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Paul D, Sinnarasan VSP, Das R, Sheikh MMR, Venkatesan A. Machine learning approach to predict blood-secretory proteins and potential biomarkers for liver cancer using omics data. J Proteomics 2024; 309:105298. [PMID: 39216516 DOI: 10.1016/j.jprot.2024.105298] [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: 06/12/2024] [Revised: 08/22/2024] [Accepted: 08/29/2024] [Indexed: 09/04/2024]
Abstract
Identifying non-invasive blood-based biomarkers is crucial for early detection and monitoring of liver cancer (LC), thereby improving patient outcomes. This study leveraged computational approaches to predict potential blood-based biomarkers for LC. Machine learning (ML) models were developed using selected features from blood-secretory proteins collected from the curated databases. The logistic regression (LR) model demonstrated the optimal performance. Transcriptome analysis across 7 LC cohorts revealed 231 common differentially expressed genes (DEGs). The encoded proteins of these DEGs were compared with the ML dataset, revealing 29 proteins overlapping with the blood-secretory dataset. The LR model also predicted 29 additional proteins as blood-secretory with the remaining protein-coding genes. As a result, 58 potential blood-secretory proteins were obtained. Among the top 20 genes, 13 common hub genes were identified. Further, area under the receiver operating characteristic curve (ROC AUC) analysis was performed to assess the genes as potential diagnostic blood biomarkers. Six genes, ESM1, FCN2, MDK, GPC3, CTHRC1 and COL6A6, exhibited an AUC value higher than 0.85 and were predicted as blood-secretory. This study highlights the potential of an integrative computational approach for discovering non-invasive blood-based biomarkers in LC, facilitating for further validation and clinical translation. SIGNIFICANCE: Liver cancer is one of the leading causes of premature death worldwide, with its prevalence and mortality rates projected to increase. Although current diagnostic methods are highly sensitive, they are invasive and unsuitable for repeated testing. Blood biomarkers offer a promising non-invasive alternative, but their wide dynamic range of protein concentration poses experimental challenges. Therefore, utilizing available omics data to develop a diagnostic model could provide a potential solution for accurate diagnosis. This study developed a computational method integrating machine learning and bioinformatics analysis to identify potential blood biomarkers. As a result, ESM1, FCN2, MDK, GPC3, CTHRC1 and COL6A6 biomarkers were identified, holding significant promise for improving diagnosis and understanding of liver cancer. The integrated method can be applied to other cancers, offering a possible solution for early detection and improved patient outcomes.
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Affiliation(s)
- Dahrii Paul
- Department of Bioinformatics, Pondicherry University, Puducherry 605014, India
| | | | - Rajesh Das
- Department of Bioinformatics, Pondicherry University, Puducherry 605014, India
| | | | - Amouda Venkatesan
- Department of Bioinformatics, Pondicherry University, Puducherry 605014, India.
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An Overview of Hepatocellular Carcinoma Surveillance Focusing on Non-Cirrhotic NAFLD Patients: A Challenge for Physicians. Biomedicines 2023; 11:biomedicines11020586. [PMID: 36831120 PMCID: PMC9953185 DOI: 10.3390/biomedicines11020586] [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: 01/14/2023] [Revised: 02/08/2023] [Accepted: 02/09/2023] [Indexed: 02/18/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver disease worldwide and it ranges from simple steatosis to hepatocellular carcinoma (HCC). HCC represents the first liver tumor and the third source of cancer death. In the next few years, the prevalence of NAFLD and consequently of HCC is estimated to increase, becoming a major public health problem. The NAFLD-HCC shows several differences compared to other causes of chronic liver disease (CLD), including the higher percentage of patients that develop HCC in the absence of liver cirrhosis. In HCC surveillance, the international guidelines suggest a six months abdominal ultrasound (US), with or without alpha-fetoprotein (AFP) evaluation, in patients with cirrhosis and in a subgroup of patients with chronic hepatitis B infection. However, this screening program reveals several limitations, especially in NAFLD patients. Thus, new biomarkers and scores have been proposed to overcome the limits of HCC surveillance. In this narrative review we aimed to explore the differences in the HCC features between NAFLD and non-NAFLD patients, and those between NAFLD-HCC developed in the cirrhotic and non-cirrhotic liver. Finally, we focused on the limits of tumor surveillance in NAFLD patients, and we explored the new biomarkers for the early diagnosis of HCC.
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Mir IH, Jyothi KC, Thirunavukkarasu C. The prominence of potential biomarkers in the diagnosis and management of hepatocellular carcinoma: Current scenario and future anticipation. J Cell Biochem 2021; 123:1607-1623. [PMID: 34897788 DOI: 10.1002/jcb.30190] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 11/13/2021] [Accepted: 11/17/2021] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the most aggressive and truculent types of cancer. Early detection of HCC is a massive concern that can boost the overall survival rates of HCC patients. As a result, there is a continual quest for advancements in screening, diagnosis, and treatment strategies to enhance the prognosis at its early stages. However, the confluence of inflammation and cirrhosis hampers the early detection of HCC. The analysis of different types of biomarkers such as tissue biomarkers, serum biomarkers, protein biomarkers, autoantibody markers, and improved imaging techniques has played a vital role in ameliorating HCC monitoring responses. Therefore biomarkers that can identify HCC early with a high degree of sensitivity and specificity might be prodigiously serviceable in the diagnosis and treatment of this notorious disorder. This study offers an overview of the contemporary understanding of several types of biomarkers implicated in hepatocarcinogenesis and their applications in monitoring, diagnosis, and prognosis presage. In additament, we address the role of image techniques associated with HCC diagnosis.
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Affiliation(s)
- Ishfaq Hassan Mir
- Department of Biochemistry and Molecular Biology, Pondicherry University, Puducherry, India
| | - K C Jyothi
- Department of Biochemistry and Molecular Biology, Pondicherry University, Puducherry, India
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Carbohydrate antigen-125, calcium, and hemoglobin as predictive clinical indicator for ocular metastasis in male liver cancer patients. Biosci Rep 2021; 40:222102. [PMID: 32090248 PMCID: PMC7040464 DOI: 10.1042/bsr20194405] [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: 12/20/2019] [Revised: 02/06/2020] [Accepted: 02/07/2020] [Indexed: 12/13/2022] Open
Abstract
Background Primary liver cancer (PLC) is a common type of cancer among men worldwide. Little is known regarding the relationship of liver cancer with ocular metastasis (OM). Drinking has been also reported to be related not only to the occurrence of liver cancer but also to the causes of some ocular lesions. Purpose A diagnostic standard for the levels of serum biomarkers associated with OM derived from liver cancer in men is urgently needed. Material and methods We examined the association between OM in liver cancer and its serum biomarkers. A total of 1254 male patients with liver cancer were recruited in this retrospective study between July 2002 and December 2012. We assessed the relationship between drinking preference and OM in male patients with liver cancer, and aimed to identify an independent prognostic factor or establish a quantitative indicator for OM. Results By assessing the potential indicators, carbohydrate antigen-125 (CA-125), calcium, and hemoglobin (Hb) were found to be most valuable in the diagnosis of OM in male patients with liver cancer. Conclusion CA-125, calcium, and Hb are independent risk factors of OM in patients with liver cancer who consume alcohol.
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Ong JR, Bamodu OA, Khang NV, Lin YK, Yeh CT, Lee WH, Cherng YG. SUMO-Activating Enzyme Subunit 1 (SAE1) Is a Promising Diagnostic Cancer Metabolism Biomarker of Hepatocellular Carcinoma. Cells 2021; 10:cells10010178. [PMID: 33477333 PMCID: PMC7830456 DOI: 10.3390/cells10010178] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 01/14/2021] [Accepted: 01/14/2021] [Indexed: 12/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most diagnosed malignancies and a leading cause of cancer-related mortality globally. This is exacerbated by its highly aggressive phenotype, and limitation in early diagnosis and effective therapies. The SUMO-activating enzyme subunit 1 (SAE1) is a component of a heterodimeric small ubiquitin-related modifier that plays a vital role in SUMOylation, a post-translational modification involving in cellular events such as regulation of transcription, cell cycle and apoptosis. Reported overexpression of SAE1 in glioma in a stage-dependent manner suggests it has a probable role in cancer initiation and progression. In this study, hypothesizing that SAE1 is implicated in HCC metastatic phenotype and poor prognosis, we analyzed the expression of SAE1 in several cancer databases and to unravel the underlying molecular mechanism of SAE1-associated hepatocarcinogenesis. Here, we demonstrated that SAE1 is over-expressed in HCC samples compared to normal liver tissue, and this observed SAE1 overexpression is stage and grade-dependent and associated with poor survival. The receiver operating characteristic analysis of SAE1 in TCGA−LIHC patients (n = 421) showed an AUC of 0.925, indicating an excellent diagnostic value of SAE1 in HCC. Our protein-protein interaction analysis for SAE1 showed that SAE1 interacted with and activated oncogenes such as PLK1, CCNB1, CDK4 and CDK1, while simultaneously inhibiting tumor suppressors including PDK4, KLF9, FOXO1 and ALDH2. Immunohistochemical staining and clinicopathological correlate analysis of SAE1 in our TMU-SHH HCC cohort (n = 54) further validated the overexpression of SAE1 in cancerous liver tissues compared with ‘normal’ paracancerous tissue, and high SAE1 expression was strongly correlated with metastasis and disease progression. The oncogenic effect of upregulated SAE1 is associated with dysregulated cancer metabolic signaling. In conclusion, the present study demonstrates that SAE1 is a targetable cancer metabolic biomarker with high potential diagnostic and prognostic implications for patients with HCC.
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Affiliation(s)
- Jiann Ruey Ong
- Department of Emergency Medicine, Taipei Medical University—Shuang Ho Hospital, New Taipei City 235, Taiwan; (J.R.O.); (N.V.K.)
- Graduate Institute of Injury Prevention and Control, Taipei Medical University, Taipei 110, Taiwan
- Department of Emergency Medicine, School of Medicine, Taipei Medical University, Taipei 110, Taiwan
| | - Oluwaseun Adebayo Bamodu
- Department of Medical Research & Education, Taipei Medical University—Shuang Ho Hospital, New Taipei City 235, Taiwan; (O.A.B.); (N.V.K.); (Y.-K.L.); (C.-T.Y.)
| | - Nguyen Viet Khang
- Department of Emergency Medicine, Taipei Medical University—Shuang Ho Hospital, New Taipei City 235, Taiwan; (J.R.O.); (N.V.K.)
- Department of Medical Research & Education, Taipei Medical University—Shuang Ho Hospital, New Taipei City 235, Taiwan; (O.A.B.); (N.V.K.); (Y.-K.L.); (C.-T.Y.)
| | - Yen-Kuang Lin
- Department of Medical Research & Education, Taipei Medical University—Shuang Ho Hospital, New Taipei City 235, Taiwan; (O.A.B.); (N.V.K.); (Y.-K.L.); (C.-T.Y.)
| | - Chi-Tai Yeh
- Department of Medical Research & Education, Taipei Medical University—Shuang Ho Hospital, New Taipei City 235, Taiwan; (O.A.B.); (N.V.K.); (Y.-K.L.); (C.-T.Y.)
- Department of Medical Laboratory Science and Biotechnology, Yuanpei University of Medical Technology, Hsinchu 300, Taiwan
| | - Wei-Hwa Lee
- Department of Pathology, Taipei Medical University—Shuang Ho Hospital, New Taipei City 235, Taiwan;
| | - Yih-Giun Cherng
- Department of Anesthesiology, Shuang Ho Hospital, Taipei Medical University, New Taipei City 235, Taiwan
- Department of Anesthesiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
- Correspondence: ; Tel.: +886-2-249-0088 (ext. 8885)
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Qian Y, Wang JW, Yu-Fang, Yuan XD, Fan YC, Gao S, Wang K. Measurement of Cyclin D2 (CCND2) Gene Promoter Methylation in Plasma and Peripheral Blood Mononuclear Cells and Alpha-Fetoprotein Levels in Patients with Hepatitis B Virus-Associated Hepatocellular Carcinoma. Med Sci Monit 2020; 26:e927444. [PMID: 33320844 PMCID: PMC7749526 DOI: 10.12659/msm.927444] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Accepted: 10/07/2020] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Alpha-fetoprotein (AFP) is widely used to screen for hepatocellular carcinoma (HCC). However, the use of this biomarker has been challenged due to its low sensitivity and high rate of false negatives. In this study, we evaluated the diagnostic capability of cyclin D2 (CCND2) promoter methylation in patients with HCC related to hepatitis B virus (HBV). MATERIAL AND METHODS Using methylation-specific PCR and quantitative real-time PCR, we measured methylation status and mRNA levels of CCND2 in plasma and peripheral blood mononuclear cells (PBMCs) from 275 subjects: 75 patients with chronic hepatitis B (CHB), 47 with liver cirrhosis (LC), 118 with HCC, and 35 healthy controls (HCs). RESULTS The methylation rate of the CCND2 promoter was significantly higher in HCC patients than in patients without HCC (P<0.001). Furthermore, advanced HCC (TNM III/IV) was associated with a significantly higher frequency of CCND2 methylation and lower CCND2 mRNA levels than early-stage disease (TNM I/II; P<0.05). Combined measurement of CCND2 methylation and AFP yielded significantly higher sensitivity and area under the curve (AUC) than AFP alone in distinguishing patients with HCC from subjects with LC and CHB (P<0.001). CONCLUSIONS CCND2 methylation may be useful for predicting HCC progression. In addition, combined measurement of CCND2 methylation and AFP could serve as a non-invasive diagnostic marker for patients with HBV-related HCC.
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Affiliation(s)
- Yu Qian
- Department of Hepatology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, P.R. China
| | - Jing-Wen Wang
- Department of Hepatology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, P.R. China
| | - Yu-Fang
- Department of Hepatology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, P.R. China
| | - Xiao-Dong Yuan
- Department of Hepatology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, P.R. China
| | - Yu-Chen Fan
- Department of Hepatology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, P.R. China
- Institute of Hepatology, Shandong University, Jinan, Shandong, P.R. China
| | - Shuai Gao
- Department of Hepatology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, P.R. China
- Institute of Hepatology, Shandong University, Jinan, Shandong, P.R. China
| | - Kai Wang
- Department of Hepatology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, P.R. China
- Institute of Hepatology, Shandong University, Jinan, Shandong, P.R. China
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Singh G, Yoshida EM, Rathi S, Marquez V, Kim P, Erb SR, Salh BS. Biomarkers for hepatocellular cancer. World J Hepatol 2020; 12:558-573. [PMID: 33033565 PMCID: PMC7522562 DOI: 10.4254/wjh.v12.i9.558] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 07/06/2020] [Accepted: 08/25/2020] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. If diagnosed early, curative treatment options such as surgical resection, loco-regional therapies, and liver transplantation are available to patients, increasing their chances of survival and improving their quality of life. Unfortunately, most patients are diagnosed with late stage HCC where only palliative treatment is available. Therefore, biomarkers which could detect HCC early with a high degree of sensitivity and specificity, may play a crucial role in the diagnosis and management of the disease. This review will aim to provide an overview of the different biomarkers of HCC comprising those used in the diagnosis of HCC in at risk populations, as well as others with potential for prognosis, risk predisposition and prediction of response to therapeutic intervention.
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Affiliation(s)
- Gurjot Singh
- Department of Medicine, University of British Columbia, Vancouver V5Z 1M9, Canada
| | - Eric M Yoshida
- Division of Gastroenterology, Department of Medicine, University of British Columbia, Vancouver V5Z 1M9, Canada
| | - Sahaj Rathi
- Division of Gastroenterology, Department of Medicine, University of British Columbia, Vancouver V5Z 1M9, Canada
| | - Vladimir Marquez
- Division of Gastroenterology, Department of Medicine, University of British Columbia, Vancouver V5Z 1M9, Canada
| | - Peter Kim
- Division of Oncological Surgery, Department of Medicine, University of British Columbia, Vancouver V5Z 1M9, Canada
| | - Siegfried R Erb
- Division of Gastroenterology, Department of Medicine, University of British Columbia, Vancouver V5Z 1M9, Canada
| | - Baljinder S Salh
- Division of Gastroenterology, Department of Medicine, University of British Columbia, Vancouver V5Z 1M9, Canada
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Guo XM, Zhu FF, Pan LW, Chen JL, Lai JC, Wu HX, Shu JC. Caprin-1 promotes HepG2 cell proliferation, invasion and migration and is associated with poor prognosis in patients with liver cancer. Oncol Lett 2020; 20:1761-1771. [PMID: 32724419 PMCID: PMC7377179 DOI: 10.3892/ol.2020.11712] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Accepted: 02/14/2020] [Indexed: 12/11/2022] Open
Abstract
The present study aimed to investigate the role of caprin-1 in liver cancer and its association with the clinicopathological features and prognosis of liver cancer, as well as the underlying mechanism of caprin-1 function. Caprin-1 expression levels in a tissue microarray containing 40 liver cancer tissues, 10 peritumoral tissues and 20 normal liver tissues were analyzed using immunohistochemistry. The clinical data of 154 patients with liver cancer were also collected from The Cancer Genome Atlas database. Kaplan-Meier analysis and a Cox proportional hazards regression model were used to assess the association between caprin-1 expression levels and survival in patients with liver cancer. The effects of caprin-1 knockdown on the mRNA levels of cyclin D1 and cyclin D2 as well as the proliferation, invasion and migration of HepG2 cells were also investigated. The expression level of caprin-1 in liver cancer tissues was significantly higher compared with normal liver tissues or cells (P<0.01). High caprin-1 expression levels were associated with advanced clinical stage (P<0.001) and enhanced tumor invasion (P<0.001). Kaplan-Meier analysis showed that the overall survival time and disease-free survival time in patients with liver cancer with high caprin-1 expression were significantly shorter compared with patients with low caprin-1 expression levels (P=0.002 and P=0.033, respectively). The Cox proportional hazards regression model showed that high caprin-1 expression levels were an independent prognostic factor for liver cancer (P<0.001). Knockdown of caprin-1 in HepG2 cells significantly downregulated mRNA expression levels of cyclin D1 and cyclin D2, inhibited cell proliferation and invasion and the cells were arrested at G0/G1 phase. In conclusion, caprin-1 may be a novel prognostic indicator for patients with liver cancer.
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Affiliation(s)
- Xin-Min Guo
- Department of Ultrasound, Guangzhou Red Cross Hospital, Medical College, Jinan University, Guangzhou, Guangdong 510220, P.R. China
| | - Fang-Fang Zhu
- Department of Ultrasound, Guangzhou Red Cross Hospital, Medical College, Jinan University, Guangzhou, Guangdong 510220, P.R. China
| | - Li-Wen Pan
- Department of Endocrinology, Guangzhou Red Cross Hospital, Medical College, Jinan University, Guangzhou, Guangdong 510220, P.R. China
| | - Jia-Lin Chen
- Department of Ultrasound, Guangzhou Red Cross Hospital, Medical College, Jinan University, Guangzhou, Guangdong 510220, P.R. China
| | - Ji-Chuang Lai
- Department of Ultrasound, Guangzhou Red Cross Hospital, Medical College, Jinan University, Guangzhou, Guangdong 510220, P.R. China
| | - Hong-Xia Wu
- Department of Ultrasound, Guangzhou Red Cross Hospital, Medical College, Jinan University, Guangzhou, Guangdong 510220, P.R. China
| | - Jian-Chang Shu
- Department of Gastroenterology, Guangzhou Red Cross Hospital, Medical College, Jinan University, Guangzhou, Guangdong 510220, P.R. China
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Xia L, Teng Q, Chen Q, Zhang F. Preparation and Characterization of Anti-GPC3 Nanobody Against Hepatocellular Carcinoma. Int J Nanomedicine 2020; 15:2197-2205. [PMID: 32280214 PMCID: PMC7125335 DOI: 10.2147/ijn.s235058] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Accepted: 03/10/2020] [Indexed: 12/15/2022] Open
Abstract
Background Glypican-3 (GPC3) is a newly identified target molecule for the early diagnosis of hepatocellular carcinoma (HCC), while targeted inhibition of GPC3 signaling may help to control the proliferation and metastasis of HCC cells. The purpose of this study was to prepare the anti-GPC3 nanobody and to investigate the affinity of the anti-GPC3 nanobodies in vitro and the anticancer effects on hepatocellular carcinoma in vivo. Methods To screen for unknown anti-GPC3 antibodies, we constructed an antibody phage display library. After three rounds of panning, positive phage clones were identified by enzyme-linked immunosorbent assay (ELISA). Further, the nanobody fusion protein was expressed in E. coli BL21 cells and purified by affinity chromatography. Competitive ELISA and flow cytometry were conducted to confirm the affinity of the anti-GPC3 nanobodies in vitro. The antitumor effects of VHHGPC3 were assessed in vivo. Results The results showed that the nanobody VHHGPC3 had specific high-affinity binding to His-GPC3 antigen. Moreover, VHHGPC3 exhibited specific binding to commercial human GPC3 and recognized the surface GPC3 protein of the hepatoma cell line HepG2. Importantly, in vivo study showed that GPC3 nanobody suppresses the growth of HepG2 and improves the survival rate of tumor mice. Discussion In summary, our new anti-GPC3 nanobody suggests a strong application potential for targeted therapy of liver cancer.
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Affiliation(s)
- Lijie Xia
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi 830046, People's Republic of China
| | - Qiao Teng
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi 830046, People's Republic of China
| | - Qi Chen
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi 830046, People's Republic of China
| | - Fuchun Zhang
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi 830046, People's Republic of China
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Jiang YL, Shang MM, Dong SZ, Chang YC. Abnormally expressed circular RNAs as novel non-invasive biomarkers for hepatocellular carcinoma: A meta-analysis. World J Gastrointest Oncol 2019; 11:909-924. [PMID: 31662829 PMCID: PMC6815919 DOI: 10.4251/wjgo.v11.i10.909] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Revised: 08/06/2019] [Accepted: 09/04/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Circular RNAs (circRNAs) are a newly discovered class of endogenous non-coding RNAs that may have roles in cancer genesis and development. In the recent literature, dysregulated circRNAs have been extensively investigated in hepatocellular carcinoma (HCC). Whether or not circRNAs are of clinical value for the management of HCC has not been characterized.
AIM To meta-analyze the diagnostic and prognostic value of abnormally expressed circRNAs in HCC.
METHODS Eligible studies were sourced from PubMed, EMBASE, and CNKI online databases. Data on patients’ clinical characteristics, including diagnostic efficacy and overall survival, were extracted. The diagnostic and prognostic parameters were respectively synthesized using the bivariate meta-analysis model and multivariate Cox hazard regression analysis based on Stata 12.0. The trim and fill method was adopted to assess the possible effects from publication bias.
RESULTS A total of 21 eligible studies were included. The pooled sensitivity, specificity, and area under the curve of abnormally expressed circRNAs in distinguishing HCC from non-cancer controls were 0.78 (95%CI: 0.69–0.85), 0.80 (95%CI: 0.74–0.86), and 0.86, respectively. Survival analyses showed that the down-regulated circRNA expression signature correlated perfectly with HCC survival [hazard ratio (HR) = 0.42, 95%CI: 0.19–0.91, P = 0.028; I2 = 92.7%, P = 0.000], whereas the HCC cases with high circRNA levels had significantly poorer prognoses than those of patients with low circRNA levels (HR = 2.22, 95%CI: 1.50–3.30, P = 0.000; I2 = 91%, P = 0.000). Moreover, abnormally expressed circRNAs were intimately associated with tumor size, differentiation grade, microvascular invasion, metastasis, TNM stage, and serum alpha fetal protein level in patients with HCC. Stratified analysis based on sample type, control source, and expression status also yielded robust results.
CONCLUSION Abnormally expressed circRNA signatures show immense potential as novel non-invasive biomarker(s) for HCC diagnosis and prognosis.
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Affiliation(s)
- Ya-Lin Jiang
- Department of Clinical Laboratory, The First Affiliated Hospital and College of Clinical Medicine of Henan University of Science and Technology, Luoyang 471003, Henan Province, China
| | - Meng-Meng Shang
- Department of Clinical Laboratory, The First Affiliated Hospital and College of Clinical Medicine of Henan University of Science and Technology, Luoyang 471003, Henan Province, China
- Department of Clinical Laboratory, The Family Planning Guidance Station of Luanchuan County, Luoyang 471500, Henan Province, China
| | - Shi-Zhen Dong
- Department of Clinical Laboratory, The First Affiliated Hospital and College of Clinical Medicine of Henan University of Science and Technology, Luoyang 471003, Henan Province, China
| | - Yong-Chao Chang
- Department of Clinical Laboratory, The First Affiliated Hospital and College of Clinical Medicine of Henan University of Science and Technology, Luoyang 471003, Henan Province, China
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Cai Z, Chen G, Zeng Y, Dong X, Li Z, Huang Y, Xin F, Qiu L, Xu H, Zhang W, Su X, Liu X, Liu J. Comprehensive Liquid Profiling of Circulating Tumor DNA and Protein Biomarkers in Long-Term Follow-Up Patients with Hepatocellular Carcinoma. Clin Cancer Res 2019; 25:5284-5294. [PMID: 31217202 DOI: 10.1158/1078-0432.ccr-18-3477] [Citation(s) in RCA: 97] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Revised: 02/27/2019] [Accepted: 06/07/2019] [Indexed: 01/27/2023]
Abstract
PURPOSE Circulating tumor DNA (ctDNA) provides a novel approach for detecting tumor burden and predicting clinical outcomes of hepatocellular carcinoma (HCC). Here, we performed a thorough evaluation of HCC circulating genetic features and further fully integrated them to build a robust strategy for HCC monitoring and prognostic outcome assessment. EXPERIMENTAL DESIGN We performed target sequencing and low-coverage whole-genome sequencing on plasma samples collected from 34 long-term follow-up patients with HCC to capture tumor somatic SNVs and CNVs, respectively. Clinical information was also obtained to evaluate the prognostic performance of ctDNA comparing with clinically applied protein biomarkers. RESULTS All plasma samples before surgery showed somatic genetic variations resembling corresponding tumor tissues. During follow-up, SNVs and CNVs dynamically changed correlating to patients' tumor burden. We integrated the comprehensive ctDNA mutation profiles to provide a robust strategy to accurately assess patients' tumor burden with high consistence comparing with imaging results. This strategy could discover tumor occurrence in advance of imaging for an average of 4.6 months, and showed superior performance than serum biomarkers AFP, AFP-L3%, and Des-Gamma-Carboxy Prothrombin (DCP). Furthermore, our strategy could precisely detect minimal residual disease (MRD) in advance and predict patients' prognostic outcomes for both relapse-free survival (P = 0.001) and overall survival (P = 0.001); further combining ctDNA with DCP could increase the sensitivity for MRD detection. CONCLUSIONS We demonstrated that plasma CNV and SNV levels dynamically correlated with patients' tumor burden in HCC. Our strategy of comprehensive mutation profile integration could accurately and better evaluate patients' prognostic risk and detect tumor occurrence in advance than traditional strategies.
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MESH Headings
- Biomarkers, Tumor/blood
- Biomarkers, Tumor/genetics
- Carcinoma, Hepatocellular/blood
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/surgery
- Circulating Tumor DNA/blood
- Circulating Tumor DNA/genetics
- Follow-Up Studies
- High-Throughput Nucleotide Sequencing/methods
- Humans
- Liver Neoplasms/blood
- Liver Neoplasms/genetics
- Liver Neoplasms/pathology
- Liver Neoplasms/surgery
- Mutation
- Neoplasm Metastasis
- Neoplasm Recurrence, Local/blood
- Neoplasm Recurrence, Local/genetics
- Neoplasm Recurrence, Local/pathology
- Neoplasm Recurrence, Local/surgery
- Prognosis
- Survival Rate
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Affiliation(s)
- Zhixiong Cai
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, P. R. China
- Mengchao Med-X Center, Fuzhou University, Fuzhou, P. R. China
- School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, P. R. China
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, P. R. China
| | - Geng Chen
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, P. R. China
- Mengchao Med-X Center, Fuzhou University, Fuzhou, P. R. China
- School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, P. R. China
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, P. R. China
| | - Yongyi Zeng
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, P. R. China
- Mengchao Med-X Center, Fuzhou University, Fuzhou, P. R. China
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, P. R. China
- Liver Disease Center, The First Affiliated Hospital of Fujian Medical University, Fuzhou, P. R. China
| | - Xiuqing Dong
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, P. R. China
- Mengchao Med-X Center, Fuzhou University, Fuzhou, P. R. China
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, P. R. China
| | - Zhenli Li
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, P. R. China
- Mengchao Med-X Center, Fuzhou University, Fuzhou, P. R. China
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, P. R. China
| | - Yanbing Huang
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, P. R. China
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, P. R. China
- Liver Disease Center, The First Affiliated Hospital of Fujian Medical University, Fuzhou, P. R. China
| | - Fuli Xin
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, P. R. China
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, P. R. China
- Liver Disease Center, The First Affiliated Hospital of Fujian Medical University, Fuzhou, P. R. China
| | - Liman Qiu
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, P. R. China
- Mengchao Med-X Center, Fuzhou University, Fuzhou, P. R. China
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, P. R. China
| | - Haipo Xu
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, P. R. China
- Mengchao Med-X Center, Fuzhou University, Fuzhou, P. R. China
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, P. R. China
| | - Wei Zhang
- Department of Respiratory and Critical Care Medicine, Changhai Hospital, The Second Military Medical University, Shanghai, P. R. China
| | - Xiaoping Su
- Children's Heart Center, the Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, P. R. China
| | - Xiaolong Liu
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, P. R. China.
- Mengchao Med-X Center, Fuzhou University, Fuzhou, P. R. China
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, P. R. China
| | - Jingfeng Liu
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, P. R. China.
- Mengchao Med-X Center, Fuzhou University, Fuzhou, P. R. China
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, P. R. China
- Liver Disease Center, The First Affiliated Hospital of Fujian Medical University, Fuzhou, P. R. China
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12
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Hu J, Wang N, Yang Y, Ma L, Han R, Zhang W, Yan C, Zheng Y, Wang X. Diagnostic value of alpha-fetoprotein combined with neutrophil-to-lymphocyte ratio for hepatocellular carcinoma. BMC Gastroenterol 2018; 18:186. [PMID: 30545306 PMCID: PMC6293657 DOI: 10.1186/s12876-018-0908-6] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2017] [Accepted: 11/13/2018] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND To investigate the diagnostic performance of alpha-fetoprotein (AFP) and neutrophil-to-lymphocyte ratio (NLR) as well as their combinations with other markers. METHODS Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), AFP and levels as well as the numbers of neutrophils and lymphocytes of all enrolled patients were collected. The NLR was calculated by dividing the number of neutrophils by the number of lymphocytes. Receiver operating characteristic (ROC) curve analysis was conducted to determine the ability of each marker and combination of markers to distinguish HCC and liver disease patients. RESULTS In total, 545 patients were included in this study. The area under the ROC curve (AUC) values for AFP, ALT, AST, and NLR were 0.775 (0.738-0.810), 0.504 (0.461-0.547), 0.660 (0.618-0.699), and 0.738 (0.699-0.774) with optimal cut-off values of 24.6 ng/mL, 111 IU/mL, 27 IU/mL, and 2.979, respectively. Of the four biomarkers, AFP and NLR showed comparable specificity (0.881 and 0.858) and sensitivity (0.561 and 0.539). The combination of AFP and NLR showed the highest AUC (0.769) with a significantly higher sensitivity (0.767) and a lower specificity (0.773) compared to AFP or NLR alone, and it had the highest sum of sensitivity and specificity (1.54) among all combinations. In patients with AFP < 20 ng/mL, the NLR showed the highest AUC and combination with other markers did not improve the diagnostic accuracy. CONCLUSIONS Our data indicate that the combination of AFP and NLR offers better diagnostic performance than either marker alone for differentiating HCC from liver disease, which may benefit clinical screening.
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Affiliation(s)
- Jian Hu
- Department of Clinical Laboratory, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, 710061, People's Republic of China
| | - Nianyue Wang
- Department of Clinical Laboratory and Liver Diseases, The Second Hospital of Nanjing, Affiliated to Medical School of Southeast University, Nanjing, 210000, China
| | - Yongfeng Yang
- Department of Clinical Laboratory and Liver Diseases, The Second Hospital of Nanjing, Affiliated to Medical School of Southeast University, Nanjing, 210000, China
| | - Li Ma
- Department of Clinical Laboratory and Liver Diseases, The Second Hospital of Nanjing, Affiliated to Medical School of Southeast University, Nanjing, 210000, China
| | - Ruilin Han
- Department of Clinical Laboratory, Peking University First Hospital, Beijing, 100000, China
| | - Wei Zhang
- Department of Mathematics & Statistics, University of Arkansas at Little Rock, Little Rock, AR, 72204, USA
| | - Cunling Yan
- Department of Clinical Laboratory, Peking University First Hospital, Beijing, 100000, China.
| | - Yijie Zheng
- Medical Scientific Affairs, Abbott Diagnostics Division, Abbott Laboratories, Shanghai, 200032, China.
| | - Xiaoqin Wang
- Department of Clinical Laboratory, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, 710061, People's Republic of China.
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13
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Ismailova G, Yenin E, Kaniev S, Bayguisova D, Tajibaev T. Morphologic and Immunologic Characteristics of Hepatocellular Carcinoma for Prognosis of Surgical Intervention. EXP CLIN TRANSPLANT 2018. [PMID: 29528012 DOI: 10.6002/ect.tond-tdtd2017.p32] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
OBJECTIVES Hepatocellular carcinoma is the predominant malignancy in patients with cirrhosis and chronic liver disease. Our aim was to assess the morphologic, radiologic, and immunologic charac teristics of hepatocellular carcinoma and liver cirrhosis concerning surgical treatment tactics. MATERIALS AND METHODS We performed a cross-sectional analysis of a prospective study performed at the JSC National Scientific Center of Surgery (named after A. Syzganov). The study included 58 patients: 31 with hepatocellular carcinoma (53.4%) and 27 with chronic liver disease (46.6%). The average age of patients was 55.6 ± 1.7 years. RESULTS Patients were tested for hepatitis B virus and hepatitis C virus infection. Patients with elevated levels of alfa-fetoprotein, alanine aminotransferase, and total bilirubin were detected. Morphologic signs of hepatocellular carcinoma with a predominance of a trabecular type rather than a solid type of tumor were found. Patients with hepatocellular carcinoma underwent surgical liver resection and transarterial chemoembolization before living-donor liver transplant. One-year survival rate of patients with hepatocellular carcinoma was 93.5%. CONCLUSIONS The diagnosis and surgical options for hepatocellular carcinoma should be studied, taking into account the expanded laboratory characteristics of cancer.
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Affiliation(s)
- Gulziya Ismailova
- From the JSC "National Scientific Center of Surgery," Almaty, Kazakhstan
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14
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Chen H, Chen S, Li S, Chen Z, Zhu X, Dai M, Kong L, Lv X, Huang Z, Qin X. Combining des-gamma-carboxyprothrombin and alpha-fetoprotein for hepatocellular carcinoma diagnosing: an update meta-analysis and validation study. Oncotarget 2017; 8:90390-90401. [PMID: 29163838 PMCID: PMC5685759 DOI: 10.18632/oncotarget.20153] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2017] [Accepted: 07/30/2017] [Indexed: 02/06/2023] Open
Abstract
Controversies about the combination of des-gamma-carboxyprothrombin (DCP) and alpha-fetoprotein (AFP) for hepatocellular carcinoma diagnosing still exist. Hence, we performed this updated meta-analysis to estimate the diagnostic value of DCP , AFP and DCP + AFP in HCC. In addition, we conducted a validation study to analyze the performance of the candidate makers. After a systematic literature review, 27 studies from 20 articles were identified from four major databases. The pooled sensitivity and specificity were 69% and 89%, respectively, for DCP; for AFP, they were 65% and 88%, respectively; and they were 82% and 85%, respectively, for DCP + AFP. The values of the area under the curve (AUC) for DCP, AFP, DCP + AFP, respectively, were 0.88, 0.75, and 0.90. The validation study confirmed that the performance of DCP + AFP (sensitivity = 84%, specificity = 86%; AUC = 0.887) was higher than that of DCP (sensitivity = 76%, specificity = 92%; AUC = 0.843) or AFP (sensitivity = 73%, specificity = 92%; AUC = 0.837) alone.
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Affiliation(s)
- Huaping Chen
- Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi, China
| | - Siyuan Chen
- Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi, China
| | - Shan Li
- Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi, China
| | - Zhijian Chen
- Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi, China
| | - Xuan Zhu
- Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi, China
| | - Meiyu Dai
- Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi, China
| | - Lingxi Kong
- Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi, China
| | - Xiaodan Lv
- Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi, China
| | - Zhili Huang
- Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi, China
| | - Xue Qin
- Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi, China
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15
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Li GJ, Chen QY, Harrison TJ, Wang XY, Hu LP, Yang QL, Li KW, Fang ZL. Des-γ carboxyprothrombin may not be a good biomarker for hepatocellular carcinoma in those chronically infected with hepatitis B virus with basal core promoter double mutations (T^{1762}, A^{1764}), a prospective study. Cancer Biomark 2017; 18:241-248. [PMID: 28085009 DOI: 10.3233/cbm-160131] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND The accuracy of des-γ -carboxyprothrombin (DCP) in the detection of hepatocellular carcinoma (HCC) in those infected hepatitis B virus (HBV) from cross-sectional or case-control studies is contradictory. OBJECTIVE To resolve this contradiction using a prospective study. METHODS Three hundred male individuals persistently infected with HBV were recruited from the Chinese cohort and followed up once per year from 2012 to 2015. Each subject was screened for HCC by measurements of serum alpha-fetoprotein (AFP), lectin-bound α -fetoprotein (AFP-L3), DCP concentrations and ultrasonographic examinations. RESULTS Nineteen HCC cases were identified. The area under receiver operating characteristic (AUROC) at first, second and third visit for AFP, AFP-L3 and DCP ranges from 0.710-0.897, 0.566-0.637 and 0.520-0.595, respectively. The rate of elevated DCP is not significantly different between the HCC cases and controls (52.6% vs. 47.4%) (P > 0.05). The incidence of HCC in subjects with elevated DCP is not significantly higher than that of those with normal DCP (9.5% vs. 4.6%) (P > 0.05). The AUROC of combinations of these biomarkers was higher than that of AFP alone at the first visit. However, it was reduced at the second visit. At the third visit, the AUROCs of AFP + DCP and AFP + AFP-L3 + DCP, but not that of AFP + AFP-L3, were higher than that of AFP alone. CONCLUSIONS AFP but DCP or AFP-L3 remains a valuable biomarker for HCC in those chronically infected with HBV. The combination with AFP-L3 and DCP may not increase the accuracy of AFP in differentiating HCC cases from controls, among those infected with HBV.
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Affiliation(s)
- Guo-Jian Li
- Department of Public Health of Guangxi Zhuang Autonomous Region, Nanning, Guangxi 530021, China
| | - Qin-Yan Chen
- Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Nanning, Guangxi 530028, China
| | | | - Xue-Yan Wang
- Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Nanning, Guangxi 530028, China
| | - Li-Ping Hu
- Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Nanning, Guangxi 530028, China.,School of Preclinical Medicine, Guangxi Medical University, Nanning, Guangxi 530021, China
| | - Qing-Li Yang
- Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Nanning, Guangxi 530028, China
| | - Kai-Wen Li
- Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Nanning, Guangxi 530028, China.,School of Preclinical Medicine, Guangxi Medical University, Nanning, Guangxi 530021, China
| | - Zhong-Liao Fang
- Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Nanning, Guangxi 530028, China
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16
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Tian MM, Fan YC, Zhao J, Gao S, Zhao ZH, Chen LY, Wang K. Hepatocellular carcinoma suppressor 1 promoter hypermethylation in serum. A diagnostic and prognostic study in hepatitis B. Clin Res Hepatol Gastroenterol 2017; 41:171-180. [PMID: 28189396 DOI: 10.1016/j.clinre.2016.10.003] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2016] [Revised: 09/20/2016] [Accepted: 10/18/2016] [Indexed: 02/04/2023]
Abstract
BACKGROUND Liver cancer ranks as the second leading cause of cancer-related mortality in man worldwide, and hepatocellular carcinoma (HCC) is the most prevalent malignant neoplasm of the liver. The sensitivity of alpha-fetoprotein (AFP) as an HCC diagnostic marker for HCC diagnosis is 39-65%, and one-third patients with HCC are missed using AFP. New biomarkers are needed to diagnose HCC at an earlier stage and to individualize treatment strategies. Hepatocellular carcinoma suppressor 1 (HCCS1) is a newly identified liver tumor suppressor gene. OBJECTIVE Our study evaluated the diagnostic value of serum HCCS1 promoter methylation in patients with HCC associated with hepatitis B. METHODS We determined the methylation status of serum HCCS1 promoter in 120 patients with HCC, 146 patients with chronic hepatitis B (CHB) and 27 healthy controls (HCs) by methylation-specific polymerase chain reaction (MSP). Evaluation of a cohort with 63 patients with HCC and 44 patients with CHB was set as a validation dataset. RESULTS The frequency of HCCS1 promoter methylation in patients with HCC was significantly higher than that in patients with CHB (P<0.001) and HCs (P<0.001), and was associated with tumor node-metastasis (TNM) stage (P=0.01). The sensitivity of serum HCCS1 promoter methylation for discriminating patients with HCC from CHB was 62.5% and that of AFP alone was 55%. Notably, the sensitivity of serum HCCS1 promoter methylation plus AFP level was 81.7%. CONCLUSION HCCS1 has potential as a biomarker for diagnosis and prognosis of patients with HCC.
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Affiliation(s)
- Ming-Ming Tian
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan 250012, China
| | - Yu-Chen Fan
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan 250012, China; Institute of Hepatology, Shandong University, Jinan 250012, China
| | - Jing Zhao
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan 250012, China
| | - Shuai Gao
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan 250012, China
| | - Ze-Hua Zhao
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan 250012, China
| | - Long-Yan Chen
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan 250012, China; Institute of Hepatology, Shandong University, Jinan 250012, China
| | - Kai Wang
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan 250012, China; Institute of Hepatology, Shandong University, Jinan 250012, China.
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17
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Montalbano M, Georgiadis J, Masterson AL, McGuire JT, Prajapati J, Shirafkan A, Rastellini C, Cicalese L. Biology and function of glypican-3 as a candidate for early cancerous transformation of hepatocytes in hepatocellular carcinoma (Review). Oncol Rep 2017; 37:1291-1300. [PMID: 28098909 DOI: 10.3892/or.2017.5387] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2016] [Accepted: 01/12/2017] [Indexed: 12/17/2022] Open
Abstract
Glypican-3 (GPC-3), a transmembrane heparan sulfate proteoglycan (HSPG), has recently been investigated as a player in tissue-dependent cellular signaling, specifically as a regulator of growth. Noteworthy, the regulatory protein has been implicated in both stimulatory and inhibitory pathways involving cell growth. Initially, GPC-3 was thought to act as a cell cycle regulator, as a loss-of-function mutation in the gene caused a hyper-proliferative state known as Simpson-Golabi-Behmel (SGB) overgrowth syndrome. Additionally, certain cancer types have displayed a downregulation of GPC-3 expression. More recently, the protein has been evaluated as a useful marker for hepatocellular carcinoma (HCC) due to its increased expression in the liver during times of growth. In contrast, the GPC-3 marker is not detectable in normal adult liver. Immunotherapy that targets GPC-3 and its affiliated proteins is under investigation as these new biomarkers may hold potential for the detection and treatment of HCC and other diseases in which GPC-3 may be overexpressed. Studies have reported that an overexpression of GPC-3 in HCC predicts a poorer prognosis. This prognostic value further pushes the question regarding GPC-3's role in the regulation and progression of HCC. This review will summarize the current knowledge regarding the clinical aspects of GPC-3, while also synthesizing the current literature with the aim to better understand this molecule's biological interactions at a molecular level, not only in the liver, but in the rest of the body as well. Due to the existing gap in the literature surrounding GPC-3, we believe further investigation of function, structure and domains, cellular localization, and other subfields is warranted to evaluate the protein as a whole, as well as its part in the study of HCC.
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Affiliation(s)
- Mauro Montalbano
- Department of Surgery, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Jeremias Georgiadis
- Department of Surgery, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Ashlyn L Masterson
- Department of Surgery, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Joshua T McGuire
- Department of Surgery, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Janika Prajapati
- Department of Surgery, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Ali Shirafkan
- Department of Surgery, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Cristiana Rastellini
- Department of Surgery, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Luca Cicalese
- Department of Surgery, University of Texas Medical Branch, Galveston, TX 77555, USA
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18
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Dulku G, Dhillon R, Goodwin M, Cheng W, Kontorinis N, Mendelson R. The role of imaging in the surveillance and diagnosis of hepatocellular cancer. J Med Imaging Radiat Oncol 2016; 61:171-179. [DOI: 10.1111/1754-9485.12568] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2016] [Accepted: 11/05/2016] [Indexed: 02/06/2023]
Affiliation(s)
- Gurjeet Dulku
- Department of Diagnostic and Interventional Radiology; Royal Perth Hospital; Perth Western Australia Australia
| | - Ravinder Dhillon
- Radiology Department; Sir Charles Gairdner Hospital; Nedlands Western Australia Australia
| | - Mark Goodwin
- Radiology Department; Austin Hospital; Melbourne Victoria Australia
| | - Wendy Cheng
- Department of Gastroenterology; Royal Perth Hospital; Perth Western Australia Australia
| | - Nick Kontorinis
- Department of Gastroenterology; Royal Perth Hospital; Perth Western Australia Australia
| | - Richard Mendelson
- Department of Diagnostic and Interventional Radiology; Royal Perth Hospital; Perth Western Australia Australia
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19
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Xing H, Yan C, Cheng L, Wang N, Dai S, Yuan J, Lu W, Wang Z, Han J, Zheng Y, Yang T. Clinical application of protein induced by vitamin K antagonist-II as a biomarker in hepatocellular carcinoma. Tumour Biol 2016; 37:15447–15456. [PMID: 27739028 DOI: 10.1007/s13277-016-5443-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2016] [Accepted: 09/23/2016] [Indexed: 12/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide. Early diagnosis improves the prognosis. Protein induced by vitamin K antagonist-II (PIVKA-II) is an effective serum biomarker for HCC diagnosis and prognosis. Combined with another serum biomarker α-fetoprotein (AFP), the sensitivity and specificity of HCC diagnosis can be improved to a maximum of 94 and 98.5 %, respectively. PIVKA-II alone or in combination with AFP and/or AFP-L3 was effective in predicting the treatment response and clinical outcome of curative hepatic resection, chemotherapy, targeted therapy, radiotherapy, and liver transplantation. Japanese clinical guidelines recommend the combined use of PIVKA-II and AFP for the diagnosis of HCC, management of high-risk population, and prognosis of anticancer treatment. Further, PIVKA-II as a functional target promoted HCC cell proliferation, invasion, and metastasis by activating c-Met and other signal transduction pathways. Inhibition of PIVKA-II may provide a selective and effective therapy for HCC.
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Affiliation(s)
- Hao Xing
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, China
| | - Cunling Yan
- Department of Clinical Laboratory, Peking University First Hospital, Beijing, China
| | - Liming Cheng
- Department of Clinical Laboratory, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Nianyue Wang
- The Second Hospital of Nanjing, Affiliated to Medical School of Southeast University, Nanjing, China
| | - Shuyang Dai
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, China
| | - Jianyong Yuan
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, China
| | - Wenfeng Lu
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, China
| | - Zhouchong Wang
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, China
| | - Jun Han
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, China
| | - Yijie Zheng
- Medical Scientific Affairs, Abbott Diagnostics, Shanghai, 200003, China.
| | - Tian Yang
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, China.
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20
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Yao M, Wang L, Fang M, Zheng W, Dong Z, Yao D. Advances in the study of oncofetal antigen glypican-3 expression in HBV-related hepatocellular carcinoma. Biosci Trends 2016; 10:337-343. [PMID: 27795482 DOI: 10.5582/bst.2016.01176] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Early specific diagnosis and effective treatment of hepatocellular carcinoma (HCC) are crucial. Expression of membrane-associated heparan sulfate proteoglycan glypican-3 (GPC-3) was recently found to increase as part of the malignant transformation of hepatocytes, and this increase is especially marked in patients with hepatitis B virus (HBV) infection, periportal cancerous embolus, or extra-hepatic metastasis. According to data from basic and clinical studies, the oncofetal antigen GPC-3 is a highly specific diagnostic biomarker of HCC and an indicator of its prognosis, and GPC-3 is also a promising target molecule for HCC gene therapy since it may play a crucial role in cell proliferation, metastasis, and invasion and it may mediate oncogenesis and oncogenic signaling pathways. This review summarizes recent advances in the use of oncofetal antigen GPC-3 to diagnose HBV-related HCC, estimate its prognosis, and its targeted therapy.
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Affiliation(s)
- Min Yao
- Department of Immunology, Medical School of Nantong University
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Van Hees S, Michielsen P, Vanwolleghem T. Circulating predictive and diagnostic biomarkers for hepatitis B virus-associated hepatocellular carcinoma. World J Gastroenterol 2016; 22:8271-8282. [PMID: 27729734 PMCID: PMC5055858 DOI: 10.3748/wjg.v22.i37.8271] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2016] [Revised: 07/18/2016] [Accepted: 08/05/2016] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis B virus (HBV) infected patients have an almost 100-fold increased risk to develop hepatocellular carcinoma (HCC). HCC is the fifth most common and third most deadly cancer worldwide. Up to 50% of newly diagnosed HCC cases are attributed to HBV infection. Early detection improves survival and can be achieved through regular screening. Six-monthly abdominal ultrasound, either alone or in combination with alpha-fetoprotein serum levels, has been widely endorsed for this purpose. Both techniques however yield limited diagnostic accuracy, which is not improved when they are combined. Alternative circulating or histological markers to predict or diagnose HCC are therefore urgently needed. Recent advances in systems biology technologies have enabled the identification of several new putative circulating biomarkers. Although results from studies assessing combinations of these biomarkers are promising, evidence for their clinical utility remains low. In addition, most of the studies conducted so far show limitations in design. Attention must be paid for instance to different ethnicities and different etiologies when studying biomarkers for hepatocellular carcinoma. This review provides an overview on the current understandings and recent progress in the field of diagnostic and predictive circulating biomarkers for hepatocellular carcinoma in chronically infected HBV patients and discusses the future prospects.
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22
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A Chemiluminescent Protein Microarray Method for Determining the Seroglycoid Fucosylation Index. Sci Rep 2016; 6:31132. [PMID: 27528397 PMCID: PMC4985809 DOI: 10.1038/srep31132] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2015] [Accepted: 07/13/2016] [Indexed: 12/21/2022] Open
Abstract
The Lens culinaris agglutinin-reactive fraction of AFP (AFP-L3) is widely used to screen for hepatocellular carcinoma (HCC) in Japan and China. We developed a chemiluminescent protein microarray for determining the AFP-L3/AFP index (the ratio of AFP-L3 to total AFP, AFP-L3%) by fixing AFP-specific antibodies and Lens culinaris lectin on aldehyde-coated glass slides. Serum samples were tested for AFP using an enzyme-linked immunosorbent assay (ELISA) to validate the microarray. AFP-L3 was detected using Hotgen Biotech glycosyl capture spin column pretreatment technology and ELISA. When the AFP cut-off value was set to 20 ng/ml, the protein microarray displayed 89.74% sensitivity and 100% specificity for HCC diagnosis, and the ELISA displayed 87.17% sensitivity and 100% specificity. When the AFP-L3% cut-off value was set to 0.1, the protein microarray displayed 56.41% sensitivity and 100% specificity for HCC diagnosis, and the ELISA displayed 53.84% sensitivity and 100% specificity. The ROC curve for the HCC diagnosis showed that the AFP area under the ROC curve (AUC = 0.996; 95% CI: 0.986-1.005) was much higher than that of AFP-L3 (AUC = 0.857; 95% CI: 0.769-0.94) and AFP-L3% (AUC = 0.827; CI: 0.730-0.924). The microarray assay used in this study is a highly sensitive, accurate, and efficient assay for the determination of the AFP-L3%.
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23
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Xiao R, Zhang X, Rong Z, Xiu B, Yang X, Wang C, Hao W, Zhang Q, Liu Z, Duan C, Zhao K, Guo X, Fan Y, Zhao Y, Johnson H, Huang Y, Feng X, Xu X, Zhang H, Wang S. Non-invasive detection of hepatocellular carcinoma serum metabolic profile through surface-enhanced Raman spectroscopy. NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE 2016; 12:2475-2484. [PMID: 27520725 DOI: 10.1016/j.nano.2016.07.014] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/24/2016] [Revised: 07/14/2016] [Accepted: 07/23/2016] [Indexed: 12/18/2022]
Abstract
The present study aims to identify distinctive Raman spectrum metabolic peaks to predict hepatocellular carcinoma (HCC). We performed a label-free, non-invasive surface-enhanced Raman spectroscopy (SERS) test on 230 serum samples including 47 HCC, 60 normal controls (NC), 68 breast cancer (BC) and 55 lung cancer (LC) by mixing Au@AgNRs with serum directly. Based on the observed SERS spectra, discriminative metabolites including tryptophan, phenylalanine, and etc. were found in HCC, when compared with BC, LC, and NC (P<0.05 in all). Common metabolites-proline, valine, adenine and thymine were found in HCC, BC and LC with compared to NC group (P<0.05). Importantly, Raman spectra of HCC serum biomarker AFP were firstly detected to analyze the HCC prominent peak. Orthogonal partial least squares discriminant analysis was adopted to assess the diagnostic accuracy; area under curve value of HCC is 0.991. This study provides new insights into the HCC metabolites detection through Raman spectroscopy.
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Affiliation(s)
- Rui Xiao
- Beijing Institute of Radiation Medicine, Beijing, China
| | - Xuhui Zhang
- Department of Bio-diagnosis, Institute of Basic Medical Sciences, Beijing, China
| | - Zhen Rong
- Beijing Institute of Radiation Medicine, Beijing, China
| | - Bingshui Xiu
- Department of Bio-diagnosis, Institute of Basic Medical Sciences, Beijing, China
| | - Xiqin Yang
- Department of Bio-diagnosis, Institute of Basic Medical Sciences, Beijing, China
| | - Chongwen Wang
- Beijing Institute of Radiation Medicine, Beijing, China
| | - Wende Hao
- Affiliated 307 Hospital, Beijing, China
| | - Qi Zhang
- National Center of Biomedical Analysis, Beijing, China
| | - Zhiqiang Liu
- Department of Bio-diagnosis, Institute of Basic Medical Sciences, Beijing, China
| | - Cuimi Duan
- Department of Bio-diagnosis, Institute of Basic Medical Sciences, Beijing, China
| | - Kai Zhao
- Department of Radiotherapy and Chemotherapy, Tangshan City People's Hospital, Tangshan, China
| | - Xu Guo
- Clinical Laboratory, 252 Hospital of PLA, Baoding, China
| | - Yawen Fan
- Department of Bio-diagnosis, Institute of Basic Medical Sciences, Beijing, China
| | - Yanfeng Zhao
- Department of Bio-diagnosis, Institute of Basic Medical Sciences, Beijing, China
| | | | - Yan Huang
- Affiliated 307 Hospital, Beijing, China
| | - Xiaoyan Feng
- Department of Bio-diagnosis, Institute of Basic Medical Sciences, Beijing, China.
| | | | - Heqiu Zhang
- Department of Bio-diagnosis, Institute of Basic Medical Sciences, Beijing, China.
| | - Shengqi Wang
- Beijing Institute of Radiation Medicine, Beijing, China.
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24
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Naboulsi W, Megger DA, Bracht T, Kohl M, Turewicz M, Eisenacher M, Voss DM, Schlaak JF, Hoffmann AC, Weber F, Baba HA, Meyer HE, Sitek B. Quantitative Tissue Proteomics Analysis Reveals Versican as Potential Biomarker for Early-Stage Hepatocellular Carcinoma. J Proteome Res 2015; 15:38-47. [DOI: 10.1021/acs.jproteome.5b00420] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Affiliation(s)
- Wael Naboulsi
- Medizinisches
Proteom-Center, Ruhr-Universität Bochum, 44801 Bochum, Germany
| | - Dominik A. Megger
- Medizinisches
Proteom-Center, Ruhr-Universität Bochum, 44801 Bochum, Germany
| | - Thilo Bracht
- Medizinisches
Proteom-Center, Ruhr-Universität Bochum, 44801 Bochum, Germany
| | - Michael Kohl
- Medizinisches
Proteom-Center, Ruhr-Universität Bochum, 44801 Bochum, Germany
| | - Michael Turewicz
- Medizinisches
Proteom-Center, Ruhr-Universität Bochum, 44801 Bochum, Germany
| | - Martin Eisenacher
- Medizinisches
Proteom-Center, Ruhr-Universität Bochum, 44801 Bochum, Germany
| | - Don Marvin Voss
- Medizinisches
Proteom-Center, Ruhr-Universität Bochum, 44801 Bochum, Germany
| | | | | | | | | | - Helmut E. Meyer
- Medizinisches
Proteom-Center, Ruhr-Universität Bochum, 44801 Bochum, Germany
| | - Barbara Sitek
- Medizinisches
Proteom-Center, Ruhr-Universität Bochum, 44801 Bochum, Germany
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25
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Lei CJ, Yao C, Pan QY, Long HC, Li L, Zheng SP, Zeng C, Huang JB. Lentivirus vectors construction of SiRNA targeting interference GPC3 gene and its biological effects on liver cancer cell lines Huh-7. ASIAN PAC J TROP MED 2015; 7:780-6. [PMID: 25129460 DOI: 10.1016/s1995-7645(14)60136-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2014] [Revised: 08/15/2014] [Accepted: 09/15/2014] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVES To build GPC3 gene short hairpin interference RNA (shRNA) slow virus vector, observe expression of Huh-7 GPC3 gene in human liver cell line proliferation apoptosis and the effect of GPC3 gene influencing on liver cancer cell growth, and provide theoretical basis for gene therapy of liver cancer. METHODS Hepatocellular carcinoma cell line Huh-7 was transfected by a RNA interference technique. GPC3 gene expression in a variety of liver cancer cell lines was detected by fluorescence quantitative PCR. Targeted GPC3 gene sequences of small interfering RNA (siRNA) PGC-shRNA-GPC3 were restructured. Stable expression cell lines of siRNA were screened and established with the help of liposomes (lipofectamine(TM2000)) as carrier transfection of human liver cell lines. In order to validate siRNA interference efficiency, GPC3 siRNA mRNA expression was detected after transfection by using RT-PCR and Western blot. The absorbance value of the cells of blank group, untransfection group and transfection group, the cell cycle and cell apoptosis were calculated, and effects of GPC3 gene on Huh-7 cell proliferation and apoptosis were observed. RESULTS In the liver cancer cell lines Huh-7, GPC3 gene showed high expression. PGC-shRNA-GPC3 recombinant plasmid was constructed successfully via sequencing validation. Stable recombinant plasmid transfected into liver cancer cell lines Huh-7 can obviously inhibit GPC3 mRNA expression level. CONCLUSIONS The targeted GPC3 siRNA can effectively inhibit the expression of GPC3.
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Affiliation(s)
- Chang-Jiang Lei
- Department of General Surgery, the Second Affiliated Hospital of Jianghan University (Wuhan City Fifth Hospital), Wuhan, Hubei, China
| | - Chun Yao
- Wuhan Institute of Hematology, the Second Affiliated Hospital of Jianghan University (Wuhan City Fifth Hospital), Wuhan, Hubei, China
| | - Qing-Yun Pan
- Integrated Department, Branch of Jianqiao, Hanyang Affiliated Hospital of Wuhan University of Science and Technology, Wuhan, Hubei, China
| | - Hao-Cheng Long
- Department of General Surgery, the Second Affiliated Hospital of Jianghan University (Wuhan City Fifth Hospital), Wuhan, Hubei, China
| | - Lei Li
- Department of General Surgery, the Second Affiliated Hospital of Jianghan University (Wuhan City Fifth Hospital), Wuhan, Hubei, China
| | - Shu-Ping Zheng
- Department of Pediatrics, the Second Affiliated Hospital of Jianghan University (Wuhan City Fifth Hospital), Wuhan, Hubei, China.
| | - Cheng Zeng
- Department of General Surgery, the Second Affiliated Hospital of Jianghan University (Wuhan City Fifth Hospital), Wuhan, Hubei, China
| | - Jian-Bin Huang
- Department of General Surgery, the Second Affiliated Hospital of Jianghan University (Wuhan City Fifth Hospital), Wuhan, Hubei, China
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26
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Kirscher L, Deán-Ben XL, Scadeng M, Zaremba A, Zhang Q, Kober C, Fehm TF, Razansky D, Ntziachristos V, Stritzker J, Szalay AA. Doxycycline Inducible Melanogenic Vaccinia Virus as Theranostic Anti-Cancer Agent. Theranostics 2015; 5:1045-57. [PMID: 26199644 PMCID: PMC4508495 DOI: 10.7150/thno.12533] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Accepted: 05/14/2015] [Indexed: 12/02/2022] Open
Abstract
We reported earlier the diagnostic potential of a melanogenic vaccinia virus based system in magnetic resonance (MRI) and optoacoustic deep tissue imaging (MSOT). Since melanin overproduction lead to attenuated virus replication, we constructed a novel recombinant vaccinia virus strain (rVACV), GLV-1h462, which expressed the key enzyme of melanogenesis (tyrosinase) under the control of an inducible promoter-system. In this study melanin production was detected after exogenous addition of doxycycline in two different tumor xenograft mouse models. Furthermore, it was confirmed that this novel vaccinia virus strain still facilitated signal enhancement as detected by MRI and optoacoustic tomography. At the same time we demonstrated an enhanced oncolytic potential compared to the constitutively melanin synthesizing rVACV system.
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Affiliation(s)
- Lorenz Kirscher
- 1. University of Würzburg, Department of Biochemistry, Am Hubland, 97074 Würzburg, Germany
| | - Xosé Luis Deán-Ben
- 4. Helmholtz Institute, IBMI, Ingolstädter Landstraße 1, 85764 Oberschleißheim, Germany
| | - Miriam Scadeng
- 3. University of San Diego, Center of Functional MRI, 9500 Gilman Drive, La Jolla, CA 92093, USA
| | - Angelika Zaremba
- 4. Helmholtz Institute, IBMI, Ingolstädter Landstraße 1, 85764 Oberschleißheim, Germany
| | - Qian Zhang
- 2. Genelux Cooperation, San Diego Science Center, 3030 Bunker Hill St, San Diego, CA 92109, USA
| | - Christina Kober
- 1. University of Würzburg, Department of Biochemistry, Am Hubland, 97074 Würzburg, Germany
| | - Thomas Felix Fehm
- 4. Helmholtz Institute, IBMI, Ingolstädter Landstraße 1, 85764 Oberschleißheim, Germany
| | - Daniel Razansky
- 4. Helmholtz Institute, IBMI, Ingolstädter Landstraße 1, 85764 Oberschleißheim, Germany
| | - Vasilis Ntziachristos
- 4. Helmholtz Institute, IBMI, Ingolstädter Landstraße 1, 85764 Oberschleißheim, Germany
| | - Jochen Stritzker
- 1. University of Würzburg, Department of Biochemistry, Am Hubland, 97074 Würzburg, Germany
- 2. Genelux Cooperation, San Diego Science Center, 3030 Bunker Hill St, San Diego, CA 92109, USA
| | - Aladar A. Szalay
- 1. University of Würzburg, Department of Biochemistry, Am Hubland, 97074 Würzburg, Germany
- 2. Genelux Cooperation, San Diego Science Center, 3030 Bunker Hill St, San Diego, CA 92109, USA
- 5. Department of Radiation Oncology, Moores Cancer Center, University of California, La Jolla, CA 92093, USA
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sFRP-4, a potential novel serum marker for chronic hepatitis B-related hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int 2015; 14:164-70. [PMID: 25865689 DOI: 10.1016/s1499-3872(15)60352-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND The current methods used for diagnosing hepatocellular carcinoma (HCC) are unsatisfactory. Here, we assessed the serum levels of secreted frizzled related protein 4 (sFRP-4) for diagnosing HCC in patients infected with chronic hepatitis B (CHB). METHODS In 272 patients with CHB enrolled, 142 were patients with HCC. Thirty-three healthy subjects were recruited as healthy controls. The CHB patients were assigned to a test group or a validation group based on the time of enrollment. Human antibody arrays were used to screen 15 patients (8 CHB-related HCC patients, 7 CHB patients) for serum markers. Four markers and one candidate marker were assessed in the test group and validation group, respectively. RESULTS Human antibody assays indicated that the serum levels of sFRP-4 in HCC patients were significantly higher than those in CHB patients (P<0.05). Additionally, serum sFRP-4 levels were significantly higher in the HCC patients than those in the non-HCC patients in both test group (79.7 vs 41.3 ng/mL; P<0.001) and validation group (89.0 vs 39.0 ng/mL; P<0.001). Areas under the Receiver Operating Characteristic curves (AUCs) for alpha-fetoprotein (AFP) and sFRP-4 were similar in both test group and validation group. In the test group, the combination of sFRP-4 (a sensitivity of 94.4%, a specificity of 60.5% at 46.4 ng/mL) and AFP (a sensitivity of 75.0%, a specificity of 87.2% at 11.3 ng/mL) showed better performance for diagnosing HCC (a sensitivity of 79.2% and a specificity of 95.3%). The AUC for combined sFRP-4 and AFP increased to 0.941 (95% CI: 0.908-0.975), and similar results were seen in the validation group. CONCLUSION sFRP-4 is a candidate serum marker for diagnosing HCC in CHB patients, and the combination of sFRP-4 with AFP may improve the diagnostic accuracy of HCC.
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28
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Ge T, Shen Q, Wang N, Zhang Y, Ge Z, Chu W, Lv X, Zhao F, Zhao W, Fan J, Qin W. Diagnostic values of alpha-fetoprotein, dickkopf-1, and osteopontin for hepatocellular carcinoma. Med Oncol 2015; 32:59. [PMID: 25652109 DOI: 10.1007/s12032-014-0367-z] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2014] [Accepted: 11/13/2014] [Indexed: 02/08/2023]
Abstract
The timely diagnosis and effective treatment are essential for improving the survival and prognosis of hepatocellular carcinoma (HCC) patients. Alpha-fetoprotein (AFP) is the most widely used biomarker for diagnosis of HCC, but the low sensitivity and specificity limits its clinical application. In this study, we evaluated the diagnostic capability of the combination of AFP with two novel potential biomarkers, dickkopf-1 (DKK1) and osteopontin (OPN), for HCC in 390 participants including 89 patients with HCC, 36 patients with liver cirrhosis, 65 patients with chronic hepatitis B, and 200 health controls. We found the combination of all three markers as a panel showed a better diagnostic performance than that of AFP alone, with increased AUC [0.948 (95% CI 0.921-0.968) vs. 0.831 (95% CI 0.790-0.867)] and sensitivity (88.76 vs. 71.91%). Moreover, this combination showed a great improvement in diagnosing early-stage HCC patients. In conclusion, the combined use of AFP, DKK1, and OPN as a biomarker panel could enhance the diagnostic ability for HCC.
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Affiliation(s)
- Tianxiang Ge
- Shanghai Medical College of Fudan University, No. 138 Yi-Xueyuan Road, Shanghai, 200032, China
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Can serum glypican-3 be a biomarker for effective diagnosis of hepatocellular carcinoma? A meta-analysis of the literature. DISEASE MARKERS 2014; 2014:127831. [PMID: 25378766 PMCID: PMC4214040 DOI: 10.1155/2014/127831] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/25/2014] [Revised: 08/21/2014] [Accepted: 09/08/2014] [Indexed: 12/25/2022]
Abstract
OBJECTIVE This review is to evaluate the diagnostic value of serum GPC3 for hepatocellular carcinoma (HCC) due to conflicting results reported. METHODS NCBI PubMed and Embase were comprehensively searched for studies that have used serum GPC3 level as a diagnostic index for HCC. The quality of the included studies was assessed. Subgroup analyses were conducted to evaluate the sensitivity and specificity of GPC3 as a HCC marker. Statistical analysis was performed with the software STATA version 12.0. RESULTS A total of 22 studies were included. The qualities of included studies were relatively poor. Among them, 18 studies have shown that serum GPC3 is a specific biomarker for HCC, and the pooled sensitivity and specificity of these studies were 69 and 93%, respectively. The other 4 studies have reported conflicting results, which were not caused by races, infection status of HBV and HCV, or assay reagents but due to one common experimental design of enrolling liver cirrhosis patients as control subjects. CONCLUSIONS This meta-analysis indicates that serum GPC3 is elevated in HCC patients compared with healthy individuals, but more studies are needed to evaluate its effectiveness to differentially diagnose HCC and liver cirrhosis.
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