation(s)
- Shasha Li
- Department of Hepatology, The Second People's Hospital of Fuyang City, Fuyang, China
| | - Peng Huang
- Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, China.,Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
| | - Andre J Jeyarajan
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
| | - Chao Ma
- Department of Gastroenterology, The Second People's Hospital of Fuyang City, Fuyang, China
| | - Ke Zhu
- Department of Gastroenterology, The Second People's Hospital of Fuyang City, Fuyang, China
| | - Chuanlong Zhu
- Department of Infectious Disease, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Ning Jiang
- Department of Hepatology, The Second People's Hospital of Fuyang City, Fuyang, China
| | - Ming Li
- Department of Hepatology, The Second People's Hospital of Fuyang City, Fuyang, China
| | - Tuo Shao
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
| | - Mingfeng Han
- Department of Pneumology, The Second People's Hospital of Fuyang City, Fuyang, China
| | - Lin Tan
- Department of Hepatology, The Second People's Hospital of Fuyang City, Fuyang, China
| | - Wenyu Lin
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
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12
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GOLM1 exacerbates CD8 + T cell suppression in hepatocellular carcinoma by promoting exosomal PD-L1 transport into tumor-associated macrophages. Signal Transduct Target Ther 2021; 6:397. [PMID: 34795203 PMCID: PMC8602261 DOI: 10.1038/s41392-021-00784-0] [Citation(s) in RCA: 114] [Impact Index Per Article: 28.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 09/14/2021] [Accepted: 09/28/2021] [Indexed: 12/11/2022] Open
Abstract
The immunosuppressive microenvironment plays an important role in tumor progression and immunotherapy responses. Golgi membrane protein 1 (GOLM1) is correlated to hepatocellular carcinoma (HCC) progression and metastasis. However, little is known about the role of GOLM1 in regulating the immunosuppressive environment and its impact on immunotherapeutic efficacy in HCC. In this study, GOLM1 was positively correlated with infiltrating tumor-associated macrophages (TAMs) expressed high levels of programmed death-ligand 1 (PD-L1) and CD8+ T cell suppression in HCC tissues. Both gain- and loss-of-function studies determined a close correlation between GOLM1 and immunosuppression. In the mechanism, GOLM1 promoted COP9 signalosome 5-mediated PD-L1 deubiquitination in HCC cells and increased the transport of PD-L1 into exosomes via suppression of Rab27b expression. Furthermore, co-culture with exosomes derived from HCC cells upregulated the expression of PD-L1 on macrophages. Zoledronic acid in combination with anti-PD-L1 therapy reduced PD-L1+ TAMs infiltration and alleviated CD8+ T cell suppression, resulting in tumor growth inhibition in the mouse HCC model. Together, our study unveils a mechanism by which GOLM1 induces CD8+ T cells suppression through promoting PD-L1 stabilization and transporting PD-L1 into TAMs with exosome dependent. Targeting PD-L1+ TAM could be a novel strategy to enhance the efficacy of anti-PD-L1 therapy in HCC.
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13
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Liu T, Liu B, Liu Y, Feng X, Jiang X, Long J, Gao Q, Yang Z. Vesicle transporter GOLT1B mediates the cell membrane localization of DVL2 and PD-L2 and promotes colorectal cancer metastasis. Cancer Cell Int 2021; 21:287. [PMID: 34059062 PMCID: PMC8166103 DOI: 10.1186/s12935-021-01991-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 05/22/2021] [Indexed: 12/11/2022] Open
Abstract
Background Colorectal cancer (CRC) is the third most diagnosed and second leading cause of cancer death worldwide. Hallmark proteins processing is usually dysregulated in cancers. Finding key regulatory molecules is of great importance for CRC metastasis intervention. GOLT1B is a vesicle transport protein which is involved in cytosolic proteins trafficking. However, its role in cancer has never been addressed. Methods CRC cell lines and subcutaneous xenograft animal model were utilized to investigate the biological function of GOLT1B. Patients samples were used to validate the correlation between GOLT1B and clinical outcome. In vivo targeted delivery of GOLT1B-siRNA was investigated in PDX (Patient derived tumor xenograft) model. Results We found that GOLT1B was highly expressed in CRC, and was an independent prognostic marker of overall survival (OS) and progression free survival (PFS). GOLT1B could promote CRC metastasis in vitro and in vivo. GOLT1B overexpression could increase DVL2 level and enhance its plasma membrane translocation, which subsequently activated downstream Wnt/β-catenin pathway and increase the nuclear β-catenin level, hence induce epithelial-mesenchymal transition (EMT). In addition, GOLT1B could also interact with PD-L2 and increase its membrane level. Co-culture of GOLT1B-overexpresed CRC cells with Jurkat cells significantly induced T cells apoptosis, which might further promote cancer cell the migration and invasion. Further, targeted delivery of GOLT1B siRNA could significantly inhibit tumor progression in GOLT1B highly expressed PDX model. Conclusion Taken together, our findings suggest that the vesicle transporter GOLT1B could promote CRC metastasis not only by assisting DVL2 translocation and activating Wnt/β-catenin pathway, but also facilitating PD-L2 membrane localization to induce immune suppression. Targeted inhibition of GOLT1B could be a potential therapeutic strategy for CRC treatment. Supplementary Information The online version contains supplementary material available at 10.1186/s12935-021-01991-z.
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Affiliation(s)
- Tengfei Liu
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510655, Guangdong, China
| | - Binbin Liu
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510655, Guangdong, China
| | - Yiting Liu
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510655, Guangdong, China
| | - Xingzhi Feng
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510655, Guangdong, China
| | - Xuefei Jiang
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510655, Guangdong, China
| | - Jiahui Long
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510655, Guangdong, China
| | - Qianling Gao
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510655, Guangdong, China
| | - Zihuan Yang
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510655, Guangdong, China.
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14
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Huang X, Liu F, Guan H, Jiang Z, Wei P, Luo Y, Jia Q. Effects of endoscopic submucosal dissection on post-operative early treatment effectiveness and serum TAT-2 and GP73 expression levels in patients with early gastric cancer. Exp Ther Med 2021; 22:806. [PMID: 34093762 PMCID: PMC8170670 DOI: 10.3892/etm.2021.10238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Accepted: 10/06/2020] [Indexed: 12/24/2022] Open
Abstract
The present study aimed to explore the effectiveness of endoscopic submucosal dissection (ESD) in the treatment of early gastric cancer (EGC) and its effect on serum tumor-associated trypsin-2 (TAT-2) and Golgi protein 73 (GP73) expression levels to provide a reference for the treatment of EGC. TAT-2 is a proteolytic target enzyme for tumor-associated trypsin inhibitor that has been previously reported to enhance invasion by promoting extracellular matrix degradation. GP73 is a novel type II Golgi membrane protein of unknown function that is expressed in the hepatocytes of patients with adult giant-cell hepatitis. A total of 161 patients with EGC treated at our hospital from April 2013 to February 2014 were selected as the study subjects. Among these, 86 patients underwent ESD (group A) and the remaining 75 underwent endoscopic mucosal resection (group B). Treatment effectiveness, incidence of complications and adverse reactions, operation time, intraoperative blood loss and length of hospital stay, as well as serum TAT-2 and GP73 expression levels, were compared between the two groups. The treatment effectiveness was significantly higher in group A than in group B (P<0.05). However, there was no significant inter-group difference in terms of incidence of complications/adverse reactions (P>0.05). After treatment, serum TAT-2 expression levels decreased in both groups (P<0.05) and serum TAT-2 expression levels were lower in group A than in group B (P<0.05). Furthermore, serum GP73 expression levels were significantly elevated in both groups (P<0.05). Kaplan-Meier survival analysis indicated no significant inter-group difference in the 5-year survival rate (P>0.05). In conclusion, ESD had a good therapeutic effect on EGC and is able to decrease serum TAT-2 expression levels and increase serum GP73 expression levels. The present study was registered into the Chinese Trials Registry (registration no. NCT02157534).
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Affiliation(s)
- Xue Huang
- Department of Gastroenterology, The Eighth Affiliated Hospital of Guangxi Medical University, Guigang, Guangxi 537100, P.R. China
| | - Fujian Liu
- Department of Gastroenterology, The Eighth Affiliated Hospital of Guangxi Medical University, Guigang, Guangxi 537100, P.R. China
| | - Hang Guan
- Department of Gastroenterology, The Eighth Affiliated Hospital of Guangxi Medical University, Guigang, Guangxi 537100, P.R. China
| | - Zhiyong Jiang
- Department of Gastroenterology, The Eighth Affiliated Hospital of Guangxi Medical University, Guigang, Guangxi 537100, P.R. China
| | - Peng Wei
- Department of Respiratory and Critical Care Medicine, The Eighth Affiliated Hospital of Guangxi Medical University, Guigang, Guangxi 537100, P.R. China
| | - Yifeng Luo
- Department of Intensive Care Unit, The Eighth Affiliated Hospital of Guangxi Medical University, Guigang, Guangxi 537100, P.R. China
| | - Qiuhong Jia
- Department of Gastroenterology, The Eighth Affiliated Hospital of Guangxi Medical University, Guigang, Guangxi 537100, P.R. China
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15
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Abstract
Hepatocellular carcinoma (HCC) is one of the most common liver malignancies and is a leading cause of cancer-related deaths. Most HCC patients are diagnosed at an advanced stage and current treatments show poor therapeutic efficacy. It is particularly urgent to explore early diagnosis methods and effective treatments of HCC. There are a growing number of studies that show GOLM1 is one of the most promising markers for early diagnosis and prognosis of HCC. It is also involved in immune regulation, activation and degradation of intracellular signaling factors and promotion of epithelial-mesenchymal transition. GOLM1 can promote HCC progression and metastasis. The understanding of the GOLM1 regulation mechanism may provide new ideas for the diagnosis, monitoring and treatment of HCC.
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Affiliation(s)
- Jiuliang Yan
- Department of Liver Surgery & Transplantation, Liver Cancer Institute & Zhongshan Hospital, Fudan University, Shanghai, 200032, China.,Key Laboratory of Carcinogenesis & Cancer Invasion (Fudan University), Ministry of Education, Fudan University, Shanghai, 200032, China
| | - Binghai Zhou
- Department of Liver Surgery & Transplantation, Liver Cancer Institute & Zhongshan Hospital, Fudan University, Shanghai, 200032, China.,Key Laboratory of Carcinogenesis & Cancer Invasion (Fudan University), Ministry of Education, Fudan University, Shanghai, 200032, China
| | - Hui Li
- Department of Liver Surgery & Transplantation, Liver Cancer Institute & Zhongshan Hospital, Fudan University, Shanghai, 200032, China.,Key Laboratory of Carcinogenesis & Cancer Invasion (Fudan University), Ministry of Education, Fudan University, Shanghai, 200032, China
| | - Lei Guo
- Department of Liver Surgery & Transplantation, Liver Cancer Institute & Zhongshan Hospital, Fudan University, Shanghai, 200032, China.,Key Laboratory of Carcinogenesis & Cancer Invasion (Fudan University), Ministry of Education, Fudan University, Shanghai, 200032, China
| | - Qinghai Ye
- Department of Liver Surgery & Transplantation, Liver Cancer Institute & Zhongshan Hospital, Fudan University, Shanghai, 200032, China.,Key Laboratory of Carcinogenesis & Cancer Invasion (Fudan University), Ministry of Education, Fudan University, Shanghai, 200032, China
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16
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Liewen H, Markuly N, Läubli H, Liu Y, Matter MS, Liewen N, Renner C, Zippelius A, Stenner F. Therapeutic Targeting of Golgi Phosphoprotein 2 (GOLPH2) with Armed Antibodies: A Preclinical Study of Anti-GOLPH2 Antibody Drug Conjugates in Lung and Colorectal Cancer Models of Patient Derived Xenografts (PDX). Target Oncol 2020; 14:577-590. [PMID: 31541350 DOI: 10.1007/s11523-019-00667-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
BACKGROUND Golgi phosphoprotein 2 (GOLPH2) has been shown to be involved in chronic inflammatory processes and carcinogenesis. GOLPH2 is prominently overexpressed in hepatocellular carcinoma, melanoma, glioblastoma, prostate, lung, and colorectal cancer. With a low and tightly regulated expression in non-malignant tissues, GOLPH2 has been proposed as an attractive target for cancer therapy. However, GOLPH2 is predominantly located intracellularly and when situated outside of the cell it is proteolytically cleaved and shed from the cell surface. Until now, GOLPH2 has been regarded as an "undruggable" target. OBJECTIVE We sought to create antibodies that specifically bind to GOLPH2 overexpressing tumor cells. PATIENTS AND METHODS Antibodies binding to membranous GOLPH2 despite shedding of the protein were generated from a scFV library screening. These antibodies target the part of GOLPH2 that remains at the cell surface after proteolytic cleavage. These antibodies were then tested in vitro and in vivo. RESULTS Two candidates (G2-1 and G2-2) showed target specific binding in vitro. Utilizing a tumor array (n = 128 tumors) with G2-2 and a reference antibody, a GOLPH2 expression scoring system was established. Rapid internalization of the antibodies was noted so this was exploited to deliver a toxic payload of pyrrolobenzodiazepine (PBD). In two patient-derived xenograft (PDX)-models, colorectal and lung cancer, the G2-2 antibody drug conjugate (ADC) displayed high efficacy with significant tumor responses (P = 0.001; P = 0.013) and improved survival (P = 0.0001; P = 0.0011) compared with controls. CONCLUSIONS Treatment with GOLPH2-directed antibodies induces durable responses in colorectal and lung cancer models. With a robust companion assay for GOLPH2 positivity at hand our findings prepare for the translation into a clinical trial.
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Affiliation(s)
- Heike Liewen
- Cureab GmbH, Benkenstrasse 254c, Technologiezentrum, 4108, Witterswil, Switzerland
| | - Norbert Markuly
- Cureab GmbH, Benkenstrasse 254c, Technologiezentrum, 4108, Witterswil, Switzerland
| | - Heinz Läubli
- Medical Oncology, University Hospital Basel & Laboratory Cancer Immunology, Department Biomedicine, University Basel, Petersgraben 4, 4031, Basel, Switzerland
| | - Yang Liu
- Medical Oncology, University Hospital Basel & Laboratory Cancer Immunology, Department Biomedicine, University Basel, Petersgraben 4, 4031, Basel, Switzerland
| | - Matthias S Matter
- Institute of Pathology, University Hospital Basel, 4031, Basel, Switzerland
| | - Nora Liewen
- University of Cologne, Albertus-Magnus-Platz, 50923, Cologne, Germany
| | - Christoph Renner
- Medical Oncology, University Hospital Basel & Laboratory Cancer Immunology, Department Biomedicine, University Basel, Petersgraben 4, 4031, Basel, Switzerland
| | - Alfred Zippelius
- Medical Oncology, University Hospital Basel & Laboratory Cancer Immunology, Department Biomedicine, University Basel, Petersgraben 4, 4031, Basel, Switzerland
| | - Frank Stenner
- Medical Oncology, University Hospital Basel & Laboratory Cancer Immunology, Department Biomedicine, University Basel, Petersgraben 4, 4031, Basel, Switzerland.
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17
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Zhang J, Zhang M, Ma H, Song X, He L, Ye X, Li X. A meta-analysis of the prognostic significance of Golgi protein 73 in hepatocellular carcinoma in Chinese patients. Arch Med Sci 2020; 16:1104-1110. [PMID: 32863999 PMCID: PMC7444708 DOI: 10.5114/aoms.2019.83821] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Accepted: 02/02/2019] [Indexed: 12/31/2022] Open
Abstract
INTRODUCTION In recent years, an increasing number of studies have revealed the possible prognostic significance of Golgi protein 73 (GP73) in hepatocellular carcinoma (HCC), but the results are still controversial. Therefore, we performed a meta-analysis to explore the possible correlation between GP73 and prognostic value in HCC. MATERIAL AND METHODS Relevant publications were searched for in PubMed, EMBASE, Cochrane Library and the Chinese Biomedical Literature Database up to March 2018. Odds ratios (ORs) or hazard ratios (HRs) and 95% confidence intervals (CI) of eligible studies were assessed by either fixed-effect or random effects models. Publication bias analysis was also performed to assess the reliability of the meta-analysis results. RESULTS In total, 9 studies including 1292 patients with HCC were included and analysed systematically in the study. The results indicated that GP73 overexpression was significantly associated with later tumour stage, higher tumour grade and poor overall survival (OS). Combined analysis of three studies showed no statistical correlation between high GP73 expression and disease-free survival (DFS). Subgroup analyses were also performed to illustrate the relationship between high GP73 expression and OS. CONCLUSIONS The meta-analysis suggested that overexpression of GP73 may be associated with poor prognosis in HCC and may also have a predictive role for HCC invasion and metastasis.
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Affiliation(s)
- Jian Zhang
- Department of Center of Integrated Traditional Chinese and Western Medicine, Peking University Ditan Teaching Hospital, Beijing, China
| | - Manka Zhang
- Department of Center of Integrated Traditional Chinese and Western Medicine, Peking University Ditan Teaching Hospital, Beijing, China
| | - Huimin Ma
- Department of Center of Integrated Traditional Chinese and Western Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Xincheng Song
- Department of Center of Integrated Traditional Chinese and Western Medicine, Peking University Ditan Teaching Hospital, Beijing, China
| | - Lingling He
- Department of Institute of Infectious Disease, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Xiaohui Ye
- Department of Institute of Infectious Disease, Peking University Ditan Teaching Hospital, Beijing, China
| | - Xin Li
- Department of Center of Integrated Traditional Chinese and Western Medicine, Peking University Ditan Teaching Hospital, Beijing, China
- Department of Center of Integrated Traditional Chinese and Western Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
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18
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Zhang Y, Tang J, Zhou X, Zhu SL, Li LQ. Diagnostic accuracy of midkine for hepatocellular carcinoma: A meta-analysis. Mol Genet Genomic Med 2019; 8:e1071. [PMID: 31777190 PMCID: PMC7005611 DOI: 10.1002/mgg3.1071] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2018] [Revised: 11/03/2019] [Accepted: 11/06/2019] [Indexed: 12/14/2022] Open
Abstract
Background There have been many reports on midkine as a promising marker in the diagnosis of hepatocellular carcinoma (HCC). However, the results are inconsistent and even conflicting. Methods This meta‐analysis was performed to investigate the accuracy of midkine in the diagnosis of HCC. Meta‐DiSc 1.4 software was used to extract data and to calculate the overall sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR). Data are presented as forest plots and summary receiver operating characteristic (SROC) curve analysis was used to summarize the overall test performance. Results Ten studies with a total of 753 HCC patients and 977 non‐HCC patients were included. The overall pooled diagnostic data were as follows: the pooled sensitivity of 0.86 (95% confidence interval [CI]: 083–0.88), the pooled specificity of 0.75 (95% CI: 0.73–0.78), the pooled PLR of 4.71 (95% CI: 2.80–7.90), the pooled NLR of 0.18 (95% CI: 0.11–0.30), and the pooled DOR of 36.83 (95% CI: 13.56–100.05). The area under curve value was 0.9266 in the overall SROC curve. Conclusion Midkine has moderate diagnostic accuracy for HCC. Due to the design limitations, results inpublished studies should be carefully interpreted. In addition, more well‐designed studies with large sample sizes should be performed to rigorously evaluate the diagnostic accuracy of the MDK.
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Affiliation(s)
- Yu Zhang
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, China
| | - Juan Tang
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, China
| | - Xiao Zhou
- Department of Breast Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, China
| | - Shao-Liang Zhu
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, China
| | - Le-Qun Li
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, China
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19
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Esawy MM, Shabana MA, Ahmed NH. Effect of sample type and storage conditions on Golgi membrane protein 73 stability. Scandinavian Journal of Clinical and Laboratory Investigation 2019; 79:491-495. [PMID: 31495236 DOI: 10.1080/00365513.2019.1661009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
GP73 is a transmembrane glycoprotein that increases in viral and non-viral liver diseases, especially in hepatocellular carcinoma. This study aims to evaluate the effect of sample type and storage conditions on GP73 concentration. Twenty subjects were enrolled in this study. Serum and citrated plasma samples were collected. Both were subjected to different time intervals and storage temperature. Baseline GP73 concentrations ranged from 1.7 to 16.9 ng/mL in serum samples, and from 1.1 to 15.3 ng/mL in citrated plasma (Mann-Whitney U test, p = .1). The acceptable change limit for GP73 was 6.1%. As the highest value of the median percentage deviation was -5.3% in both sample types at different storage condition so, deviations were within the accepted limits. But there were considerable variations in the GP-73 concentrations after 2 cycles of freezing and thawing at -20 °C. This study shows that both serum and citrated plasma can be used for the measurement of GP73 concentration. GP73 seems to be stable under common storage conditions, but it may be unstable with frequent cycles of freezing and thawing.
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Affiliation(s)
- Marwa M Esawy
- Department of Clinical Pathology, Faculty of Human Medicine, Zagazig University , Zagazig , Egypt
| | - Marwa A Shabana
- Department of Clinical Pathology, Faculty of Human Medicine, Zagazig University , Zagazig , Egypt
| | - Nabila H Ahmed
- Department of Tropical Medicine, Faculty of Human Medicine, Zagazig University , Zagazig , Egypt
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Zhu J, Warner E, Parikh ND, Lubman DM. Glycoproteomic markers of hepatocellular carcinoma-mass spectrometry based approaches. MASS SPECTROMETRY REVIEWS 2019; 38:265-290. [PMID: 30472795 PMCID: PMC6535140 DOI: 10.1002/mas.21583] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/11/2018] [Accepted: 10/19/2018] [Indexed: 05/03/2023]
Abstract
Hepatocellular carcinoma (HCC) is the third most-common cause of cancer-related death worldwide. Most cases of HCC develop in patients that already have liver cirrhosis and have been recommended for surveillance for an early onset of HCC. Cirrhosis is the final common pathway for several etiologies of liver disease, including hepatitis B and C, alcohol, and increasingly non-alcoholic fatty liver disease. Only 20-30% of patients with HCC are eligible for curative therapy due primarily to inadequate early-detection strategies. Reliable, accurate biomarkers for HCC early detection provide the highest likelihood of curative therapy and survival; however, current early-detection methods that use abdominal ultrasound and serum alpha fetoprotein are inadequate due to poor adherence and limited sensitivity and specificity. There is an urgent need for convenient and highly accurate validated biomarkers for HCC early detection. The theme of this review is the development of new methods to discover glycoprotein-based markers for detection of HCC with mass spectrometry approaches. We outline the non-mass spectrometry based methods that have been used to discover HCC markers including immunoassays, capillary electrophoresis, 2-D gel electrophoresis, and lectin-FLISA assays. We describe the development and results of mass spectrometry-based assays for glycan screening based on either MALDI-MS or ESI analysis. These analyses might be based on the glycan content of serum or on glycan screening for target molecules from serum. We describe some of the specific markers that have been developed as a result, including for proteins such as Haptoglobin, Hemopexin, Kininogen, and others. We discuss the potential role for other technologies, including PGC chromatography and ion mobility, to separate isoforms of glycan markers. Analyses of glycopeptides based on new technologies and innovative softwares are described and also their potential role in discovery of markers of HCC. These technologies include new fragmentation methods such as EThcD and stepped HCD, which can identify large numbers of glycopeptide structures from serum. The key role of lectin extraction in various assays for intact glycopeptides or their truncated versions is also described, where various core-fucosylated and hyperfucosylated glycopeptides have been identified as potential markers of HCC. Finally, we describe the role of LC-MRMs or lectin-FLISA MRMs as a means to validate these glycoprotein markers from patient samples. These technological advancements in mass spectrometry have the potential to lead to novel biomarkers to improve the early detection of HCC.
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Affiliation(s)
- Jianhui Zhu
- Department of Surgery, The University of Michigan, Ann Arbor 48109, Michigan
| | - Elisa Warner
- Department of Surgery, The University of Michigan, Ann Arbor 48109, Michigan
| | - Neehar D. Parikh
- Department of Internal Medicine, The University of Michigan, Ann Arbor 48109, Michigan
| | - David M. Lubman
- Department of Surgery, The University of Michigan, Ann Arbor 48109, Michigan
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Hou X, Yang L, Jiang X, Liu Z, Li X, Xie S, Li G, Liu J. Role of microRNA-141-3p in the progression and metastasis of hepatocellular carcinoma cell. Int J Biol Macromol 2019; 128:331-339. [PMID: 30695725 DOI: 10.1016/j.ijbiomac.2019.01.144] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Revised: 01/24/2019] [Accepted: 01/25/2019] [Indexed: 12/16/2022]
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer related death worldwide. However, the mechanisms underlying HCC progression and metastasis are still in obscure. Here, we used bioinformatic analysis to identify miRNAs that regulate GP73, a specific marker for HCC diagnosis and prognosis. The correlations between miR-141-3p and clinic-pathological factors were analyzed in HCC patient samples; proliferation, migration, invasion, and colony formation were studied using established HCC cell lines. Expression levels of target genes (miR-141-3p, GP73, E-cadherin, N-cadherin, occludin, vimentin, and cytokeratin 18) were detected by either Western blot or qRT-PCR analysis. Xenograft models were established to evaluate tumor growth and metastasis. MiR-141-3p was significantly reduced in HCC tumors and cell lines, highly correlated with tumor progression. In contrast, GP73 was negatively correlated with miR-141-3p in HCC tumors. MiR-141-3p overexpression significantly decreased HCC cell proliferation, migration, and invasion by inhibiting epithelial-mesenchymal transition (EMT). GP73 overexpression partially restored the inhibitory effects of miR-141-3p, while miR-141-3p overexpression markedly inhibited tumor growth and pulmonary metastasis, which were partially reversed by GP73 overexpression. Our findings suggest that miR-141-3p targets GP73 to reverse EMT, subsequently inhibiting HCC progression and metastasis. Thus, overexpression of miR-141-3p could serve as a therapeutic strategy to arrest HCC.
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Affiliation(s)
- Xu Hou
- Department of Hepatobiliary Surgery, Liaocheng People Hospital, Liaocheng, Shandong, China
| | - Le Yang
- Department of Transcranial Doppler, Liaocheng People Hospital, Liaocheng, Shandong, China
| | - Xiaohong Jiang
- Zhong Yuan Academy of Biological Medicine, Liaocheng People's Hospital/Affiliated Liaocheng University, Liaocheng, Shandong, China
| | - Zhiheng Liu
- Department of Hepatobiliary Surgery, Liaocheng People Hospital, Liaocheng, Shandong, China
| | - Xuehua Li
- Department of Hepatobiliary Surgery, Liaocheng People Hospital, Liaocheng, Shandong, China
| | - Shuli Xie
- Department of Hepatobiliary and Pancreatic Surgery, First Hospital of Norman Bethune Medical College, Jilin University, Changchun, Jilin, China
| | - Guangbing Li
- Department of Liver Transplantation and Hepatobiliary Surgery, Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China
| | - Jun Liu
- Department of Liver Transplantation and Hepatobiliary Surgery, Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China.
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Farag RMA, Al Ayobi D, Alsaleh KA, Kwon HJ, EL-Ansary A, Dawoud EA. Studying the Impact of Golgi Protein 73 Serving as a Candidate Biomarker in Early Diagnosis for Hepatocellular Carcinoma
among Saudi Patients. Asian Pac J Cancer Prev 2019; 20:215-220. [PMID: 30678434 PMCID: PMC6485586 DOI: 10.31557/apjcp.2019.20.1.215] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Accepted: 12/20/2018] [Indexed: 12/13/2022] Open
Abstract
Background: Due to the prevalence of Hepatocellular carcinoma (HCC) in Saudi Arabia, using new markers to give best diagnostic performance than alpha-feto protein (AFP) are important in early diagnosis. The aim of this work was to compare the significance between serum and mRNA Golgi glypican73 (GP-73) as newly identified diagnostic and prognostic markers for HCC among Saudi patients. Materials and Methods: A total of 300 subjects were divided into: 250 blood samples where 145 samples from HCC, 105 samples from chronic liver cirrhosis (CLC) and 50 normal controls were investigated for serum GP73 (sGP73) by ELISA. GP-73 mRNA from peripheral blood mononuclear cells was amplified by RT-PCR. The sensitivity and specificity of both techniques was compared. Results: Serum Golgi glypican 73 was significantly higher in HCC group compared to cirrhotic and normal controls (p<0.001). Sensitivity and specificity were 95% for sGP-73, 100% and 90% for Golgi glypican 73 mRNA. The combination of sensitivity between AFP and sGP73 was 80% and 95% respectively. Conclusion: Both serum Golgi glypican-73 and GP-73Mrna are good diagnostic biomarkers for early detection of HCC in Saudi patients. RT-PCR is more accurate and sensitive (100%) than ELISA (95%) in detecting Golgi glypican 73.
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Affiliation(s)
- Randa Mohamed Ahmed Farag
- Health Sciences Research Center (HSCR), Princess Nourah bint Abdulrahman University (PNU), Kingdom Saudi Arabia.
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Zhou Y, Li W, Tseng Y, Zhang J, Liu J. Developing slow-off dickkopf-1 aptamers for early-diagnosis of hepatocellular carcinoma. Talanta 2018; 194:422-429. [PMID: 30609553 DOI: 10.1016/j.talanta.2018.10.014] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Revised: 09/25/2018] [Accepted: 10/03/2018] [Indexed: 01/10/2023]
Abstract
In this work, we obtained fast-off and slow-off aptamer recognizing dickkopf-1(DKK1), a promising biomarker for detection of early-stage hepatocellular carcinoma (HCC), with high affinity in a single SELEX procedure. The two types of aptamer possessed distinct characteristics confirmed via different validation methods. In comparison to fast-off aptamers, slow-off aptamers were proven more suitable for aptamer-based ELISA assay. Using slow dissociation SELEX, slow-off aptamers were selectively retained. Meanwhile, a mutant (34del) of slow-off D10 was estimated with picomolar affinity (371.9 pM). The mutant was further truncated into 39nt before pairing with an antibody in the aptamer-based ELISA. The aptamer-target-antibody construction showed similar performance as conventional ELISA with a detection limit of 62.5 pg/ml. Quantification in 60 sera samples with the construction was also correlated with conventional ELISA. The results demonstrated novel DKK1 aptamer could replace capture antibody for potential early HCC diagnosis.
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Affiliation(s)
- Yin Zhou
- Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
| | - Wenshuai Li
- Department of Digestive Diseases of Huashan Hospital, Collaborative Innovation Center of Genetics and Development, Fudan University, Shanghai 200040, China
| | - Yujen Tseng
- Department of Digestive Diseases of Huashan Hospital, Collaborative Innovation Center of Genetics and Development, Fudan University, Shanghai 200040, China
| | - Jun Zhang
- Department of Digestive Diseases of Huashan Hospital, Collaborative Innovation Center of Genetics and Development, Fudan University, Shanghai 200040, China.
| | - Jie Liu
- Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China; Department of Digestive Diseases of Huashan Hospital, Collaborative Innovation Center of Genetics and Development, Fudan University, Shanghai 200040, China.
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Song YX, Xu ZC, Li HL, Yang PL, Du JK, Xu J. Overexpression of GP73 promotes cell invasion, migration and metastasis by inducing epithelial-mesenchymal transition in pancreatic cancer. Pancreatology 2018; 18:812-821. [PMID: 30217697 DOI: 10.1016/j.pan.2018.08.009] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2018] [Revised: 07/26/2018] [Accepted: 08/17/2018] [Indexed: 12/11/2022]
Abstract
Pancreatic cancer is one of the most difficult clinical cases to diagnose with a very low 5-year survival rate of 5%, regardless of the advances made in both the medical and surgical treatment of the disease. One of the contributing factors for the high mortality rate seen of pancreatic cancer patients is the lack of effective chemotherapies, which is believed to be due to drug-resistance. Based on recent evidence, epithelial-mesenchymal transition (ETM) of pancreatic cancer cells has been found to be associated with the development of drug resistance and an increase in cell invasion. Therefore, we conducted the present study in order to investigate the regulatory effects of Golgi protein-73 (GP73) on PC. GP73 and EMT-related gene expressions in PC, along with the adjacent and chronic pancreatitis tissues were determined by means of RT-qPCR and Western blot analysis. Cultured PC cells were treated with pAdTrack-CMV, si-NC, GP73 overexpression, Si-GP73, Snail-siRNA and GP73 + Snail-siRNA. Cell invasion, migration and metastasis were measured in vitro and in vivo. The results revealed that the PC tissues and chronic pancreatitis tissues exhibited diminished E-cadherin expression and amplified GP73, N-cadherin, Vimentin and Snail expression. In response to GP73 gene silencing, PC cells presented with increased E-cadherin expression and decreased N-cadherin, Vimentin, Snail expression in addition to the inhibition of the number of invasive cells, tumor volume and number of liver lesions. These findings highly indicated that the overexpression of GP73 promotes cell invasion, migration and metastasis by inducing EMT in PC.
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Affiliation(s)
- Yin-Xue Song
- Department of Emergency, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China
| | - Zhi-Chao Xu
- Department of Emergency, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China
| | - Hui-Ling Li
- Department of Emergency, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China
| | - Pei-Lei Yang
- Department of Emergency, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China
| | - Jun-Kai Du
- Department of Emergency, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China
| | - Jing Xu
- Department of Emergency, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China.
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Li H, Yang LL, Xiao Y, Deng WW, Chen L, Wu L, Zhang WF, Sun ZJ. Overexpression of Golgi Phosphoprotein 2 Is Associated With Poor Prognosis in Oral Squamous Cell Carcinoma. Am J Clin Pathol 2018; 150:74-83. [PMID: 29788173 DOI: 10.1093/ajcp/aqy029] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
OBJECTIVES The aims of this study were to investigate the relationship between Golgi phosphoprotein 2 (GOLPH2) and oral squamous cell carcinoma (OSCC) and explore the clinical significance of GOLPH2 in OSCC. METHODS Tissue microarrays from human OSCC samples were stained for GOLPH2 expression and clinicopathologic features. Kaplan-Meier analysis was used to compare the survival of patients with high GOLPH2 expression and patients with low GOLPH2 expression. RESULTS We found GOLPH2 is highly expressed in OSCC tissue, and the GOLPH2 expression in metastatic lymph nodes is higher than in tumor tissue. Our data indicate that patients with higher GOLPH2 expression have poor overall survival compared with those with lower GOLPH2 expression. This study demonstrated that GOLPH2 was associated with CD44, SOX2, Slug, B7-H3, B7-H4, TIM3, and VISTA. CONCLUSIONS These findings suggest GOLPH2 is a potential marker for estimating the patient's prognosis and may be a target for molecular-targeted therapy against OSCC.
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Affiliation(s)
- Hao Li
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Lei-Lei Yang
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Yao Xiao
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Wei-Wei Deng
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Lei Chen
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Lei Wu
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Wen-Feng Zhang
- Department of Oral and Maxillofacial Head Neck Surgery, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Zhi-Jun Sun
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China
- Department of Oral and Maxillofacial Head Neck Surgery, School & Hospital of Stomatology, Wuhan University, Wuhan, China
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Xu Z, Shen J, Pan X, Wei M, Liu L, Wei K, Liu L, Yang H, Huang J. Predictive value of serum Golgi protein 73 for prominent hepatic necroinflammation in chronic HBV infection. J Med Virol 2018; 90:1053-1062. [PMID: 29424455 DOI: 10.1002/jmv.25045] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2017] [Accepted: 01/25/2018] [Indexed: 12/17/2022]
Abstract
As a noninvasive marker, serum alanine aminotransferase (ALT) has limitations, because a large proportion of patients chronically infected with hepatitis B virus (HBV) suffer from severe hepatic necroinflammation, but have normal or mildly elevated ALT. In the present study, we aimed to investigate the potential value of serum Golgi protein 73 (GP73) in predicting significant hepatic necroinflamation among chronic HBV infected patients. A cohort of 497 chronic HBV infected patients was retrospectively recruited. Liver biopsy was performed in all patients and serum GP73 levels were measured by enzyme-linked immunosorbent assay. Serum GP73 increased in parallel with the increase in hepatic necroinflammatory activity grade (r = 0.682) and the stage of liver fibrosis (r = 0.539). The positive correlation of serum GP73 with the degree of hepatic necroinflammatory activity was statistically significant, while serum GP73 with the stage of liver fibrosis was weaker than that with hepatic necroinflammation. Furthermore, serum GP73 levels were significantly greater in patients with normal or mildly elevated ALT and significant hepatic necroinflammation (≥G2) than in patients with minimal to mild hepatic necroinflammation. The sensitivity and specificity of GP73 for the diagnosis of G2 hepatic necroinflammation was 42.35% and 95.0%, respectively, at a cut-off value of 88.38 ng/mL. When the cut-off value was set at 124.76 ng/mL, the sensitivity and specificity of GP73 for the diagnosis of G3 hepatic necroinflammation was 55.56% and 97.29%, respectively. These findings indicate that GP73 holds promise as an important candidate for diagnosing significant hepatic necroinflammation.
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Affiliation(s)
- Zhengju Xu
- Clinical Liver Center, The 180th Hospital of the People's Liberation Army, Quanzhou, P.R. China
| | - Jiankun Shen
- Clinical Liver Center, The 180th Hospital of the People's Liberation Army, Quanzhou, P.R. China
| | - Xingnan Pan
- Clinical Liver Center, The 180th Hospital of the People's Liberation Army, Quanzhou, P.R. China
| | - Meijuan Wei
- Central Laboratory of Clinical Hepatology, The 180th Hospital of the People's Liberation Army, Quanzhou, P.R. China
| | - Liguan Liu
- Clinical Liver Center, The 180th Hospital of the People's Liberation Army, Quanzhou, P.R. China
| | - Kaipeng Wei
- Central Laboratory of Clinical Hepatology, The 180th Hospital of the People's Liberation Army, Quanzhou, P.R. China
| | - Lifei Liu
- Department of Pathology, The 180th Hospital of the People's Liberation Army, Quanzhou, P.R. China
| | - Huanwen Yang
- Clinical Liver Center, The 180th Hospital of the People's Liberation Army, Quanzhou, P.R. China
| | - Jinfa Huang
- Clinical Liver Center, The 180th Hospital of the People's Liberation Army, Quanzhou, P.R. China
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Zhang W, Kim H, Lv J, Zhao N, Ma X. Golgi Phosphoprotein 2 Is a Novel Regulator of IL-12 Production and Macrophage Polarization. THE JOURNAL OF IMMUNOLOGY 2018; 200:1480-1488. [DOI: 10.4049/jimmunol.1700897] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/20/2017] [Accepted: 12/04/2017] [Indexed: 12/14/2022]
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Markers of clinical utility in the differential diagnosis and prognosis of prostate cancer. Mod Pathol 2018; 31:S143-155. [PMID: 29297492 DOI: 10.1038/modpathol.2017.168] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2017] [Revised: 11/02/2017] [Accepted: 11/03/2017] [Indexed: 12/13/2022]
Abstract
Molecular diagnostics is a rapidly evolving area of surgical pathology, that is gradually beginning to transform our diagnostical procedures for a variety of tumors. Next to molecular prognostication that has begun to complement our histological diagnosis in breast cancer, additional testing to detect targets and to predict therapy response has become common practice in breast and lung cancer. Prostate cancer is a bit slower in this respect, as it is still largely diagnosed and classified on morphological grounds. Our diagnostic immunohistochemical armamentarium of basal cell markers and positive markers of malignancy now allows to clarify the majority of lesions, if applied to the appropriate morphological context (and step sections). Prognostic immunohistochemistry remains a problematic and erratic yet tempting research field that provides information on tumor relevance of proteins, but little hard data to integrate into our diagnostic workflow. Main reasons are various issues of standardization that hamper the reproducibility of cut-off values to delineate risk categories. Molecular testing of DNA-methylation or transcript profiling may be much better standardized and this review discusses a couple of commercially available tests: The ConfirmDX test measures DNA-methylation to estimate the likelihood of cancer detection on a repeat biopsy and may help to reduce unnecessary biopsies. The tests Prolaris, OncotypeDX Prostate, and Decipher all are transcript tests that have shown to provide prognostic data independent of clinico-pathological parameters and that may aid in therapy planning. However, further validation and more comparative studies will be needed to clarify the many open questions concerning sampling bias and tumor heterogeneity.
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Dong M, Chen ZH, Li X, Li XY, Wen JY, Lin Q, Ma XK, Wei L, Chen J, Ruan DY, Lin ZX, Wang TT, Wu DH, Wu XY. Serum Golgi protein 73 is a prognostic rather than diagnostic marker in hepatocellular carcinoma. Oncol Lett 2017; 14:6277-6284. [PMID: 29113278 PMCID: PMC5661440 DOI: 10.3892/ol.2017.6938] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2016] [Accepted: 07/03/2017] [Indexed: 12/19/2022] Open
Abstract
Serum Golgi protein 73 (sGP73) is a candidate diagnostic biomarker for hepatocellular carcinoma (HCC). However, current evidence of its diagnostic value is conflicting, primarily due to the small sample sizes of previous studies, and its prognostic role in HCC also remains unclear. In the present study, sGP73 levels in 462 patients with HCC, 186 patients with liver cirrhosis, and 83 healthy controls were evaluated using ELISA, and it was identified that the median sGP73 levels were significantly higher in the HCC (18.7 ng/ml) and liver cirrhosis (18.5 ng/ml) patients than in the healthy controls (0 ng/ml; both P<0.001); however, the levels did not significantly differ between the HCC and liver cirrhosis groups (P=0.632). sGP73 had an inferior sensitivity and specificity for HCC diagnosis (27.79 and 77.96%, respectively) compared with α-fetoprotein (57.36 and 90.96%, respectively; P<0.001). In the HCC group, a high level of sGP73 was associated with aggressive clinicopathological features and independently predicted poor overall survival (OS) time (P<0.001). Additionally, in patients with resectable HCC, a high level of sGP73 was associated with significantly decreased disease-free survival (P<0.001) and OS (P=0.039) times compared with a low level of sGP73. This study demonstrated that sGP73 is unsuitable as a diagnostic marker for the early detection of HCC; however, it is an independent negative prognostic marker, providing a novel risk stratification factor and a potential therapeutic molecular target for HCC.
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Affiliation(s)
- Min Dong
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Zhan-Hong Chen
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
- Department of Medical Oncology of Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong 510060, P.R. China
| | - Xing Li
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Xiao-Yun Li
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
- Department of Medical Oncology, The First Affiliated Hospital, Henan University, Kaifeng, Henan 475001, P.R. China
| | - Jing-Yun Wen
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Qu Lin
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Xiao-Kun Ma
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Li Wei
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Jie Chen
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Dan-Yun Ruan
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Ze-Xiao Lin
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Tian-Tian Wang
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Dong-Hao Wu
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Xiang-Yuan Wu
- Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
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Cao Z, Li Z, Wang Y, Liu Y, Mo R, Ren P, Chen L, Lu J, Li H, Zhuang Y, Liu Y, Wang X, Zhao G, Tang W, Xiang X, Wang H, Cai W, Liu L, Zhu C, Bao S, Xie Q. Assessment of serum Golgi protein 73 as a biomarker for the diagnosis of significant fibrosis in patients with chronic HBV infection. J Viral Hepat 2017; 24 Suppl 1:57-65. [PMID: 29082644 DOI: 10.1111/jvh.12786] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Accepted: 09/14/2017] [Indexed: 12/15/2022]
Abstract
Transient elastography (TE) is accurate in staging fibrosis noninvasively. However, a reliable serum biomarker with comparable accuracy is also important, especially when TE is unreliable/unavailable. Therefore, we aimed to evaluate the diagnostic performance of serum Golgi protein 73 (GP73) for significant fibrosis in patients with chronic HBV infection. A total of 801 patients with chronic liver disease (CLD; 492 chronic HBV infection and 309 non-HBV liver disease) with liver biopsy performance were enrolled. Healthy controls (n = 180) and hepatocellular carcinoma (HCC) patients (n = 85) were included for comparisons. Liver biopsy was used as the reference method for fibrosis staging. Serum GP73 level was measured in duplicate in double-blind fashion. Serum GP73 was highest in HCC but also significantly higher in chronic hepatitis B than in healthy controls. The elevation of serum GP73 in non-HCC patients was significantly associated with the presence of significant fibrosis independently of ALT level, liver stiffness (LS) value, inflammation grade and other confounding factors. The diagnostic performance of serum GP73 was accurate in antiviral-naïve HBV patients (area under the receiver operating curve [AUROC], 0.76 95% CI: 0.72-0.81) but not in patients with ongoing antiviral treatment (AUROC, 0.60). The utility of serum GP73 was also confirmed in non-HBV CLD (AUROC, 0.80 95% CI: 0.75-0.85). Serum GP73 was comparable to LS (AUROC, 0.78 95% CI: 0.73-0.82) and significantly better than AST to platelet ratio index (APRI) (AUROC, 0.67 95% CI: 0.62-0.72) and FIB-4 (AUROC, 0.68 95% CI: 0.63-0.73). In conclusion, serum GP73 is an accurate serum marker for significant fibrosis in chronic HBV infection, with higher accuracy than APRI and FIB-4. Serum GP73 is potentially a complementary tool for TE when evaluating the necessity of antiviral treatment, particularly in patients without definite antiviral indication.
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Affiliation(s)
- Z Cao
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Z Li
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Y Wang
- Department of Hepatology, The Affiliated Infectious Diseases Hospital of Soochow University, Suzhou, China
| | - Y Liu
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - R Mo
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - P Ren
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - L Chen
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - J Lu
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - H Li
- Department of Infectious Disease, The Third Hospital of Changzhou, Jiangsu, China
| | - Y Zhuang
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Y Liu
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - X Wang
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - G Zhao
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - W Tang
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - X Xiang
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - H Wang
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - W Cai
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - L Liu
- Department of Infectious Disease, The Third Hospital of Changzhou, Jiangsu, China
| | - C Zhu
- Department of Hepatology, The Affiliated Infectious Diseases Hospital of Soochow University, Suzhou, China
| | - S Bao
- Discipline of Pathology, School of Medical Sciences and Bosch Institute, University of Sydney, Sydney, NSW, Australia
| | - Q Xie
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Zhang Y, Hu W, Wang L, Han B, Lin R, Wei N. Association of GOLPH2 expression with survival in non-small-cell lung cancer: clinical implications and biological validation. Biomark Med 2017; 11:967-977. [PMID: 28880107 DOI: 10.2217/bmm-2017-0199] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
AIM We investigated the role of GOLPH2 in non-small-cell lung cancer (NSCLC). METHODS We analyzed the relationship between the expression of GOLPH2 and the clinical pathological characteristics of patients with NSCLC. The function of GOLPH2 in NSCLC cell lines was also explored through overexpression and knockdown studies. RESULTS The positive expression rate of GOLPH2 protein in NSCLC tissue was higher than that of normal lung tissue. We found that positive GOLPH2 expression was closely associated with unfavorable features of patients with NSCLC. The GOLPH2 expression was an independent predictor of the prognosis of patients with NSCLC. That GOLPH2 can promote the proliferation and invasion of NSCLC cells. CONCLUSION The GOLPH2 is a novel marker for NSCLC.
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Affiliation(s)
- Yu Zhang
- Department of Thoracic Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Wenteng Hu
- Department of Thoracic Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Liwei Wang
- Department of Thoracic Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Biao Han
- Department of Thoracic Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Ruijiang Lin
- Department of Thoracic Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Ning Wei
- Department of Thoracic Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
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Ai N, Liu W, Li ZG, Ji H, Li B, Yang G. High expression of GP73 in primary hepatocellular carcinoma and its function in the assessment of transcatheter arterial chemoembolization. Oncol Lett 2017; 14:3953-3958. [PMID: 28943903 DOI: 10.3892/ol.2017.6697] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2015] [Accepted: 04/03/2017] [Indexed: 02/06/2023] Open
Abstract
Golgi glycoprotein 73 (GP73) is a type II Golgi transmembrane protein and a potential novel marker for the diagnosis of primary hepatocellular carcinoma (PHC). However, its reliability as a serum marker for the diagnosis of PHC following transcatheter arterial chemoembolization (TACE) remains unknown. The aim of the present study was to evaluate the diagnostic value of serum GP73 levels in patients with PHC, to determine its diagnostic accuracy in patients with PHC following TACE. Reverse transcription-quantitative polymerase chain reaction analysis was used to measure GP73 expression in PHC and adjacent para-carcinomatous liver tissue in 40 patients with PHC, and 15 normal liver samples from benign hepatic tumors. The associations between GP73 expression levels with clinicopathological characteristics of the patients were also analyzed. Serum GP73 levels were detected by ELISA in 68 patients with PHC following TACE and 29 healthy individuals. The levels of serum GP73 were tested 2 days prior to intervention, and 7 and 30 days following TACE. GP73 mRNA expression levels in PHC were significantly higher than in the corresponding para-carcinomatous liver and normal liver samples. High expression levels of GP73 mRNA were associated with tumor size, vascular invasion and tumor differentiation, suggesting augmented tumor invasion and metastasis. The expression levels of serum GP73 were markedly higher in the patients with PHC compared with healthy individuals. Serum GP73 levels in the 68 patients with PHC were higher compared with the 29 normal controls [152.5 (76.4-284.5) compared with 49.3 (12.6-26.7) µg/l], and the difference was statistically significant (P<0.01). High levels of serum GP73 were associated with tumor differentiation. The levels of Barcelona clinic liver cancer stage A, B and C were 92.12 (38.9-135.2), 122.9 (55.2-178.5), and 162.55 (110.8-232.9) µg/l, respectively (P<0.05). The serum GP73 levels 7 days following TACE [99.2 (66.7-150.8)] were significantly lower than prior to TACE, and the difference was statistically significant (P<0.05). In the group of 49 patients with serum α-fetoprotein (AFP) levels <400 µg/l, the serum GP73 levels were >132 µg/l. Serum GP73 levels may serve as a potential independent diagnostic marker for PHC, and the combined evaluation of serum GP73 and AFP may increase the diagnostic efficiency of PHC. Significant overexpression of GP73 mRNA was associated with aggressive PHC. However, further research is required to confirm the potential of GP73 as a diagnostic marker.
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Affiliation(s)
- Ning Ai
- Department of Radiology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Wei Liu
- Department of Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Zhi-Gang Li
- Department of Radiology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Hong Ji
- Department of General Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Bo Li
- Department of Radiology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Guang Yang
- Department of Radiology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
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Li B, Li B, Guo T, Sun Z, Li X, Li X, Chen L, Zhao J, Mao Y. Artificial neural network models for early diagnosis of hepatocellular carcinoma using serum levels of α-fetoprotein, α-fetoprotein-L3, des-γ-carboxy prothrombin, and Golgi protein 73. Oncotarget 2017; 8:80521-80530. [PMID: 29113322 PMCID: PMC5655217 DOI: 10.18632/oncotarget.19298] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2017] [Accepted: 06/02/2017] [Indexed: 02/07/2023] Open
Abstract
More than 70% of hepatocellular carcinoma (HCC) cases develop as a consequence of liver cirrhosis (LC). Here we have evaluated the diagnostic potential of four serum biomarkers, and developed models for HCC diagnosis and differentiation from LC patients. Serum levels of α-fetoprotein (AFP), AFP-L3, des-γ-carboxy prothrombin (DCP), and Golgi protein 73 (GP73) were analyzed in 114 advanced HCC patients, 81 early stage HCC patients, and 152 LC patients. Multilayer perceptron (MLP) and radial basis function (RBF) neural networks were used to construct the diagnostic models. Using all stages, HCC diagnostic models had a higher sensitivity (>70%) than the individual serum biomarkers, whereas only early stage HCC diagnostic models had a higher specificity (>80%). The early stage HCC diagnostic models could not be used as HCC screening tools due to their low sensitivity (about 40%). These results suggest that a combination of the two models might be used as a screening tool to distinguish early stage HCC patients from LC patients, thus improving prevention and treatment of HCC.
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Affiliation(s)
- Bo Li
- Center for Clinical Laboratory, 302 Millitary Hospital, Beijing, China
| | - Boan Li
- Center for Clinical Laboratory, 302 Millitary Hospital, Beijing, China
| | - Tongsheng Guo
- Center for Clinical Laboratory, 302 Millitary Hospital, Beijing, China
| | - Zhiqiang Sun
- Center for Clinical Laboratory, 302 Millitary Hospital, Beijing, China
| | - Xiaohan Li
- Center for Clinical Laboratory, 302 Millitary Hospital, Beijing, China.,Graduate student team, Medical University of PLA, Beijing, China
| | - Xiaoxi Li
- Center for Clinical Laboratory, 302 Millitary Hospital, Beijing, China
| | - Lin Chen
- Center for Clinical Laboratory, 302 Millitary Hospital, Beijing, China.,Graduate student team, Medical University of PLA, Beijing, China
| | - Jing Zhao
- Center for Clinical Laboratory, 302 Millitary Hospital, Beijing, China
| | - Yuanli Mao
- Center for Clinical Laboratory, 302 Millitary Hospital, Beijing, China.,Graduate student team, Medical University of PLA, Beijing, China
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Betesh L, Comunale MA, Wang M, Liang H, Hafner J, Karabudak A, Giama NH, Moser CD, Miyoshi E, Roberts LR, Block TM, Mehta A. Identification of fucosylated Fetuin-A as a potential biomarker for cholangiocarcinoma. Proteomics Clin Appl 2017; 11. [PMID: 28561948 DOI: 10.1002/prca.201600141] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2016] [Revised: 05/11/2017] [Accepted: 05/23/2017] [Indexed: 01/10/2023]
Abstract
PURPOSE Cholangiocarcinoma (CCA) is a malignancy of the bile ducts. The purpose of this discovery study was to identify effective serum markers for surveillance of cholangiocarcinoma. EXPERIMENTAL DESIGN Using a glycomic method, patients with CCA were determined to have increased levels of alpha-1,3 and alpha-1,6 linked fucosylated glycan. Proteomic analysis of the serum fucosylated proteome identified proteins such as alpha-2-macroglobulin, kininogen, hemopexin, fetuin-A, alpha-1 anti-trypsin, and ceruloplasmin as being hyperfucosylated in HCC. The levels of these glycoproteins in 109 patients with CCA, primary sclerosing cholangitis (PSC), and control patients were compared to the performance of CA-19-9, the current "gold standard" assay for cholangiocarcinoma. RESULTS Fucosylated Fetuin-A (fc-Fetuin-A) had the best ability to differentiate CCA from PSC, with an AUROC of 0.812 or 0.8665 at differentiating CCA from those with PSC or other liver disease. CA-19-9 had poor ability to differentiate PSC from cholangiocarcinoma (AUROC of 0.625). CONCLUSION AND CLINICAL RELEVANCE Using glycomic and proteomic methods we identified a set of proteins that contain altered glycan in the sera of those with CCA. One of these proteins, fucosylated Fetuin-A may have value in the surveillance of people at risk for the development of cholangiocarcinoma.
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Affiliation(s)
- Lucy Betesh
- Department of Cell and Molecular Pharmacology, Medical University of South Carolina, Charleston, SC, USA
| | - Mary Ann Comunale
- Department of Cell and Molecular Pharmacology, Medical University of South Carolina, Charleston, SC, USA
| | - Mengjun Wang
- Department of Cell and Molecular Pharmacology, Medical University of South Carolina, Charleston, SC, USA
| | - Hongyan Liang
- Department of Cell and Molecular Pharmacology, Medical University of South Carolina, Charleston, SC, USA
| | - Julie Hafner
- The Baruch Blumberg Institute, Doylestown, PA, USA
| | | | - Nasra H Giama
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Catherine D Moser
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Eiji Miyoshi
- Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Japan
| | - Lewis R Roberts
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Timothy M Block
- Department of Cell and Molecular Pharmacology, Medical University of South Carolina, Charleston, SC, USA
| | - Anand Mehta
- Department of Cell and Molecular Pharmacology, Medical University of South Carolina, Charleston, SC, USA
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Li B, Li B, Guo T, Sun Z, Li X, Li X, Wang H, Chen W, Chen P, Mao Y. The Clinical Values of Serum Markers in the Early Prediction of Hepatocellular Carcinoma. BIOMED RESEARCH INTERNATIONAL 2017; 2017:5358615. [PMID: 28540298 PMCID: PMC5429927 DOI: 10.1155/2017/5358615] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/09/2016] [Accepted: 03/09/2017] [Indexed: 12/18/2022]
Abstract
The early prediction values of diagnostic markers for hepatocellular carcinoma (HCC) are still unclear at present. This study evaluated the prediction value of ten serum markers in HCC. A total of 109 cases of hepatic cirrhosis patients were followed up for 36 months and the relationship between the lifetime risk of developing HCC and levels of serum markers was analyzed. 31.2 (34/109) percent of hepatic cirrhosis patients developed HCC during the study's timeframe. Higher alpha-fetoprotein (AFP), alpha-fetoprotein-L3 (AFP-L3), alanine aminotransferase (ALT), and AFP-L3/AFP ratio levels are potential risk factors for malignization in hepatic cirrhosis patients (RR = 2.99, 2.92, 2.72, and 2.34); serum Golgi protein 73 (GP73) level of hepatic cirrhosis patients decreased significantly after developing HCC (t = 2.212; p = 0.041). The detection of ALT, AFP, AFP-L3, and GP73 has a certain guiding significance to predict the risk of HCC in hepatic cirrhosis patients.
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Affiliation(s)
- Bo Li
- Center for Clinical Laboratory, 302 Military Hospital, Beijing, China
| | - Boan Li
- Center for Clinical Laboratory, 302 Military Hospital, Beijing, China
| | - Tongsheng Guo
- Center for Clinical Laboratory, 302 Military Hospital, Beijing, China
| | - Zhiqiang Sun
- Center for Clinical Laboratory, 302 Military Hospital, Beijing, China
| | - Xiaohan Li
- Center for Clinical Laboratory, 302 Military Hospital, Beijing, China
- Graduate Student Team, Medical University of PLA, Beijing, China
| | - Xiaoxi Li
- Center for Clinical Laboratory, 302 Military Hospital, Beijing, China
| | - Han Wang
- Center for Clinical Laboratory, 302 Military Hospital, Beijing, China
| | - Weijiao Chen
- Center for Clinical Laboratory, 302 Military Hospital, Beijing, China
| | - Peng Chen
- Center for Clinical Laboratory, 302 Military Hospital, Beijing, China
| | - Yuanli Mao
- Center for Clinical Laboratory, 302 Military Hospital, Beijing, China
- Graduate Student Team, Medical University of PLA, Beijing, China
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Zhang X, Zhu C, Wang T, Jiang H, Ren Y, Zhang Q, Wu K, Liu F, Liu Y, Wu J. GP73 represses host innate immune response to promote virus replication by facilitating MAVS and TRAF6 degradation. PLoS Pathog 2017; 13:e1006321. [PMID: 28394926 PMCID: PMC5398727 DOI: 10.1371/journal.ppat.1006321] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2016] [Revised: 04/20/2017] [Accepted: 03/28/2017] [Indexed: 12/31/2022] Open
Abstract
Hepatitis C virus (HCV) infection is a leading cause of chronic liver diseases and hepatocellular carcinoma (HCC) and Golgi protein 73 (GP73) is a serum biomarker for liver diseases and HCC. However, the mechanism underlying GP73 regulates HCV infection is largely unknown. Here, we revealed that GP73 acts as a novel negative regulator of host innate immunity to facilitate HCV infection. GP73 expression is activated and correlated with interferon-beta (IFN-β) production during HCV infection in patients’ serum, primary human hepatocytes (PHHs) and human hepatoma cells through mitochondrial antiviral signaling protein (MAVS), TNF receptor-associated factor 6 (TRAF6) and mitogen-activated protein kinase kinase/extracellular regulated protein kinase (MEK/ERK) pathway. Detailed studies revealed that HCV infection activates MAVS that in turn recruits TRAF6 via TRAF-interacting-motifs (TIMs), and TRAF6 subsequently directly recruits GP73 to MAVS via coiled-coil domain. After binding with MAVS and TRAF6, GP73 promotes MAVS and TRAF6 degradation through proteasome-dependent pathway. Moreover, GP73 attenuates IFN-β promoter, IFN-stimulated response element (ISRE) and nuclear factor κB (NF-κB) promoter and down-regulates IFN-β, IFN-λ1, interleukin-6 (IL-6) and IFN-stimulated gene 56 (ISG56), leading to the repression of host innate immunity. Finally, knock-down of GP73 down-regulates HCV infection and replication in Huh7-MAVSR cells and primary human hepatocytes (PHHs), but such repression is rescued by GP73m4 (a mutant GP73 resists to GP73-shRNA#4) in Huh7-MAVSR cells, suggesting that GP73 facilitates HCV infection. Taken together, we demonstrated that GP73 acts as a negative regulator of innate immunity to facilitate HCV infection by interacting with MAVS/TRAF6 and promoting MAVS/TRAF6 degradation. This study provides new insights into the mechanism of HCV infection and pathogenesis, and suggests that GP73 is a new potential antiviral target in the prevention and treatment of HCV associated diseases. Golgi protein 73 (GP73) is a serum biomarker for liver diseases and hepatocellular carcinoma (HCC). In this study, the authors reveal that GP73 acts as a novel negative regulator of host innate immunity to facilitate hepatitis C virus (HCV) infection. GP73 expression is activated and correlated with IFN-β production during HCV infection in patients’ serum, primary human hepatocytes (PHHs) and human hepatoma cells through mitochondrial antiviral signaling protein (MAVS), TNF receptor-associated factor 6 (TRAF6) and MEK/ERK pathway. They further demonstrate that during viral infection, MAVS recruits TRAF6 that subsequently directly binds with GP73. After binding with MAVS and TRAF6, GP73 promotes MAVS and TRAF6 degradation. Moreover, GP73 attenuates IFN-β promoter, IFN-stimulated response element (ISRE) and NF-κB promoter and down-regulates IFN-β, IFN-λ1, interleukin-6 (IL-6) and IFN-stimulated gene 56 (ISG56), leading to the repression of host innate immunity and the facilitation of virus infection. These results reveal a novel mechanism by which GP73 acts as a novel negative regulator of host innate immunity to facilitate virus infection and also provide new insights into the therapeutic design of anti-HCV drugs.
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Affiliation(s)
- Xuewu Zhang
- State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, P. R. China
| | - Chengliang Zhu
- State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, P. R. China
| | - Tianci Wang
- State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, P. R. China
| | - Hui Jiang
- State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, P. R. China
| | - Yahui Ren
- State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, P. R. China
| | - Qi Zhang
- State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, P. R. China
| | - Kailang Wu
- State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, P. R. China
| | - Fang Liu
- State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, P. R. China
- * E-mail: (JW); (YL); (FL)
| | - Yingle Liu
- State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, P. R. China
- * E-mail: (JW); (YL); (FL)
| | - Jianguo Wu
- State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, P. R. China
- * E-mail: (JW); (YL); (FL)
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Shaker MK, Abdel Fattah HI, Sabbour GS, Montasser IF, Abdelhakam SM, El Hadidy E, Yousry R, El Dorry AK. Annexin A2 as a biomarker for hepatocellular carcinoma in Egyptian patients. World J Hepatol 2017; 9:469-476. [PMID: 28396717 PMCID: PMC5368624 DOI: 10.4254/wjh.v9.i9.469] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2016] [Revised: 01/06/2017] [Accepted: 03/12/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the clinical utility of serum annexin A2 (ANXA2) as a diagnostic marker for early hepatocellular carcinoma (HCC). METHODS This study was performed in HCC Clinic of Ain Shams University Hospitals, Cairo, Egypt and included: Group 1: Fifty patients with early stage HCC (Barcelona Clinic Liver Cancer stage A); Group 2: Twenty five patients with chronic liver disease; and Control Group: Fifteen healthy, age- and sex-matched subjects who were seronegative for viral hepatitis markers. The following laboratory investigations were done: Viral hepatitis markers [hepatitis B surface antigen and hepatitis C virus (HCV) antibodies], HCV RNA in HCV antibody-positive patients, serum alpha fetoprotein (AFP), and serum ANXA2 levels. RESULTS In this study, 88% of HCC patients (n = 44) were HCV-positive, while HBV infection represented only 8% of all HCC patients (n = 4); and two patients were negative for both viral markers. A highly significant difference was found between patients with HCC and chronic liver disease as well as controls with regard to serum ANXA2 levels (130, IQR 15-240; 15, IQR 15-17; and 17, IQR 15-30 ng/mL, respectively). The area under the curve of ANXA2 was 0.865; the cut-off value was established to be 18 ng/mL with a diagnostic sensitivity of 74% and a specificity of 88%, while the sensitivity and specificity of AFP at the cut-off value of 200 ng/dL were 20% and 100%, respectively. CONCLUSION Serum ANXA2 may serve as a biomarker for the early detection of HCC.
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Affiliation(s)
- Mohamed K Shaker
- Mohamed K Shaker, Iman F Montasser, Sara M Abdelhakam, Department of Tropical Medicine, Faculty of Medicine, Ain Shams University, Cairo 11341, Egypt
| | - Hanzada I Abdel Fattah
- Mohamed K Shaker, Iman F Montasser, Sara M Abdelhakam, Department of Tropical Medicine, Faculty of Medicine, Ain Shams University, Cairo 11341, Egypt
| | - Ghada S Sabbour
- Mohamed K Shaker, Iman F Montasser, Sara M Abdelhakam, Department of Tropical Medicine, Faculty of Medicine, Ain Shams University, Cairo 11341, Egypt
| | - Iman F Montasser
- Mohamed K Shaker, Iman F Montasser, Sara M Abdelhakam, Department of Tropical Medicine, Faculty of Medicine, Ain Shams University, Cairo 11341, Egypt
| | - Sara M Abdelhakam
- Mohamed K Shaker, Iman F Montasser, Sara M Abdelhakam, Department of Tropical Medicine, Faculty of Medicine, Ain Shams University, Cairo 11341, Egypt
| | - Eman El Hadidy
- Mohamed K Shaker, Iman F Montasser, Sara M Abdelhakam, Department of Tropical Medicine, Faculty of Medicine, Ain Shams University, Cairo 11341, Egypt
| | - Rehab Yousry
- Mohamed K Shaker, Iman F Montasser, Sara M Abdelhakam, Department of Tropical Medicine, Faculty of Medicine, Ain Shams University, Cairo 11341, Egypt
| | - Ahmed K El Dorry
- Mohamed K Shaker, Iman F Montasser, Sara M Abdelhakam, Department of Tropical Medicine, Faculty of Medicine, Ain Shams University, Cairo 11341, Egypt
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A sensitive three monoclonal antibodies based automatic latex particle-enhanced turbidimetric immunoassay for Golgi protein 73 detection. Sci Rep 2017; 7:40090. [PMID: 28054632 PMCID: PMC5215377 DOI: 10.1038/srep40090] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Accepted: 12/01/2016] [Indexed: 12/17/2022] Open
Abstract
Golgi protein 73 (GP73) is a novel and potential marker for diagnosing hepatocellular carcinoma (HCC) that has been found to be abnormally elevated in liver disease. A latex particle-enhanced turbidimetric immunoassay (LTIA) was recently introduced and licensed for application in a variety of automated clinical chemistry analyzers. However, no studies have reported sufficient data on analytical performance of this method when using 3 monoclonal antibodies for GP73 measurement. The experimental conditions were firstly optimized and range of linearity, diagnostic potential, clinical relevance were compared with the LTIA based on polyclonal antibodies and ELISA. Dilution tests for the LTIA using 3 monoclonal antibodies produced a calibration curve from 10 to 350 ng/mL while the polyclonal antibodies produced the curve from 20 to 320 ng/mL. The detection limit was achieved at 1.82 ng/mL concentration. Within-run CV was obtained in the range of 1.5-2.9% and ROC curves indicated sensitivity and specificity of the LTIA based on 3 monoclonal antibodies were 96.7% and 93.3%, respectively, higher than for the polyclonal antibodies (94.6% and 72.4%) and ELISA (70.0% and 83.3%). Therefore, the LTIA assay based on 3 monoclonal antibodies is thus applicable in quantification of GP73 concentration in automated biochemistry analyzers.
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Semik E, Gurgul A, Ząbek T, Ropka-Molik K, Koch C, Mählmann K, Bugno-Poniewierska M. Transcriptome analysis of equine sarcoids. Vet Comp Oncol 2016; 15:1370-1381. [PMID: 27779365 DOI: 10.1111/vco.12279] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2016] [Revised: 09/23/2016] [Accepted: 09/24/2016] [Indexed: 01/28/2023]
Abstract
Equine sarcoids are the most commonly detected skin tumours in Equidae. In the present research, a comparative transcriptomic analysis was performed which aimed at looking inside a tumour biology and identification of the expression profile as a potential source of cancer specific genes useful as biomarkers. We have used Horse Gene Expression Microarray data from matched equine sarcoids and tumour-distant skin samples. In total, 901 significantly differentially expressed genes (DEGs) between lesional and healthy skin samples have been identified (fold change ≥ 2; P < 0.05). The large subset of DEGs, with decreased expression, was associated with a suppression of malignant transformation, whereas several overexpressed genes were involved in the processes associated with growth and progression of a tumour or immune system activity. Our results, as a first to date, showed comprehensive transcriptome analysis of skin tumour in horses and pinpointed significant pathways and genes related with oncogenesis processes.
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Affiliation(s)
- E Semik
- Department of Genomics and Molecular Biology of Animals, National Research Institute of Animal Production, Balice, Poland
| | - A Gurgul
- Department of Genomics and Molecular Biology of Animals, National Research Institute of Animal Production, Balice, Poland
| | - T Ząbek
- Department of Genomics and Molecular Biology of Animals, National Research Institute of Animal Production, Balice, Poland
| | - K Ropka-Molik
- Department of Genomics and Molecular Biology of Animals, National Research Institute of Animal Production, Balice, Poland
| | - C Koch
- ISME - Equine Clinic Bern, Department of Clinical Veterinary Medicine, Vetsuisse Faculty, University of Bern, Bern, Switzerland
| | - K Mählmann
- Equine Clinic, General Surgery and Radiology, Freie Universität Berlin, Berlin, Germany
| | - M Bugno-Poniewierska
- Department of Genomics and Molecular Biology of Animals, National Research Institute of Animal Production, Balice, Poland
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Zhang X, Wang T, Dai X, Zhang Y, Jiang H, Zhang Q, Liu F, Wu K, Liu Y, Zhou H, Wu J. Golgi protein 73 facilitates the interaction of hepatitis C virus NS5A with apolipoprotein E to promote viral particle secretion. Biochem Biophys Res Commun 2016; 479:683-689. [PMID: 27697522 DOI: 10.1016/j.bbrc.2016.09.152] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2016] [Accepted: 09/28/2016] [Indexed: 12/12/2022]
Abstract
Hepatitis C virus (HCV) infection is one of the leading causes of chronic liver diseases and hepatocellular carcinoma (HCC). Golgi protein 73 (GP73), a resident Golgi membrane protein, is a novel serum biomarker for the diagnosis of liver diseases and HCC. Although previous studies have demonstrated that HCV upregulates GP73 expression and GP73 promotes HCV secretion through its interaction with apolipoprotein E (ApoE), the exact mechanism underlying GP73 regulates HCV secretion remains unclear. In this study, we demonstrated that GP73 mediates the interaction of ApoE with HCV NS5A protein to promote HCV secretion. We revealed that GP73 is colocalized with HCV replication complex in infected-Huh7.5.1 cells. Further studies demonstrated that GP73 interacted with both NS5A and ApoE proteins. Furthermore, knockdown of GP73 significantly reduced the binding of NS5A with ApoE, and the production of virus particles in culture supernatant. Taken together, our studies revealed that GP73 promotes HCV secretion by directly mediating the interaction of ApoE with HCV replication complex through binding with HCV NS5A.
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Affiliation(s)
- Xuewu Zhang
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China
| | - Tianci Wang
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China
| | - Xuechen Dai
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China
| | - Yecheng Zhang
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China
| | - Hui Jiang
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China
| | - Qi Zhang
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China
| | - Fang Liu
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China
| | - Kailang Wu
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China
| | - Yingle Liu
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China.
| | - Hong Zhou
- Department of Clinical Laboratory, Wuhan Medical Treatment Center, Wuhan 430023, China.
| | - Jianguo Wu
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China.
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Wang F, Huang J, Zhu Z, Ma X, Cao L, Zhang Y, Chen W, Dong Y. Transcriptome Analysis of WHV/c-myc Transgenic Mice Implicates Cytochrome P450 Enzyme 17A1 as a Promising Biomarker for Hepatocellular Carcinoma. Cancer Prev Res (Phila) 2016; 9:739-49. [PMID: 27339169 DOI: 10.1158/1940-6207.capr-16-0023] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Accepted: 06/13/2016] [Indexed: 11/16/2022]
Abstract
Early detection of hepatocellular carcinoma (HCC) is critical for successful treatment and favorable prognosis. To identify novel HCC biomarkers, we used the WHV/c-myc transgenic (Tg) mice, an animal model of hepatocarcinogenesis. By analyzing their gene expression profiling, we investigated differentially expressed genes in livers of wild-type and Tg mice. The cytochrome P450, family 17, subfamily A, polypeptide 1 (CYP17A1), a hepatic P450 enzyme, was revealed to be overexpressed in the liver tissues of Tg mice at both preneoplastic and neoplastic stages. Mouse-to-human validation demonstrated that CYP17A1 mRNA and protein were also significantly increased in human HCC tissues compared with paired nontumor tissues (P = 0.00041 and 0.00011, respectively). Immunohistochemical studies showed that CYP17A1 was overexpressed in 67% (58 of 87) of HCC, and strong staining of CYP17A1 was observed in well-differentiated HCCs. Consistent with this, the median serum levels of CYP17A1 were also significantly higher in patients with HCC (140.2 ng/mL, n = 776) compared with healthy controls (31.4 ng/mL, n = 366) and to those with hepatitis B virus (57.5 ng/mL, n = 160), cirrhosis (46.1 ng/mL, n = 147), lung cancer (27.4 ng/mL, n = 109), and prostate cancer (42.1 ng/mL, n = 130; all P < 0.001). Notably, the elevations were seen in most AFP-negative HCC cases. Altogether, through mouse-to-human search and validation, we found that CYP17A1 is overexpressed in HCCs and it has great potentiality as a noninvasive marker for HCC detection. These results provide a rationale for the future development and clinical application of CYP17A1 measurement to diagnose HCC more precisely. Cancer Prev Res; 9(9); 739-49. ©2016 AACR.
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Affiliation(s)
- Feng Wang
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, Yunnan Province, China
| | - Jian Huang
- Department of Oncology, The 1st. Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, China
| | - Zhu Zhu
- Department of Oncology, The 1st. Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, China
| | - Xiao Ma
- Key Laboratory of Pu-erh Tea Science of Ministry of Education, Yunnan Agricultural University, Kunming, Yunnan Province, China
| | - Li Cao
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, Yunnan Province, China
| | - Yongzhi Zhang
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, Yunnan Province, China
| | - Wei Chen
- College of Biological big data, Yunan Agricultural University, Kunming, Yunnan Province, China
| | - Yang Dong
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, Yunnan Province, China. College of Biological big data, Yunan Agricultural University, Kunming, Yunnan Province, China.
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Jiang K, Li W, Shang S, Sun L, Guo K, Zhang S, Liu Y. Aberrant expression of Golgi protein 73 is indicative of a poor outcome in hepatocellular carcinoma. Oncol Rep 2016; 35:2141-2150. [PMID: 26820712 DOI: 10.3892/or.2016.4601] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2015] [Accepted: 12/17/2015] [Indexed: 11/06/2022] Open
Abstract
Golgi protein 73 (GP73), a resident Golgi type-II membrane protein, is often upregulated in hepatocytes. In the present study, shRNA-mediated suppression of GP73 expression in hepatocellular carcinoma (HCC) cell lines (MHCC97H, HCCLM3) resulted in a significant inhibition of cell motility and invasion and also led to the regression of epithelial-mesenchymal transition phenotypes. In contrast, overexpression of GP73 in the SMMC7721 cell line retrieved the expression of EMT markers, and promoted cell motility and invasion. High expression of GP73 was also found in HCC tissues with metastasis, as detected by western blot and immunohistochemistry analyses. Kaplan-Meier survival analysis showed that the survival of patients with high GP73 expression was significantly poorer than that of patients with low GP73 expression (p=0.027). Our findings demonstrated an important role of GP73 in HCC metastasis, and indicated that GP73 is a candidate target for HCC therapy.
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Affiliation(s)
- Kai Jiang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, P.R. China
| | - Wei Li
- Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, P.R. China
| | - Shuxin Shang
- Department of Clinical Laboratory, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Lu Sun
- Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, P.R. China
| | - Kun Guo
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, P.R. China
| | - Shu Zhang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, P.R. China
| | - Yinkun Liu
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, P.R. China
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Li QW, Chen HB, Li ZY, Shen P, Qu LL, Gong LL, Xu HP, Pang L, Si J. Preparation and characterization of anti-GP73 monoclonal antibodies and development of double-antibody sandwich ELISA. Asian Pac J Cancer Prev 2015; 16:2043-9. [PMID: 25773808 DOI: 10.7314/apjcp.2015.16.5.2043] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Serum Golgi protein 73 (GP73) as a novel and potential marker for diagnosing hepatocellular carcinoma (HCC) have been found to be elevated in HCC patients and associated with clinical variables representing tumor growth and invasiveness. The aim of this study was to prepare a pair of monoclonal antibodys (mAbs) against GP73 and develop a newly designed double-antibody sandwich enzyme-linked immunosorbent assay (s-ELISA), which would be used in the detection of serum GP73 (sGP73) as well as in the diagnosis of HCC. MATERIALS AND METHODS Produced by prokaryotic expression, the purified recombinant GP73 (rGP73), produced by prokaryotic expression, was used to immunize the Balb/c mice. Two hybridoma cell lines against GP73 were obtained by fusing mouse Sp2/0 myeloma cells with spleen cells from the immunized mice. The titers of anti-GP73 mAb reached 1:243,000. Western blotting analysis and Immunohistochemistry staining revealed that anti-GP73 mAb could recognize GP73 protein. The double-antibody s-ELISA was successfully established and validated by 119 HCC and 103 normal serum samples. RESULTS showed that the detection limit of this method could reach 1.56 ng/ml, and sGP73 levels in HCC group (mean=190.6 ng/ml) were much higher than those of in healthy controls (mean=70.92 ng/ml). CONCLUSIONS Results of our study not only showed that sGP73 levels of HCC patients were significantly higher than those of healthy controls, but also indicated that the laboratory homemade anti-GP73 mAbs could be the optimal tool used in evaluating sGP73 levels, which would provide a solid foundation for subsequent clinical applications.
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Affiliation(s)
- Qi-Wen Li
- Department of Laboratory Medicine, The Second Affiliated Hospital, Nanjing Medical University, Nanjing, China E-mail :
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Jiang K, Shang S, Li W, Guo K, Qin X, Zhang S, Liu Y. Multiple lectin assays for detecting glyco-alteration of serum GP73 in liver diseases. Glycoconj J 2015; 32:657-664. [PMID: 26342810 DOI: 10.1007/s10719-015-9614-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2015] [Revised: 08/04/2015] [Accepted: 08/10/2015] [Indexed: 12/15/2022]
Abstract
Serum GP73 is a functional resident Golgi type II membrane protein with three potential N-glycosylation sites. In this study, we used multiple lectin assays to analyze glycan patterns of serum GP73 and evaluated its diagnostic value for distinguishing hepatocellular carcinoma (HCC) from liver cirrhosis (LC). Firstly, Antibody overlay lectin microarray and lectin blot were performed to observe altered glycans of GP73. Fucosylated structures were found to increase significantly in LC compared with HCC patients. Then, AAL ELISA assay using ELISA Index was utilized to measure fucosylation level of GP73 on its protein level (Fuc-GP73). ELISA Indices of 54 LC and 54 HCC patients was obtained and the area under the ROC curve (AUC) was 0.807 with a sensitivity of 85.2% and a specificity of 63.0% (cutoff of 3.182). In addition, combining Fuc-GP73 and AFP-L3 greatly improved the diagnostic accuracy (AUC = 0.953) and the diagnostic values were 94.4% sensitivity at 88.9% specificity. These data indicated that multiple lectin assays could contribute to pre-clinical evaluation of focused glycoprotein and Fuc-GP73 could act as a potential glycobiomarker complementary to AFP-L3 for discrimination of HCC from LC patients.
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Affiliation(s)
- Kai Jiang
- Cancer Research Center, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China
| | - Shuxin Shang
- Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Wei Li
- Cancer Research Center, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China
| | - Kun Guo
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, China
| | - Xue Qin
- Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Shu Zhang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, China.
| | - Yinkun Liu
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, China
- Cancer Research Center, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China
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Yin H, Tan Z, Wu J, Zhu J, Shedden KA, Marrero J, Lubman DM. Mass-Selected Site-Specific Core-Fucosylation of Serum Proteins in Hepatocellular Carcinoma. J Proteome Res 2015; 14:4876-84. [PMID: 26403951 PMCID: PMC4636958 DOI: 10.1021/acs.jproteome.5b00718] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
A mass spectrometry-based methodology has been developed to screen for changes in site-specific core-fucosylation (CF) of serum proteins in early stage HCC with different etiologies. The methods involve depletion of high-abundance proteins, trypsin digestion of medium-to-low-abundance proteins into peptides, iTRAQ labeling, and Lens culinaris Agglutinin (LCA) enrichment of CF peptides, followed by endoglycosidase F3 digestion before mass spectrometry analysis. 1300 CF peptides from 613 CF proteins were identified from patients sera, where 20 CF peptides were differentially expressed in alcohol (ALC)-related HCC samples compared with ALC-related cirrhosis samples and 26 CF peptides changed in hepatitis C virus (HCV)-related HCC samples compared with HCV-related cirrhosis samples. Among these, we found three CF peptides from fibronectin upregulated in ALC-related HCC samples compared with ALC-related cirrhosis samples with an AUC (area under the curve) value of 0.89 at site 1007 with a specificity of 85.7% at a sensitivity of 92.9% (generated with 10-fold cross-validation). When combined with the AFP index, the AUC value reached to 0.92 with a specificity of 92.9% at a sensitivity of 100%, significantly improved compared to that with AFP alone (LR test p < 0.001). In HCV-related samples, the CF level of cadherin-5 at site 61 showed the best AUC value of 0.75 but was not as promising as that of fibronectin site 1007 for ALC-related samples. The CF peptides of fibronectin may serve as potential biomarkers for early stage HCC screening in ALC-related cirrhosis patients.
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Affiliation(s)
- Haidi Yin
- Department of Surgery, University of Michigan Medical Center , Ann Arbor, Michigan 48109, United States
| | - Zhijing Tan
- Department of Surgery, University of Michigan Medical Center , Ann Arbor, Michigan 48109, United States
| | - Jing Wu
- Department of Surgery, University of Michigan Medical Center , Ann Arbor, Michigan 48109, United States
| | - Jianhui Zhu
- Department of Surgery, University of Michigan Medical Center , Ann Arbor, Michigan 48109, United States
| | - Kerby A Shedden
- Department of Statistics, University of Michigan , Ann Arbor, Michigan 48109, United States
| | - Jorge Marrero
- Liver Transplantation Program, University of Texas Southwestern Medical Center , Dallas, Texas 75390, United States
| | - David M Lubman
- Department of Surgery, University of Michigan Medical Center , Ann Arbor, Michigan 48109, United States
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Pan J, Zhang YF, Yang HY, Xu HF, Lu X, Sang XT, Zhong SX, Mao YL. The response of Golgi protein 73 to transcatheter arterial chemoembolization in patients with hepatocellular carcinoma may relate to the influence of certain chemotherapeutics. Hepatobiliary Pancreat Dis Int 2015; 14:406-12. [PMID: 26256086 DOI: 10.1016/s1499-3872(15)60403-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND Golgi protein 73 (GP73) is a promising biomarker of hepatocellular carcinoma (HCC). It decreases after surgical resection, and resumes upon recurrence, indicating a potential indicator for the effectiveness of the treatment. But changes of GP73 after transcatheter arterial chemoembolization (TACE) have not been reported so far. This study was to investigate the dynamic changes of GP73 in HCC patients after TACE treatment, and the possible underlying mechanisms in the cell cultures. METHODS Blood samples were collected from 72 HCC patients, before TACE, at day 1 and day 30 after TACE. GP73 levels were measured by Western blotting. The dynamic changes of GP73 were analyzed and compared with image changes and clinical data. The effects of chemotherapeutic agents (5-FU and pirarubicin) on GP73 expression were tested in three HCC cell lines (HepG2, HCCLM3 and MHCC97H). RESULTS The GP73 level was significantly elevated at day 1 and day 30 after TACE in HCC patients compared with that before the procedure (P<0.05). There was no statistical difference between the two time points after TACE, nor correlation between GP73 levels and clinicopathological features, tumor metastasis, and patient survival. Pirarubicin, not 5-FU, significantly increased GP73 expression in three cell lines. CONCLUSIONS Unlike surgical resection which decreases the GP73 level, TACE significantly increased GP73 expression in patients with HCC. No correlations were observed among GP73 levels, tumor characteristics and prognosis of patients with HCC.
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Affiliation(s)
- Jie Pan
- Department of Radiology and Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China.
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Liu X, Wan X, Lu S, Zhang L, Yu S, Lu X. Evaluation of a magnetic particles-based chemiluminescence enzyme immunoassay for Golgi protein 73 in human serum. Clin Chim Acta 2015; 445:54-9. [PMID: 25801213 DOI: 10.1016/j.cca.2015.03.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2014] [Revised: 03/07/2015] [Accepted: 03/09/2015] [Indexed: 12/15/2022]
Abstract
BACKGROUND Golgi protein 73 (GP73) is regarded as a potential serum biomarker for early diagnosis of hepatocellular carcinoma (HCC). We developed a rapid magnetic particles-based chemiluminescence enzyme immunoassay (MPs-CLEIA) for the determination of serum GP73. METHODS Fluorescein isothiocyanate (FITC) and alkaline phosphatase (ALP) were used to label 2 different monoclonal antibodies to GP73. Serum GP73 was captured with labeled antibodies and formed a sandwiched immunoreaction. The magnetic particles (MPs) coated with anti-FITC antibody were used as a means of separation of the GP73 protein from other serum proteins. After adding the enzyme substrate solution, the relative light unit (RLU) was measured. A MPs-CLEIA for serum GP73 was established and evaluated. RESULTS The RLU was directly proportional to the concentration of GP73. The method linearity was 5-600 μg/l. Limit of the blank was 2.19 μg/l. The intra- and inter-assay imprecision was <3% and <5%, respectively. The average recoveries were between 95% and 105%. The proposed method showed a good correlation with a commercial ELISA assay (r=0.983, p<0.001). We also evaluated the efficiency of serum GP73 measurement for the diagnosis of HCC using this assay. The area under the receiver operating characteristic curve was 0.822 (95% CI, 0.73-0.89), and the sensitivity and specificity, with cut-off value of 115.6 μg/l, were 75.4% and 92.1%, respectively. CONCLUSIONS The proposed method demonstrates an acceptable performance for quantifying serum GP73. This assay could be appropriate for routine use in clinical laboratories.
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Affiliation(s)
- Xiangyi Liu
- Department of Medical Laboratory, Beijing Tongren Hospital, Capital Medical University, Beijing, PR China
| | - Xiaohua Wan
- Department of Medical Laboratory, Beijing Tongren Hospital, Capital Medical University, Beijing, PR China
| | - Sheng Lu
- Beijing Ranos Medical Technology Co., Ltd, Beijing, PR China
| | - Lijun Zhang
- Department of Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, PR China
| | - Shaohua Yu
- Beijing Hotgen Biotechnology Co., Ltd., Beijing, PR China
| | - Xinxin Lu
- Department of Medical Laboratory, Beijing Tongren Hospital, Capital Medical University, Beijing, PR China.
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Xu Z, Liu L, Pan X, Wei K, Wei M, Liu L, Yang H, Liu Q. Serum Golgi protein 73 (GP73) is a diagnostic and prognostic marker of chronic HBV liver disease. Medicine (Baltimore) 2015; 94:e659. [PMID: 25816035 PMCID: PMC4554005 DOI: 10.1097/md.0000000000000659] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2015] [Revised: 02/21/2015] [Accepted: 02/24/2015] [Indexed: 12/17/2022] Open
Abstract
Alanine aminotransferase (ALT) is the most commonly used marker of liver injury, but normal ALT levels are seen in a proportion of chronic hepatitis B virus (HBV)-infected patients with severe liver injury. Golgi protein 73 (GP73) is a promising alternative marker of liver injury. This study assessed the relation between GP73 levels and liver disease severity, monitored the kinetic changes in GP73 levels in chronic HBV patients receiving entecavir (ETV) therapy, and investigated the potential diagnostic and prognostic values of serum GP73 as a new liver injury biomarker in chronic HBV infections. This study enrolled 1150 patients with chronic HBV infections, 200 of whom were retrospectively enrolled in this study after receiving 1 year of ETV treatment. GP73 expression in liver tissue was detected by immunohistochemistry. GP73 levels in single or serial serum samples were measured by enzyme-linked immunosorbent assay. Immunohistochemical analysis indicated that GP73 protein expression in the liver increased progressively with pathologic progression from nonexistent or mild hepatitis to severe hepatitis and cirrhosis during chronic HBV infection. Serum GP73 levels were positively correlated with the disease severity of chronic HBV infections (r = 0.58, P < 0.001). In patients with normal ALT levels, serum GP73 concentrations were significantly higher in patients with prominent hepatic inflammatory injury and fibrosis than in patients without hepatic inflammatory injury or fibrosis. Serum GP73 concentrations and GP73 protein expression were decreased in the liver tissues of patients whose ALT levels normalized after 1 year of ETV antiviral therapy. Changes in serum GP73 levels were closely associated with changes in liver injury severity, and, therefore, GP73 may be an effective new liver inflammatory injury biomarker, and could be useful for monitoring the prognosis of chronic HBV infectious patients with normal ALT levels.
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Affiliation(s)
- Zhengju Xu
- From the Clinical Liver Center (ZX, Liguan Liu, XP, HY, QL); Central Laboratory of Clinical Hepatology (KW, MW); and Department of Pathology (Lifei Liu), The 180th Hospital of the People's Liberation Army, Quanzhou, China
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Abstract
Liver cancer is the fifth most common cancer, but the second leading cause of cancer death, in the world, with more than 700,000 fatalities annually. The major etiology of liver cancer is infection with an hepatotropic virus such as hepatitis B virus or hepatitis C virus infection. While chronic viral infection remains the main cause of liver disease and risk of hepatocellular carcinoma (HCC), rates of nonviral-associated HCC are occurring at an alarmingly increasing rate. Like many cancers, survival rates are closely associated with time of detection. If HCC is caught early, survival rates can be as high as 50%. Regrettably, most cases of HCC are caught late where survival rates can be as low as 2-7%. Thus, there has been great interest in discovering serum biomarkers that could be used to identify those with HCC. To this end, many groups have examined the N-linked glycans to identify changes that occur with HCC. As the liver secretes the vast majority of proteins into the serum, this has often been a starting point for study. In serum, alterations in core fucosylation, outer-arm fucosylation, increased sialylation, and glycan branching have been observed in patients with HCC. Similar findings have been found directly in HCC tissue suggesting that these glycan changes may play a role in tumor formation and development.
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Affiliation(s)
- Anand Mehta
- Department of Microbiology and Immunology, Drexel University College of Medicine, Doylestown, Pennsylvania, USA
| | - Harmin Herrera
- Department of Microbiology and Immunology, Drexel University College of Medicine, Doylestown, Pennsylvania, USA
| | - Timothy Block
- Department of Microbiology and Immunology, Drexel University College of Medicine, Doylestown, Pennsylvania, USA
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Xu Z, Pan X, Wei K, Ding H, Wei M, Yang H, Liu Q. Serum Golgi protein 73 levels and liver pathological grading in cases of chronic hepatitis B. Mol Med Rep 2014; 11:2644-52. [PMID: 25524053 PMCID: PMC4337480 DOI: 10.3892/mmr.2014.3114] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2014] [Accepted: 11/25/2014] [Indexed: 12/20/2022] Open
Abstract
The present study was designed to assess the correlation between serum Golgi protein 73 (GP73) and liver pathological grading and staging in patients with chronic hepatitis B (CHB). Two hundred and fifty‑three patients with chronic hepatitis B virus (HBV) infections were enrolled in the present study. All patients received a serum GP73 test, and 91 CHB patients underwent liver biopsy. GP73 expression in liver tissue was assessed by immunohistochemical analysis. The results indicated that serum GP73 levels were positively correlated with disease progression in patients with chronic HBV infection (r=0.677). There was no significant difference in serum GP73 levels between hepatitis B e antigen‑positive and ‑negative patients (P>0.05). There were also no significant differences in serum GP73 levels among specimens with varying HBV DNA contents (P>0.05). Serum GP73 levels were positively correlated with increased liver pathological grading (r=0.737) and staging (r=0.692), and immunohistochemical analysis indicated that GP73 protein expression increased concurrently with liver pathological grading and staging. In conclusion, serum GP73 was found to be correlated with liver pathological grading and staging in patients with CHB, and may be an effective indicator for the evaluation of disease progression. However, serum GP73 levels were not associated with HBV replication.
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Affiliation(s)
- Zhengju Xu
- Clinical Liver Center, The 180th Hospital of the People's Liberation Army, Quanzhou, Fujian 362000, P.R. China
| | - Xingnan Pan
- Clinical Liver Center, The 180th Hospital of the People's Liberation Army, Quanzhou, Fujian 362000, P.R. China
| | - Kaipeng Wei
- Central Laboratory of Clinical Hepatology, The 180th Hospital of the People's Liberation Army, Quanzhou, Fujian 362000, P.R. China
| | - Hongbing Ding
- Liver Center Clinical Pathology, The 180th Hospital of the People's Liberation Army, Quanzhou, Fujian 362000, P.R. China
| | - Meijuan Wei
- Central Laboratory of Clinical Hepatology, The 180th Hospital of the People's Liberation Army, Quanzhou, Fujian 362000, P.R. China
| | - Huanwen Yang
- Clinical Liver Center, The 180th Hospital of the People's Liberation Army, Quanzhou, Fujian 362000, P.R. China
| | - Qian Liu
- Clinical Liver Center, The 180th Hospital of the People's Liberation Army, Quanzhou, Fujian 362000, P.R. China
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