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Zhao J, Hu Z, Zheng X, Lin Y, Liu X, Zhang J, Peng J, Gao H. Blood biomarkers of hepatocellular carcinoma: a critical review. Front Cell Dev Biol 2024; 12:1489836. [PMID: 39650722 PMCID: PMC11621223 DOI: 10.3389/fcell.2024.1489836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Accepted: 11/13/2024] [Indexed: 12/11/2024] Open
Abstract
Hepatocellular Carcinoma (HCC) is a malignant tumor with high morbidity and mortality worldwide, which represents a serious threat to human life, health and quality of life. Blood-based detection is essential for HCC screening, early diagnosis, prognosis evaluation, and surveillance. Current non-invasive detection strategy including serum alpha-fetoprotein (AFP), ultrasound, computerized tomography, and magnetic resonance imaging. The limited specificity of an AFP and the dependence on operator experience and diagnostic personnel for ultrasound have constrained their utility in early HCC diagnosis. In recent years, with the development of various detection technologies, there has been an increasing focus on exploring blood-based detection markers for HCC. The types of markers include protein markers, DNA mutation, DNA epigenetic modification, mRNA, miRNA, and so on. However, numerous methodological and biological factors limit the clinical sensitivity and generalization performance of these new biomarkers. In this review, we describe the state-of-the-art technologies for cfDNA analysis, and discuss outstanding biological and technical challenges that, if addressed, would substantially improve HCC diagnostics and patient care.
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Affiliation(s)
- Junsheng Zhao
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Zekai Hu
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Xiaoping Zheng
- Hangzhou Tongchuang Medical Laboratory, Department of pathology, Hangzhou, China
| | - Yajie Lin
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Xiao Liu
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Junjie Zhang
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan (Hangzhou) Hospital Affiliated to Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Jing Peng
- Department of Breast Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Hainv Gao
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan (Hangzhou) Hospital Affiliated to Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
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Lominadze Z, Shaik MR, Choi D, Zaffar D, Mishra L, Shetty K. Hepatocellular Carcinoma Genetic Classification. Cancer J 2023; 29:249-258. [PMID: 37796642 PMCID: PMC10686192 DOI: 10.1097/ppo.0000000000000682] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/07/2023]
Abstract
ABSTRACT Hepatocellular carcinoma (HCC) represents a significant global burden, with management complicated by its heterogeneity, varying presentation, and relative resistance to therapy. Recent advances in the understanding of the genetic, molecular, and immunological underpinnings of HCC have allowed a detailed classification of these tumors, with resultant implications for diagnosis, prognostication, and selection of appropriate treatments. Through the correlation of genomic features with histopathology and clinical outcomes, we are moving toward a comprehensive and unifying framework to guide our diagnostic and therapeutic approach to HCC.
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Affiliation(s)
- Zurabi Lominadze
- Division of Gastroenterology and Hepatology, University of Maryland School of Medicine
| | | | - Dabin Choi
- Department of Medicine, University of Maryland Medical Center
| | - Duha Zaffar
- Department of Medicine, University of Maryland Midtown Medical Center
| | - Lopa Mishra
- Feinstein Institutes for Medical Research and Cold Spring Harbor Laboratory; Divisions of Gastroenterology and Hepatology, Northwell Health
| | - Kirti Shetty
- Division of Gastroenterology and Hepatology, University of Maryland School of Medicine
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3
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Eletreby R, Elsharkawy M, Taha AA, Hassany M, Abdelazeem A, El-Kassas M, Soliman A. Evaluation of GALAD Score in Diagnosis and Follow-up of Hepatocellular Carcinoma after Local Ablative Therapy. J Clin Transl Hepatol 2023; 11:334-340. [PMID: 36643039 PMCID: PMC9817041 DOI: 10.14218/jcth.2022.00013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 04/21/2022] [Accepted: 07/04/2022] [Indexed: 01/18/2023] Open
Abstract
BACKGROUND AND AIMS Strategies for detection of early hepatocellular carcinoma (HCC) are still limited. The GALAD score is a serum biomarker-based model designed to predict the probability of having HCC. We aimed to assess the ability of GALAD score to diagnose early HCC and its validity to follow patients after local ablation therapy. METHODS This multicenter prospective study included 108 patients in two groups, 58 HCC patients (67 focal lesions) with local ablative therapy (study group), and a control group of 50 patients with liver cirrhosis. The GALAD scores of the study and control groups, and of the HCC patients before and after ablative therapy were compared. RESULTS Most patients were men (74.1% in study group and 76% in controls) with hepatitis C virus infection (98.30% in the study group, and 94% in controls). GALAD scores were significantly higher in HCC patients than in those with benign cirrhosis (2.65 vs. -0.37, p=0.001). Ablative therapy was successful in 94.4% of focal lesions <2 cm, and in 86.10% of 2-5 cm lesions. The GALAD score was also significantly lower at 1 month after ablation in patients with well-ablated tumors (2.19 vs. 0.98, p=0.001). The best cutoff values of GALAD score for diagnosis of early HCC, and for prediction of well ablation of HCC were 0.74 and ≤3.31 (areas under the curve of 0.92 and 0.75, sensitivities of 84.48% and 76.19%, specificities of 89.13% and 83.33%, positive predictive values of 90.74% and 94.1%, and negative predictive values of 82% and 35.7% respectively). CONCLUSION The GALAD score was effective for the diagnosis of early HCC and for follow-up after ablative therapy.
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Affiliation(s)
- Rasha Eletreby
- Endemic Medicine Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Marwa Elsharkawy
- Clinical and Chemical Pathology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Alaa Awad Taha
- Hepatogastroenterology Department, Theodore Bilharz Research Institute, Giza, Egypt
| | - Mohamed Hassany
- Hepatogastroenterology Department, National Hepatology and Tropical Medicine Research Institute, Cairo, Egypt
| | - Amr Abdelazeem
- Endemic Medicine Department, Faculty of Medicine, Helwan University, Cairo, Egypt
| | - Mohamed El-Kassas
- Endemic Medicine Department, Faculty of Medicine, Helwan University, Cairo, Egypt
| | - Ahmed Soliman
- Endemic Medicine Department, Faculty of Medicine, Cairo University, Cairo, Egypt
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Mattox DE, Bailey-Kellogg C. Comprehensive analysis of lectin-glycan interactions reveals determinants of lectin specificity. PLoS Comput Biol 2021; 17:e1009470. [PMID: 34613971 PMCID: PMC8523061 DOI: 10.1371/journal.pcbi.1009470] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2021] [Revised: 10/18/2021] [Accepted: 09/22/2021] [Indexed: 12/23/2022] Open
Abstract
Lectin-glycan interactions facilitate inter- and intracellular communication in many processes including protein trafficking, host-pathogen recognition, and tumorigenesis promotion. Specific recognition of glycans by lectins is also the basis for a wide range of applications in areas including glycobiology research, cancer screening, and antiviral therapeutics. To provide a better understanding of the determinants of lectin-glycan interaction specificity and support such applications, this study comprehensively investigates specificity-conferring features of all available lectin-glycan complex structures. Systematic characterization, comparison, and predictive modeling of a set of 221 complementary physicochemical and geometric features representing these interactions highlighted specificity-conferring features with potential mechanistic insight. Univariable comparative analyses with weighted Wilcoxon-Mann-Whitney tests revealed strong statistical associations between binding site features and specificity that are conserved across unrelated lectin binding sites. Multivariable modeling with random forests demonstrated the utility of these features for predicting the identity of bound glycans based on generalized patterns learned from non-homologous lectins. These analyses revealed global determinants of lectin specificity, such as sialic acid glycan recognition in deep, concave binding sites enriched for positively charged residues, in contrast to high mannose glycan recognition in fairly shallow but well-defined pockets enriched for non-polar residues. Focused fine specificity analysis of hemagglutinin interactions with human-like and avian-like glycans uncovered features representing both known and novel mutations related to shifts in influenza tropism from avian to human tissues. As the approach presented here relies on co-crystallized lectin-glycan pairs for studying specificity, it is limited in its inferences by the quantity, quality, and diversity of the structural data available. Regardless, the systematic characterization of lectin binding sites presented here provides a novel approach to studying lectin specificity and is a step towards confidently predicting new lectin-glycan interactions.
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Affiliation(s)
- Daniel E. Mattox
- Program in Quantitative Biomedical Sciences, Geisel School of Medicine at Dartmouth College, Hanover, New Hampshire, United States of America
| | - Chris Bailey-Kellogg
- Program in Quantitative Biomedical Sciences, Geisel School of Medicine at Dartmouth College, Hanover, New Hampshire, United States of America
- Department of Computer Science, Dartmouth College, Hanover, New Hampshire, United States of America
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Tabu K, Mawatari S, Oda K, Taniyama O, Toyodome A, Ijuin S, Sakae H, Kumagai K, Kanmura S, Ido A. Highly sensitive Lens culinaris agglutinin-reactive fraction of α-fetoprotein is a predictive marker for hepatocarcinogenesis in long-term observation of patients with chronic liver disease. Mol Clin Oncol 2021; 15:174. [PMID: 34276993 PMCID: PMC8278410 DOI: 10.3892/mco.2021.2336] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Accepted: 06/03/2021] [Indexed: 11/25/2022] Open
Abstract
Highly sensitive Lens culinaris agglutinin-reactive fraction of α-fetoprotein (hs-AFP-L3) is a specific marker for hepatocellular carcinoma (HCC) and has been reliable in cases with a low serum α-fetoprotein (AFP) level. However, the biomarkers that contribute to hepatocarcinogenesis during the long-term observation are not yet clear. The present study reported the clinical utility of hs-AFP-L3 in the long-term observation of patients with chronic liver disease. The subjects were 106 patients with chronic liver disease without HCC or a history of HCC treatment and who had been followed for >12 months. hs-AFP-L3 was measured using cryopreserved serum. The factors contributing to hepatocarcinogenesis were examined using univariate and multivariate analyses. The median observation period was 88 months (15-132 months). The cumulative incidence of HCC was 10.5% at 5 years and 19.6% at 10 years. The univariate analysis revealed that age ≥55 years old, platelet count ≤13.1x104/µl, hyaluronic acid ≥80.8 ng/ml, alanine transaminase ≥47 U/l, AFP ≥6.3 ng/ml, hs-AFP-L3 ≥3.5% and des-γ-carboxy prothrombin (DCP) ≥25 mAU/ml were significant factors. In the multivariate analysis, platelet count ≤13.1x104/µl [hazard ratio (HR), 4.966; 95% confidence interval (CI), 1.597-15.437; P=0.006] and hs-AFP-L3 ≥3.5% (HR, 5.450; 95% CI, 1.522-19.512; P=0.009) were extracted as significant factors contributing to hepatocarcinogenesis. In addition, for cases with AFP <20 ng/ml, a multivariate analysis revealed that hs-AFP-L3 ≥4.9% (HR, 11.608; 95% CI, 2.422-55.629; P=0.002) and DCP ≥25 mAU/ml (HR, 3.936; 95% CI, 1.088-14.231; P=0.037) were significant factors contributing to hepatocarcinogenesis. hs-AFP-L3 is a useful marker for predicting hepatocarcinogenesis in the long-term observation of patients with chronic liver disease.
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Affiliation(s)
- Kazuaki Tabu
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan
| | - Seiichi Mawatari
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan
| | - Kohei Oda
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan
| | - Ohki Taniyama
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan
| | - Ai Toyodome
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan
| | - Sho Ijuin
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan
| | - Haruka Sakae
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan
| | - Kotaro Kumagai
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan
| | - Shuji Kanmura
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan
| | - Akio Ido
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan
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Liu M, Wu R, Liu X, Xu H, Chi X, Wang X, Zhan M, Wang B, Peng F, Gao X, Shi Y, Wen X, Ji Y, Jin Q, Niu J. Validation of the GALAD Model and Establishment of GAAP Model for Diagnosis of Hepatocellular Carcinoma in Chinese Patients. J Hepatocell Carcinoma 2020; 7:219-232. [PMID: 33123501 PMCID: PMC7591054 DOI: 10.2147/jhc.s271790] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2020] [Accepted: 09/17/2020] [Indexed: 12/24/2022] Open
Abstract
Purpose GALAD is a statistical model for estimating the likelihood of having hepatocellular carcinoma (HCC) based on gender, age, AFP, AFP-L3, and PIVKA-II. We aimed to assess its performance and build new models in China, where hepatitis B virus (HBV) is the leading etiology of HCC. Patients and Methods We built the GALAD-C model with the same five variables in GALAD, and the GAAP model with gender, age, AFP, and PIVKA-II, using logistic regression based on 242 patients with HCC and 283 patients with chronic liver disease (CLD). We also collected 50 patients with other malignant liver tumors (OMTs) and 50 healthy controls (HCs). A test dataset (169 patients with HCC and 139 with CLD) was used to test the performance of GAAP. Results The GALAD-C and GAAP models achieved comparable performance (area under the receiver operating characteristic curve [AUC], 0.922 vs 0.914), and both were superior to GALAD, PIVKA-II, AFP, and AFP-L3% (AUCs, 0.891, 0.869, 0.750, and 0.711) for discrimination of HCC from CLD for the entire dataset. The AUCs of the GALAD, GALAD-C and GAAP models were excellent for the hepatitis C virus (HCV) subgroup (0.939, 0.958 and 0.954), and for discrimination HCC from HCs (0.988, 0.982, and 0.979), but were relatively lower for the HBV subgroup (0.855, 0.904, and 0.894), and for HCC within Milan Criteria (0.810, 0.841, and 0.840). They were not superior to AFP (0.873) for discrimination of HCC from OMT (0.873, 0.809, and 0.823). GAAP achieved an AUC of 0.922 in the test dataset. Conclusion GALAD was excellent for discrimination of HCC from CLD in the HCV subgroup of a cohort of Chinese patients. The GAAP and GALAD-C models achieved better performance compared with GALAD. These three models exhibited better performance in patients with an HCV etiology than those with HBV.
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Affiliation(s)
- Miaoxia Liu
- Department of Hepatology, First Hospital of Jilin University, Changchun, Jilin Province 130021, People's Republic of China.,Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou 510515, People's Republic of China
| | - Ruihong Wu
- Department of Hepatology, First Hospital of Jilin University, Changchun, Jilin Province 130021, People's Republic of China.,Phase I Clinical Research Center, First Hospital of Jilin University, Changchun, Jilin Province 130021, People's Republic of China
| | - Xu Liu
- Department of Hepatology, First Hospital of Jilin University, Changchun, Jilin Province 130021, People's Republic of China
| | - Hongqin Xu
- Department of Hepatology, First Hospital of Jilin University, Changchun, Jilin Province 130021, People's Republic of China
| | - Xiumei Chi
- Department of Hepatology, First Hospital of Jilin University, Changchun, Jilin Province 130021, People's Republic of China.,Phase I Clinical Research Center, First Hospital of Jilin University, Changchun, Jilin Province 130021, People's Republic of China
| | - Xiaomei Wang
- Department of Hepatology, First Hospital of Jilin University, Changchun, Jilin Province 130021, People's Republic of China
| | - Mengru Zhan
- Department of Hepatology, First Hospital of Jilin University, Changchun, Jilin Province 130021, People's Republic of China
| | - Bao Wang
- Department of Hepatology, First Hospital of Jilin University, Changchun, Jilin Province 130021, People's Republic of China
| | - Fei Peng
- Department of Hepatology, First Hospital of Jilin University, Changchun, Jilin Province 130021, People's Republic of China
| | - Xiuzhu Gao
- Department of Hepatology, First Hospital of Jilin University, Changchun, Jilin Province 130021, People's Republic of China.,Phase I Clinical Research Center, First Hospital of Jilin University, Changchun, Jilin Province 130021, People's Republic of China
| | - Ying Shi
- Department of Hepatology, First Hospital of Jilin University, Changchun, Jilin Province 130021, People's Republic of China
| | - Xiaoyu Wen
- Department of Hepatology, First Hospital of Jilin University, Changchun, Jilin Province 130021, People's Republic of China
| | - Yali Ji
- Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou 510515, People's Republic of China
| | - Qinglong Jin
- Department of Hepatology, First Hospital of Jilin University, Changchun, Jilin Province 130021, People's Republic of China
| | - Junqi Niu
- Department of Hepatology, First Hospital of Jilin University, Changchun, Jilin Province 130021, People's Republic of China
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7
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Belur S, Jagadeesh N, Swamy BM, Inamdar SR. A core fucose specific lectin from Cephalosporium curvulum induces cellular apoptosis in hepatocellular and pancreatic cancer cells and effective in detecting AFP. Glycoconj J 2020; 37:435-444. [PMID: 32367479 DOI: 10.1007/s10719-020-09921-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Revised: 01/24/2020] [Accepted: 03/18/2020] [Indexed: 01/15/2023]
Abstract
Cephalosporium curvulum lectin (CSL), a lectin from pathogenic fungus has exquisite specificity towards α1-6 linkage of core fucosylated glycans, expressed in hepatocellular and pancreatic cancer. Interaction and effect of CSL and other fucose specific lectins LCA and AOL on HepG2 and PANC-1 cells was investigated. CSL, LCA and AOL exhibited strong binding to PANC-1 cells which could be effectively blocked by competing glycoprotein mucin. Effect of CSL, LCA and AOL on PANC-1 and HepG2 cells was determined by MTT assay and all the three lectins inhibited the cell growth which could be blocked by mucin, cell cycle analysis revealed that CSL increased hypodiploid HepG2 cell population indicating cellular apoptosis. CSL induced apoptosis in HepG2 cells was confirmed by Annexin V/PI assay. CSL induced increase in early apoptotic HepG2 cell population, a time dependent increase in the expression of caspases-3, 9 and cytochrome-c was observed by western blotting suggesting the possible involvement of intrinsic caspase dependent apoptosis. Increase in ROS and decrease in MMP demonstrated involvement of intrinsic caspase dependent apoptosis. Quantification of AFP in HCC patients using CSL lectin-antibody sandwich ELISA, supports diagnostic potential of CSL.
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Affiliation(s)
- Shivakumar Belur
- Department of Studies in Biochemistry, Karnatak University, Dharwad, 580003, India
| | | | - Bale M Swamy
- Department of Studies in Biochemistry, Karnatak University, Dharwad, 580003, India
| | - Shashikala R Inamdar
- Department of Studies in Biochemistry, Karnatak University, Dharwad, 580003, India.
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8
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Wang W, Wei C. Advances in the early diagnosis of hepatocellular carcinoma. Genes Dis 2020; 7:308-319. [PMID: 32884985 PMCID: PMC7452544 DOI: 10.1016/j.gendis.2020.01.014] [Citation(s) in RCA: 263] [Impact Index Per Article: 52.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Revised: 01/10/2020] [Accepted: 01/20/2020] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most prevalent cancers globally. In contrast to the declining death rates observed for all other common cancers such as breast, lung, and prostate cancers, the death rates for HCC continue to increase by ~2–3% per year because HCC is frequently diagnosed late and there is no curative therapy for an advanced HCC. The early diagnosis of HCC is truly a big challenge. Over the past years, the early diagnosis of HCC has relied on surveillance with ultrasonography (US) and serological assessments of alpha-fetoprotein (AFP). However, the specificity and sensitivity of US/AFP is not satisfactory enough to detect early onset HCC. Recent technological advancements offer hope for early HCC diagnosis. Herein, we review the progress made in HCC diagnostics, with a focus on emerging imaging techniques and biomarkers for early disease diagnosis.
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Affiliation(s)
- Weiyi Wang
- Xiamen Amplly Bio-engineering Co., Ltd, Xiamen, PR China
| | - Chao Wei
- Xiamen Amplly Bio-engineering Co., Ltd, Xiamen, PR China
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9
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Multiplexed Proteomic Approach for Identification of Serum Biomarkers in Hepatocellular Carcinoma Patients with Normal AFP. J Clin Med 2020; 9:jcm9020323. [PMID: 31979338 PMCID: PMC7074125 DOI: 10.3390/jcm9020323] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 01/13/2020] [Accepted: 01/21/2020] [Indexed: 02/07/2023] Open
Abstract
Alpha fetoprotein (AFP) has been used as a serologic indicator of hepatocellular carcinoma (HCC). We aimed to identify an HCC-specific serum biomarker for diagnosis using a multiplexed proteomic technique in HCC patients with normal AFP levels. A total of 152 patients were included from Guro Hospital, Korea University. Among 267 identified proteins, 28 and 86 proteins showed at least a two-fold elevation or reduction in expression, respectively. Multiple reaction monitoring (MRM) analysis of 41 proteins revealed 10 proteins were differentially expressed in patients with liver cirrhosis and HCC patients with normal AFP. A combination of tripartite motif22 (Trim22), seprase, and bone morphogenetic protein1 had an area under receiver operating characteristic of 0.957 for HCC diagnosis. Real-time PCR and western blot analysis of the paired tumor/non-tumor liver tissue in HCC revealed a reduced expression of Trim22 in the tumor tissue. Also, serum levels of Trim22 were significantly reduced in HCC patients with normal AFP compared to those with liver cirrhosis (p = 0.032). Inhibition of Trim22 increased cellular proliferation in human hepatoma cell lines, whereas overexpression of Trim22 decreased cellular proliferation in hepatoma cell lines. In conclusion, the combination of three serum markers improved the chance of diagnosing HCC. MRM-based quantification of the serum protein in patients with normal AFP provides the potential for early diagnosis of HCC.
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10
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Lou J, Zhang L, Lv S, Zhang C, Jiang S. Biomarkers for Hepatocellular Carcinoma. BIOMARKERS IN CANCER 2017; 9:1-9. [PMID: 28469485 PMCID: PMC5345949 DOI: 10.1177/1179299x16684640] [Citation(s) in RCA: 79] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/20/2016] [Accepted: 11/26/2016] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide. The HCC diagnosis is usually achieved by biomarkers, which can also help in prognosis prediction. Furthermore, it might represent certain therapeutic interventions through some combinations of biomarkers. Here, we review on our current understanding of HCC biomarkers.
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Affiliation(s)
- Jiatao Lou
- Department of Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - LingFei Zhang
- Center for RNA Research, State Key Laboratory of Molecular Biology, Chinese Academy of Sciences (CAS), Shanghai, China.,Department of Anatomy, Histology & Embryology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Shaogang Lv
- Department of Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Chenzi Zhang
- Department of Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Shuai Jiang
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA
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11
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Zhu J, Wu J, Yin H, Marrero J, Lubman DM. Mass Spectrometric N-Glycan Analysis of Haptoglobin from Patient Serum Samples Using a 96-Well Plate Format. J Proteome Res 2015; 14:4932-9. [PMID: 26448449 DOI: 10.1021/acs.jproteome.5b00662] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Alterations in glycosylation of serum glycoproteins can provide unique and highly specific fingerprints of malignancy. Our previous mass spectrometric study revealed that the bifucosylation level of serum haptoglobin was distinctly increased in hepatocellular carcinoma (HCC) patients versus liver cirrhosis of all three major etiologies. We have thus developed a method for the analysis of large numbers of serum samples based on a 96-well plate platform for the evaluation of fucosylation changes of serum haptoglobin between HCC versus cirrhosis. Haptoglobin was isolated from the serum of individual patient samples based on an HPLC column immobilized with antihaptoglobin antibody via hydrazide immobilization chemistry. Only 10 μL of serum was required for glycan extraction and processing for MALDI-QIT mass spectrometry analysis using the 96-well plate format. The bifucosylation degrees of haptoglobin in individuals were calculated using a quantitative glycomics method. The MS data confirmed that the bifucosylated tetra-anntenary glycan was upregulated in HCC samples of all etiologies. This study provides a parallel method for processing glycan content for haptoglobin and evaluating detailed changes in glycan structures for a potentially large cohort of clinical serum samples.
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Affiliation(s)
- Jianhui Zhu
- Department of Surgery, University of Michigan Medical Center , 1150 West Medical Center Drive, Ann Arbor, Michigan 48109, United States
| | - Jing Wu
- Department of Surgery, University of Michigan Medical Center , 1150 West Medical Center Drive, Ann Arbor, Michigan 48109, United States
| | - Haidi Yin
- Department of Surgery, University of Michigan Medical Center , 1150 West Medical Center Drive, Ann Arbor, Michigan 48109, United States
| | - Jorge Marrero
- Department of Internal Medicine, UT Southwestern Medical Center , 5323 Harry Hines Boulevard, Dallas, Texas 75390, United States
| | - David M Lubman
- Department of Surgery, University of Michigan Medical Center , 1150 West Medical Center Drive, Ann Arbor, Michigan 48109, United States
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Tsuchiya N, Sawada Y, Endo I, Saito K, Uemura Y, Nakatsura T. Biomarkers for the early diagnosis of hepatocellular carcinoma. World J Gastroenterol 2015; 21:10573-10583. [PMID: 26457017 PMCID: PMC4588079 DOI: 10.3748/wjg.v21.i37.10573] [Citation(s) in RCA: 372] [Impact Index Per Article: 37.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2015] [Revised: 05/21/2015] [Accepted: 08/31/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer and the second leading cause of cancer-related deaths worldwide. Although the prognosis of patients with HCC is generally poor, the 5-year survival rate is > 70% if patients are diagnosed at an early stage. However, early diagnosis of HCC is complicated by the coexistence of inflammation and cirrhosis. Thus, novel biomarkers for the early diagnosis of HCC are required. Currently, the diagnosis of HCC without pathological correlation is achieved by analyzing serum α-fetoprotein levels combined with imaging techniques. Advances in genomics and proteomics platforms and biomarker assay techniques over the last decade have resulted in the identification of numerous novel biomarkers and have improved the diagnosis of HCC. The most promising biomarkers, such as glypican-3, osteopontin, Golgi protein-73 and nucleic acids including microRNAs, are most likely to become clinically validated in the near future. These biomarkers are not only useful for early diagnosis of HCC, but also provide insight into the mechanisms driving oncogenesis. In addition, such molecular insight creates the basis for the development of potentially more effective treatment strategies. In this article, we provide an overview of the biomarkers that are currently used for the early diagnosis of HCC.
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Glycosylation-Based Serum Biomarkers for Cancer Diagnostics and Prognostics. BIOMED RESEARCH INTERNATIONAL 2015; 2015:490531. [PMID: 26509158 PMCID: PMC4609776 DOI: 10.1155/2015/490531] [Citation(s) in RCA: 148] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/02/2015] [Revised: 05/28/2015] [Accepted: 05/31/2015] [Indexed: 12/13/2022]
Abstract
Cancer is the second most common cause of death in developed countries with approximately 14 million newly diagnosed individuals and over 6 million cancer-related deaths in 2012. Many cancers are discovered at a more advanced stage but better survival rates are correlated with earlier detection. Current clinically approved cancer biomarkers are most effective when applied to patients with widespread cancer. Single biomarkers with satisfactory sensitivity and specificity have not been identified for the most common cancers and some biomarkers are ineffective for the detection of early stage cancers. Thus, novel biomarkers with better diagnostic and prognostic performance are required. Aberrant protein glycosylation is well known hallmark of cancer and represents a promising source of potential biomarkers. Glycoproteins enter circulation from tissues or blood cells through active secretion or leakage and patient serum is an attractive option as a source for biomarkers from a clinical and diagnostic perspective. A plethora of technical approaches have been developed to address the challenges of glycosylation structure detection and determination. This review summarises currently utilised glycoprotein biomarkers and novel glycosylation-based biomarkers from the serum glycoproteome under investigation as cancer diagnostics and for monitoring and prognostics and includes details of recent high throughput and other emerging glycoanalytical techniques.
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Kim H, Kim K, Jin J, Park J, Yu SJ, Yoon JH, Kim Y. Measurement of glycosylated alpha-fetoprotein improves diagnostic power over the native form in hepatocellular carcinoma. PLoS One 2014; 9:e110366. [PMID: 25310463 PMCID: PMC4195728 DOI: 10.1371/journal.pone.0110366] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2014] [Accepted: 09/12/2014] [Indexed: 12/19/2022] Open
Abstract
Serum alpha-fetoprotein (AFP) has long been used as a diagnostic marker for hepatocellular carcinoma (HCC), albeit controversially. Although it remains widely used in clinics, the value of AFP in HCC diagnosis has recently been challenged due to its significant rates of false positive and false negative findings. To improve the efficacy of AFP as HCC diagnostic marker, we developed a method of measuring total and glycosylated AFP by multiple reaction monitoring (MRM)-MS. In this study, we verified the total amount of AFP (nonglycopeptide levels) and the degree of glycosylated AFP (deglycopeptide levels) in 60 normal (41 men and 19 women; mean age 53 years; range 32–74 years), 35 LC (23 men and 12 women; mean age 56 years; range 43–78 years; HBV-related), and 60 HCC subjects (42 men and 18 women; mean age 58 years; range 38–76 years; HBV-related; 30 stage I, 15 stage II, and 10 stage III). By MRM-MS analysis, the nonglycopeptide had 56.7% sensitivity, 68.3% specificity, and an AUC of 0.687 [cutoff value: ≥0.02 (light/heavy ratio)], comparing the normal and HCC group, whereas the deglycopeptide had 93.3% sensitivity, 68.3% specificity, and an AUC of 0.859 [cutoff value: ≥0.02 (light/heavy ratio)]. In comparing the stage I HCC subgroup with the LC group, the nonglycopeptide had a sensitivity of 66.7%, specificity of 80.0%, and an AUC of 0.712 [cutoff value: ≥0.02 (light/heavy ratio)], whereas the deglycopeptide had a sensitivity of 96.7%, specificity of 80.0%, and an AUC of 0.918 [cutoff value: ≥0.02 (light/heavy ratio)]. These data demonstrate that the discriminatory power of the deglycopeptide is greater than that of the nonglycopeptide. We conclude that deglycopeptide can distinguish cancer status between normal subjects and HCC patients better than nonglycopeptide.
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Affiliation(s)
- Hyunsoo Kim
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Kyunggon Kim
- Department of Biomedical Engineering, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jonghwa Jin
- Department of Biomedical Engineering, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jiyoung Park
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Su Jong Yu
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jung-Hwan Yoon
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Youngsoo Kim
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea
- Department of Biomedical Engineering, Seoul National University College of Medicine, Seoul, Republic of Korea
- * E-mail:
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Wang L, Yao M, Dong Z, Zhang Y, Yao D. Circulating specific biomarkers in diagnosis of hepatocellular carcinoma and its metastasis monitoring. Tumour Biol 2014; 35:9-20. [PMID: 24006223 PMCID: PMC3907675 DOI: 10.1007/s13277-013-1141-0] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2013] [Accepted: 08/23/2013] [Indexed: 12/18/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common and rapidly fatal malignancies worldwide with a multifactorial, multistep, complex process and poor prognosis. Its early diagnosis and metastasis monitoring are of the utmost importance. Hepatoma tissues synthesize various tumor-related proteins, genes, enzymes, microRNA, etc. and then secrete into the blood. Detections of circulating biomarkers are useful to find tumor at an early stage or monitor metastasis after postoperative treatment. This paper summarizes recent studies of specific biomarkers at early diagnosis or in monitoring metastasis or postoperative recurrence of HCC.
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Affiliation(s)
- Li Wang
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, 226001 Jiangsu Province China
- Department of Medical Informatics, Medical School of Nantong University, Nantong, 226001 Jiangsu Province China
| | - Min Yao
- Department of Medical Immunology, Medical School of Nantong University, Nantong, 226001 Jiangsu Province China
| | - Zhizhen Dong
- Department of Diagnostics, Affiliated Hospital of Nantong University, Nantong, 226001 Jiangsu Province China
| | - Yun Zhang
- Institute of Medicine, Nanjing Medical University, Nanjing, 210029 Jiangsu Province China
| | - Dengfu Yao
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, 226001 Jiangsu Province China
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