|
1
|
Liu L, Hao S, Gou S, Tang X, Zhang Y, Cai D, Xiao M, Zhang X, Zhang D, Shen J, Li Y, Chen Y, Zhao Y, Deng S, Wu X, Li M, Zhang Z, Xiao Z, Du F. Potential applications of dual haptoglobin expression in the reclassification and treatment of hepatocellular carcinoma. Transl Res 2024; 272:19-40. [PMID: 38815898 DOI: 10.1016/j.trsl.2024.05.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 05/07/2024] [Accepted: 05/22/2024] [Indexed: 06/01/2024]
Abstract
HCC is a malignancy characterized by high incidence and mortality rates. Traditional classifications of HCC primarily rely on tumor morphology, phenotype, and multicellular molecular levels, which may not accurately capture the cellular heterogeneity within the tumor. This study integrates scRNA-seq and bulk RNA-seq to spotlight HP as a critical gene within a subgroup of HCC malignant cells. HP is highly expressed in HCC malignant cells and lowly expressed in T cells. Within malignant cells, elevated HP expression interacts with C3, promoting Th1-type responses via the C3/C3AR1 axis. In T cells, down-regulating HP expression favors the expression of Th1 cell-associated marker genes, potentially enhancing Th1-type responses. Consequently, we developed a "HP-promoted Th1 response reclassification" gene set, correlating higher activity scores with improved survival rates in HCC patients. Additionally, four predictive models for neoadjuvant treatment based on HP and C3 expression were established: 1) Low HP and C3 expression with high Th2 cell infiltration; 2) High HP and low C3 expression with high Th2 cell infiltration; 3) High HP and C3 expression with high Th1 cell infiltration; 4) Low HP and high C3 expression with high Th1 cell infiltration. In conclusion, the HP gene selected from the HCC malignant cell subgroup (Malignant_Sub 6) might serve as a potential ally against the tumor by promoting Th1-type immune responses. The establishment of the "HP-promoted Th1 response reclassification" gene set offers predictive insights for HCC patient survival prognosis and neoadjuvant treatment efficacy, providing directions for clinical treatments.
Collapse
Affiliation(s)
- Lin Liu
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan Luzhou 646000, China; Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Sichuan Luzhou, 646000, China; South Sichuan Institute of Translational Medicine, Sichuan Luzhou 646000, China
| | - Siyu Hao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan Luzhou 646000, China; Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Sichuan Luzhou, 646000, China; South Sichuan Institute of Translational Medicine, Sichuan Luzhou 646000, China
| | - Shuang Gou
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan Luzhou 646000, China; Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Sichuan Luzhou, 646000, China; South Sichuan Institute of Translational Medicine, Sichuan Luzhou 646000, China
| | - Xiaolong Tang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan Luzhou 646000, China; Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Sichuan Luzhou, 646000, China; South Sichuan Institute of Translational Medicine, Sichuan Luzhou 646000, China
| | - Yao Zhang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan Luzhou 646000, China; Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Sichuan Luzhou, 646000, China; South Sichuan Institute of Translational Medicine, Sichuan Luzhou 646000, China
| | - Dan Cai
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan Luzhou 646000, China; Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Sichuan Luzhou, 646000, China; South Sichuan Institute of Translational Medicine, Sichuan Luzhou 646000, China
| | - Mintao Xiao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan Luzhou 646000, China; Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Sichuan Luzhou, 646000, China; South Sichuan Institute of Translational Medicine, Sichuan Luzhou 646000, China
| | - Xinyi Zhang
- Department of Anaesthesia and Intensive Care, Faculty of Medicine, The Chinese University of Hong Kong, China
| | - Duoli Zhang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan Luzhou 646000, China; Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Sichuan Luzhou, 646000, China; South Sichuan Institute of Translational Medicine, Sichuan Luzhou 646000, China
| | - Jing Shen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan Luzhou 646000, China; Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Sichuan Luzhou, 646000, China; South Sichuan Institute of Translational Medicine, Sichuan Luzhou 646000, China
| | - Yan Li
- Public Center of Experimental Technology, Southwest Medical University, Sichuan Luzhou 646000, China
| | - Yu Chen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan Luzhou 646000, China; Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Sichuan Luzhou, 646000, China; South Sichuan Institute of Translational Medicine, Sichuan Luzhou 646000, China
| | - Yueshui Zhao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan Luzhou 646000, China; Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Sichuan Luzhou, 646000, China; South Sichuan Institute of Translational Medicine, Sichuan Luzhou 646000, China
| | - Shuai Deng
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan Luzhou 646000, China; Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Sichuan Luzhou, 646000, China; South Sichuan Institute of Translational Medicine, Sichuan Luzhou 646000, China
| | - Xu Wu
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan Luzhou 646000, China; Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Sichuan Luzhou, 646000, China; South Sichuan Institute of Translational Medicine, Sichuan Luzhou 646000, China
| | - Mingxing Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan Luzhou 646000, China; Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Sichuan Luzhou, 646000, China; South Sichuan Institute of Translational Medicine, Sichuan Luzhou 646000, China
| | - Zhuo Zhang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan Luzhou 646000, China
| | - Zhangang Xiao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan Luzhou 646000, China; Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Sichuan Luzhou, 646000, China; South Sichuan Institute of Translational Medicine, Sichuan Luzhou 646000, China
| | - Fukuan Du
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan Luzhou 646000, China; Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Sichuan Luzhou, 646000, China; South Sichuan Institute of Translational Medicine, Sichuan Luzhou 646000, China.
| |
Collapse
|
|
2
|
Reyes CDG, Mojgan A, Fowowe M, Onigbinde S, Daramola O, Lubman DM, Mechref Y. Differential expression of N-glycopeptides derived from serum glycoproteins in mild cognitive impairment (MCI) patients. Proteomics 2024; 24:e2300620. [PMID: 38602241 PMCID: PMC11749004 DOI: 10.1002/pmic.202300620] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 03/15/2024] [Accepted: 03/19/2024] [Indexed: 04/12/2024]
Abstract
Mild cognitive impairment (MCI) is an early stage of memory loss that affects cognitive abilities with the aging of individuals, such as language or visual/spatial comprehension. MCI is considered a prodromal phase of more complicated neurodegenerative diseases such as Alzheimer's. Therefore, accurate diagnosis and better understanding of the disease prognosis will facilitate prevention of neurodegeneration. However, the existing diagnostic methods fail to provide precise and well-timed diagnoses, and the pathophysiology of MCI is not fully understood. Alterations of the serum N-glycoproteome expression could represent an essential contributor to the overall pathophysiology of neurodegenerative diseases and be used as a potential marker to assess MCI diagnosis using less invasive procedures. In this approach, we identified N-glycopeptides with different expressions between healthy and MCI patients from serum glycoproteins. Seven of the N-glycopeptides showed outstanding AUC values, among them the antithrombin-III Asn224 + 4-5-0-2 with an AUC value of 1.00 and a p value of 0.0004. According to proteomics and ingenuity pathway analysis (IPA), our data is in line with recent publications, and the glycoproteins carrying the identified N-sites play an important role in neurodegeneration.
Collapse
Affiliation(s)
| | - Atashi Mojgan
- Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX 79409-1061
| | - Mojibola Fowowe
- Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX 79409-1061
| | - Sherifdeen Onigbinde
- Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX 79409-1061
| | - Oluwatosin Daramola
- Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX 79409-1061
| | - David M. Lubman
- Department of Surgery, The University of Michigan, Ann Arbor, MI 48109
| | - Yehia Mechref
- Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX 79409-1061
| |
Collapse
|
|
3
|
Bi M, Gao K, Bai B, Tian Z. Benchmark N-glycoproteomics study of common differential tissue and serum N-glycoproteins of patients with hepatocellular carcinoma. Anal Chim Acta 2024; 1322:343066. [PMID: 39182988 DOI: 10.1016/j.aca.2024.343066] [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: 06/03/2024] [Revised: 07/30/2024] [Accepted: 08/05/2024] [Indexed: 08/27/2024]
Abstract
For hepatocellular carcinoma (HCC), N-glycosylation has been proved to be widely involved in various aspects of the disease, including development, metastasis, subtyping, diagnosis and prognosis. The common practice is to discover biomarkers in situ of cancer occurrence (i.e., cancer vs. adjacent tissues) yet to clinically monitor in sera because of non-invasiveness. This study benchmarks N-glycoproteomics characterization of common differential tissue and serum N-glycoproteins of patients with HCC. Differential N-glycosylation in matched tissue and serum samples from the same patients were quantitatively characterized at the intact N-glycopeptide molecular level, and 29 common N-glycoproteins were found. Subcellular localization analysis was carried out to confirm the tissue originality. Secreted N-glycoprotein APOH was up-regulated, and transmembrane and intracellular N-glycoproteins including OSMR, GAT2, CSF-1 and MAGI3 were down-regulated.
Collapse
Affiliation(s)
- Ming Bi
- School of Chemical Science & Engineering, Tongji University, Shanghai, 200092, China
| | - Ke Gao
- Department of Liver Surgery and Transplantation, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Bing Bai
- Department of Laboratory Medicine, Center of precision Medicine, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, 210008, China.
| | - Zhixin Tian
- School of Chemical Science & Engineering, Tongji University, Shanghai, 200092, China.
| |
Collapse
|
|
4
|
Meng L, Wang B, Zhang S, Zhang S, Cai T, Ding CF, Yan Y. One-step fabrication of dipeptide-based bifunctional polymer for individual enrichment of glycopeptides and phosphopeptides from serum. J Chromatogr A 2024; 1730:465173. [PMID: 39025024 DOI: 10.1016/j.chroma.2024.465173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 07/11/2024] [Accepted: 07/15/2024] [Indexed: 07/20/2024]
Abstract
A dipeptide-based bifunctional material immobilized with Ti4+ (denoted as APE-MBA-VPA-Ti4+) was developed using precipitation polymerization. This polymer combines hydrophilic interaction liquid chromatography (HILIC) and immobilized metal affinity chromatography (IMAC) enrichment strategies, allowing for the individual and simultaneous enrichment of glycopeptides and phosphopeptides. It demonstrated high sensitivity (0.1 fmol μL-1 for glycopeptides, 0.005 fmol μL-1 for phosphopeptides), strong selectivity (molar ratio HRP: BSA = 1:1000, β-casein: BSA = 1:2500), consistent reusability (10 cycles) and satisfactory recovery rate (93.5 ± 1.8 % for glycopeptides, 91.6 ± 0.6 % for phosphopeptides) in the individual enrichment. Utilizing nano LC-MS/MS technology, the serum of liver cancer patients was analyzed after enrichment individually, resulting in the successful capture of 333 glycopeptides covering 262 glycosylation sites, corresponding to 131 glycoproteins, as well as 67 phosphopeptides covering 57 phosphorylation sites, related to 48 phosphoproteins. In comparison, the serum of normal healthy individuals yielded a total of 283 glycopeptides covering 244 glycosylation sites corresponding to 126 glycoproteins, as well as 66 phosphopeptides covering 56 phosphorylation sites related to 37 phosphoproteins. Label-free quantification identified 10 differentially expressed glycoproteins and 8 differentially expressed phosphoproteins in the serum of liver cancer patients. Among them, glycoproteins (HP, BCHE, AGT, C3, and PROC) and phosphoproteins (ZYX, GOLM1, GP1BB, CLU, and TNXB) showed upregulation and displayed potential as biomarkers for liver cancer.
Collapse
Affiliation(s)
- Luyan Meng
- Ningbo No.2 Hospital, Ningbo, Zhejiang, 315099, PR China; Guoke Ningbo Life Science and Health Industry Research Institute, Ningbo, Zhejiang, 315020, PR China
| | - Bing Wang
- School of Material Science and Chemical Engineering, Ningbo University, Ningbo, Zhejiang, 315211, PR China
| | - Sijia Zhang
- Ningbo No.2 Hospital, Ningbo, Zhejiang, 315099, PR China
| | - Shun Zhang
- Ningbo No.2 Hospital, Ningbo, Zhejiang, 315099, PR China; Guoke Ningbo Life Science and Health Industry Research Institute, Ningbo, Zhejiang, 315020, PR China
| | - Ting Cai
- Ningbo No.2 Hospital, Ningbo, Zhejiang, 315099, PR China; Guoke Ningbo Life Science and Health Industry Research Institute, Ningbo, Zhejiang, 315020, PR China.
| | - Chuan-Fan Ding
- Guoke Ningbo Life Science and Health Industry Research Institute, Ningbo, Zhejiang, 315020, PR China; School of Material Science and Chemical Engineering, Ningbo University, Ningbo, Zhejiang, 315211, PR China.
| | - Yinghua Yan
- Guoke Ningbo Life Science and Health Industry Research Institute, Ningbo, Zhejiang, 315020, PR China; School of Material Science and Chemical Engineering, Ningbo University, Ningbo, Zhejiang, 315211, PR China.
| |
Collapse
|
|
5
|
Pradita T, Chen YJ, Su TH, Chang KH, Chen PJ, Chen YJ. Data Independent Acquisition Mass Spectrometry Enhanced Personalized Glycosylation Profiling of Haptoglobin in Hepatocellular Carcinoma. J Proteome Res 2024; 23:3571-3584. [PMID: 38994555 PMCID: PMC11301664 DOI: 10.1021/acs.jproteome.4c00227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Revised: 06/24/2024] [Accepted: 06/27/2024] [Indexed: 07/13/2024]
Abstract
Aberrant glycosylation has gained significant interest for biomarker discovery. However, low detectability, complex glycan structures, and heterogeneity present challenges in glycoprotein assay development. Using haptoglobin (Hp) as a model, we developed an integrated platform combining functionalized magnetic nanoparticles and zwitterionic hydrophilic interaction liquid chromatography (ZIC-HILIC) for highly specific glycopeptide enrichment, followed by a data-independent acquisition (DIA) strategy to establish a deep cancer-specific Hp-glycosylation profile in hepatitis B virus (HBV, n = 5) and hepatocellular carcinoma (HCC, n = 5) patients. The DIA strategy established one of the deepest Hp-glycosylation landscapes (1029 glycopeptides, 130 glycans) across serum samples, including 54 glycopeptides exclusively detected in HCC patients. Additionally, single-shot DIA searches against a DIA-based spectral library outperformed the DDA approach by 2-3-fold glycopeptide coverage across patients. Among the four N-glycan sites on Hp (N-184, N-207, N-211, N-241), the total glycan type distribution revealed significantly enhanced detection of combined fucosylated-sialylated glycans, which were the most dominant glycoforms identified in HCC patients. Quantitation analysis revealed 48 glycopeptides significantly enriched in HCC (p < 0.05), including a hybrid monosialylated triantennary glycopeptide on the N-184 site with nearly none-to-all elevation to differentiate HCC from the HBV group (HCC/HBV ratio: 2462 ± 766, p < 0.05). In summary, DIA-MS presents an unbiased and comprehensive alternative for targeted glycoproteomics to guide discovery and validation of glyco-biomarkers.
Collapse
Affiliation(s)
- Tiara Pradita
- Institute
of Chemistry, Academia Sinica, Taipei 115, Taiwan
- Sustainable
Chemical Science and Technology, Taiwan International Graduate Program, Academia Sinica, Taipei 115, Taiwan
- Department
of Applied Chemistry, National Yang Ming
Chiao Tung University, Hsinchu 300, Taiwan
| | - Yi-Ju Chen
- Institute
of Chemistry, Academia Sinica, Taipei 115, Taiwan
| | - Tung-Hung Su
- Division
of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei 100, Taiwan
- Hepatitis
Research Center, National Taiwan University
Hospital, Taipei 100, Taiwan
| | - Kun-Hao Chang
- Institute
of Chemistry, Academia Sinica, Taipei 115, Taiwan
- Molecular
Science and Technology Program, Taiwan International Graduate Program, Academia Sinica, Taipei 115, Taiwan
- Department
of Chemistry, National Tsing-Hua University, Hsinchu 300, Taiwan
| | - Pei-Jer Chen
- Division
of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei 100, Taiwan
- Hepatitis
Research Center, National Taiwan University
Hospital, Taipei 100, Taiwan
- Graduate
Institute of Clinical Medicine, National
Taiwan University College of Medicine, Taipei 100, Taiwan
- Department
of Medical Research, National Taiwan University
Hospital, Taipei 100, Taiwan
| | - Yu-Ju Chen
- Institute
of Chemistry, Academia Sinica, Taipei 115, Taiwan
- Sustainable
Chemical Science and Technology, Taiwan International Graduate Program, Academia Sinica, Taipei 115, Taiwan
- Department
of Chemistry, National Taiwan University, Taipei 106, Taiwan
| |
Collapse
|
|
6
|
Cao X, Hu Z, Sheng X, Sun Z, Yang L, Shu H, Liu X, Yan G, Zhang L, Liu C, Zhang Y, Wang H, Lu H. Glyco-signatures in patients with advanced lung cancer during anti-PD-1/PD-L1 immunotherapy. Acta Biochim Biophys Sin (Shanghai) 2024; 56:1099-1107. [PMID: 38952341 PMCID: PMC11464919 DOI: 10.3724/abbs.2024110] [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: 01/23/2024] [Accepted: 03/25/2024] [Indexed: 07/03/2024] Open
Abstract
Immune checkpoint inhibitors (ICIs) targeting programmed cell death 1/programmed cell death ligand-1 (PD-1/PD-L1) have significantly prolonged the survival of advanced/metastatic patients with lung cancer. However, only a small proportion of patients can benefit from ICIs, and clinical management of the treatment process remains challenging. Glycosylation has added a new dimension to advance our understanding of tumor immunity and immunotherapy. To systematically characterize anti-PD-1/PD-L1 immunotherapy-related changes in serum glycoproteins, a series of serum samples from 12 patients with metastatic lung squamous cell carcinoma (SCC) and lung adenocarcinoma (ADC), collected before and during ICIs treatment, are firstly analyzed with mass-spectrometry-based label-free quantification method. Second, a stratification analysis is performed among anti-PD-1/PD-L1 responders and non-responders, with serum levels of glycopeptides correlated with treatment response. In addition, in an independent validation cohort, a large-scale site-specific profiling strategy based on chemical labeling is employed to confirm the unusual characteristics of IgG N-glycosylation associated with anti-PD-1/PD-L1 treatment. Unbiased label-free quantitative glycoproteomics reveals serum levels' alterations related to anti-PD-1/PD-L1 treatment in 27 out of 337 quantified glycopeptides. The intact glycopeptide EEQFN 177STYR (H3N4) corresponding to IgG4 is significantly increased during anti-PD-1/PD-L1 treatment (FC=2.65, P=0.0083) and has the highest increase in anti-PD-1/PD-L1 responders (FC=5.84, P=0.0190). Quantitative glycoproteomics based on protein purification and chemical labeling confirms this observation. Furthermore, obvious associations between the two intact glycopeptides (EEQFN 177STYR (H3N4) of IgG4, EEQYN 227STFR (H3N4F1) of IgG3) and response to treatment are observed, which may play a guiding role in cancer immunotherapy. Our findings could benefit future clinical disease management.
Collapse
Affiliation(s)
- Xinyi Cao
- Institutes of Biomedical Sciences and Shanghai Cancer CenterFudan UniversityShanghai200032China
- Department of Laboratory MedicineHuashan HospitalFudan UniversityShanghai200040China
| | - Zhihuang Hu
- Department of Medical OncologyFudan University Shanghai Cancer CenterShanghai200032China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghai200032China
| | | | - Zhenyu Sun
- Institutes of Biomedical Sciences and Shanghai Cancer CenterFudan UniversityShanghai200032China
| | - Lijun Yang
- Department of ChemistryFudan UniversityShanghai200433China
| | - Hong Shu
- Department of Clinical LaboratoryGuangxi Medical University Cancer HospitalNanning530021China
| | - Xiaojing Liu
- Department of ChemistryFudan UniversityShanghai200433China
| | - Guoquan Yan
- Institutes of Biomedical Sciences and Shanghai Cancer CenterFudan UniversityShanghai200032China
| | - Lei Zhang
- Institutes of Biomedical Sciences and Shanghai Cancer CenterFudan UniversityShanghai200032China
| | - Chao Liu
- Beijing Advanced Innovation Center for Precision MedicineBeihang UniversityBeijing100083China
| | - Ying Zhang
- Institutes of Biomedical Sciences and Shanghai Cancer CenterFudan UniversityShanghai200032China
- Department of ChemistryFudan UniversityShanghai200433China
- NHC Key Laboratory of Glycoconjugates ResearchFudan UniversityShanghai200032China
| | - Huijie Wang
- Institutes of Biomedical Sciences and Shanghai Cancer CenterFudan UniversityShanghai200032China
- Department of Medical OncologyFudan University Shanghai Cancer CenterShanghai200032China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghai200032China
| | - Haojie Lu
- Institutes of Biomedical Sciences and Shanghai Cancer CenterFudan UniversityShanghai200032China
- Department of ChemistryFudan UniversityShanghai200433China
- NHC Key Laboratory of Glycoconjugates ResearchFudan UniversityShanghai200032China
| |
Collapse
|
|
7
|
Molnarova K, Krizek T, Kozlik P. The potential of polyaniline-coated stationary phase in hydrophilic interaction liquid chromatography-based solid-phase extraction for glycopeptide enrichment. J Chromatogr B Analyt Technol Biomed Life Sci 2024; 1237:124099. [PMID: 38547700 DOI: 10.1016/j.jchromb.2024.124099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 03/06/2024] [Accepted: 03/17/2024] [Indexed: 04/13/2024]
Abstract
Glycopeptide enrichment is a crucial step in glycoproteomic analysis, often achieved through solid-phase extraction (SPE) on polar stationary phases in hydrophilic interaction liquid chromatography (HILIC). This study explores the potential of polyaniline (PANI)-coated silica gel for enriching human immunoglobulin G (IgG). Experimental conditions were varied to assess their impact on glycopeptide enrichment efficiency, comparing PANI-cotton wool SPE with conventional cotton wool as SPE sorbents. Two formic acid concentrations (0.1% and 1%) in elution solvent were tested, revealing that higher concentrations led to earlier elution of studied glycopeptides, especially for sialylated glycopeptides. Substituting formic acid with acetic acid increased the interaction of neutral glycopeptides with the PANI-modified sorbent, while sialylated glycopeptides showed no significant change in enrichment efficiency. Acetonitrile concentration in the elution solvent (5%, 10%, and 20%) affected the enrichment efficiency with most glycopeptides eluting at the lowest acetonitrile concentration. The acetonitrile concentration in conditioning and washing solutions (65%, 75%, and 85%) played a crucial role; at 65% acetonitrile, glycopeptides were least retained on the stationary phase, and neutral glycopeptides were even detected in the flow-through fraction. This study shows the potential of in-house-prepared PANI-modified sorbents for SPE-HILIC glycopeptide enrichment, highlighting the crucial role of tuning experimental conditions in sample preparation to enhance enrichment efficiency and selectivity.
Collapse
Affiliation(s)
- Katarina Molnarova
- Department of Analytical Chemistry, Faculty of Science, Charles University, Prague, Czech Republic
| | - Tomas Krizek
- Department of Analytical Chemistry, Faculty of Science, Charles University, Prague, Czech Republic
| | - Petr Kozlik
- Department of Analytical Chemistry, Faculty of Science, Charles University, Prague, Czech Republic.
| |
Collapse
|
|
8
|
Lin Y, Lubman DM. The role of N-glycosylation in cancer. Acta Pharm Sin B 2024; 14:1098-1110. [PMID: 38486989 PMCID: PMC10935144 DOI: 10.1016/j.apsb.2023.10.014] [Citation(s) in RCA: 23] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Revised: 09/26/2023] [Accepted: 10/07/2023] [Indexed: 03/17/2024] Open
Abstract
Despite advances in understanding the development and progression of cancer in recent years, there remains a lack of comprehensive characterization of the cancer glycoproteome. Glycoproteins play an important role in medicine and are involved in various human disease conditions including cancer. Glycan-moieties participate in fundamental cancer processes like cell signaling, invasion, angiogenesis, and metastasis. Aberrant N-glycosylation significantly impacts cancer processes and targeted therapies in clinic. Therefore, understanding N-glycosylation in a tumor is essential for comprehending disease progression and discovering anti-cancer targets and biomarkers for therapy monitoring and diagnosis. This review presents the fundamental process of protein N-glycosylation and summarizes glycosylation changes in tumor cells, including increased terminal sialylation, N-glycan branching, and core-fucosylation. Also, the role of N-glycosylation in tumor signaling pathways, migration, and metabolism are discussed. Glycoproteins and glycopeptides as potential biomarkers for early detection of cancer based on site specificity have been introduced. Collectively, understanding and exploring the cancer glycoproteome, along with its role in medicine, implication in cancer and other human diseases, highlights the significance of N-glycosylation in tumor processes, necessitating further research for potential anti-cancer targets and biomarkers.
Collapse
Affiliation(s)
- Yu Lin
- Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
| | - David M. Lubman
- Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
| |
Collapse
|
|
9
|
Liu L, Liu L, Wang Y, Fang Z, Bian Y, Zhang W, Wang Z, Gao X, Zhao C, Tian M, Liu X, Qin H, Guo Z, Liang X, Dong M, Nie Y, Ye M. Robust Glycoproteomics Platform Reveals a Tetra-Antennary Site-Specific Glycan Capping with Sialyl-Lewis Antigen for Early Detection of Gastric Cancer. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2306955. [PMID: 38084450 PMCID: PMC10916543 DOI: 10.1002/advs.202306955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Revised: 11/16/2023] [Indexed: 03/07/2024]
Abstract
The lack of efficient biomarkers for the early detection of gastric cancer (GC) contributes to its high mortality rate, so it is crucial to discover novel diagnostic targets for GC. Recent studies have implicated the potential of site-specific glycans in cancer diagnosis, yet it is challenging to perform highly reproducible and sensitive glycoproteomics analysis on large cohorts of samples. Here, a highly robust N-glycoproteomics (HRN) platform comprising an automated enrichment method, a stable microflow LC-MS/MS system, and a sensitive glycopeptide-spectra-deciphering tool is developed for large-scale quantitative N-glycoproteome analysis. The HRN platform is applied to analyze serum N-glycoproteomes of 278 subjects from three cohorts to investigate glycosylation changes of GC. It identifies over 20 000 unique site-specific glycans from discovery and validation cohorts, and determines four site-specific glycans as biomarker candidates. One candidate has branched tetra-antennary structure capping with sialyl-Lewis antigen, and it significantly outperforms serum CEA with AUC values > 0.89 compared against < 0.67 for diagnosing early-stage GC. The four-marker panel can provide improved diagnostic performances. Besides, discrimination powers of four candidates are also testified with a verification cohort using PRM strategy. This findings highlight the value of this strong tool in analyzing aberrant site-specific glycans for cancer detection.
Collapse
Affiliation(s)
- Luyao Liu
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical PhysicsChinese Academy of SciencesDalian116023China
- University of Chinese Academy of SciencesBeijing101408China
| | - Lei Liu
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical PhysicsChinese Academy of SciencesDalian116023China
- University of Chinese Academy of SciencesBeijing101408China
| | - Yan Wang
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical PhysicsChinese Academy of SciencesDalian116023China
| | - Zheng Fang
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical PhysicsChinese Academy of SciencesDalian116023China
| | - Yangyang Bian
- The College of Life SciencesNorthwest UniversityXi'an710127China
| | - Wenyao Zhang
- State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive DiseasesFourth Military Medical UniversityXi'an710068China
| | - Zhongyu Wang
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical PhysicsChinese Academy of SciencesDalian116023China
| | - Xianchun Gao
- State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive DiseasesFourth Military Medical UniversityXi'an710068China
| | - Changrui Zhao
- MOE Key Laboratory of Bio‐Intelligent Manufacturing, School of BioengineeringDalian University of TechnologyDalian116024China
| | - Miaomiao Tian
- State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive DiseasesFourth Military Medical UniversityXi'an710068China
| | - Xiaoyan Liu
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical PhysicsChinese Academy of SciencesDalian116023China
| | - Hongqiang Qin
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical PhysicsChinese Academy of SciencesDalian116023China
| | - Zhimou Guo
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical PhysicsChinese Academy of SciencesDalian116023China
| | - Xinmiao Liang
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical PhysicsChinese Academy of SciencesDalian116023China
| | - Mingming Dong
- MOE Key Laboratory of Bio‐Intelligent Manufacturing, School of BioengineeringDalian University of TechnologyDalian116024China
| | - Yongzhan Nie
- State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive DiseasesFourth Military Medical UniversityXi'an710068China
| | - Mingliang Ye
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical PhysicsChinese Academy of SciencesDalian116023China
- University of Chinese Academy of SciencesBeijing101408China
- State Key Laboratory of Medical ProteomicsBeijing102206China
| |
Collapse
|
|
10
|
Zhu Y. Plasma/Serum Proteomics based on Mass Spectrometry. Protein Pept Lett 2024; 31:192-208. [PMID: 38869039 PMCID: PMC11165715 DOI: 10.2174/0109298665286952240212053723] [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: 11/22/2023] [Revised: 01/22/2024] [Accepted: 01/31/2024] [Indexed: 06/14/2024]
Abstract
Human blood is a window of physiology and disease. Examination of biomarkers in blood is a common clinical procedure, which can be informative in diagnosis and prognosis of diseases, and in evaluating treatment effectiveness. There is still a huge demand on new blood biomarkers and assays for precision medicine nowadays, therefore plasma/serum proteomics has attracted increasing attention in recent years. How to effectively proceed with the biomarker discovery and clinical diagnostic assay development is a question raised to researchers who are interested in this area. In this review, we comprehensively introduce the background and advancement of technologies for blood proteomics, with a focus on mass spectrometry (MS). Analyzing existing blood biomarkers and newly-built diagnostic assays based on MS can shed light on developing new biomarkers and analytical methods. We summarize various protein analytes in plasma/serum which include total proteome, protein post-translational modifications, and extracellular vesicles, focusing on their corresponding sample preparation methods for MS analysis. We propose screening multiple protein analytes in the same set of blood samples in order to increase success rate for biomarker discovery. We also review the trends of MS techniques for blood tests including sample preparation automation, and further provide our perspectives on their future directions.
Collapse
Affiliation(s)
- Yiying Zhu
- Department of Chemistry, Tsinghua University, Beijing, China
| |
Collapse
|
|
11
|
Wang J, Wang F, Wang N, Zhang MY, Wang HY, Huang GL. Diagnostic and Prognostic Value of Protein Post-translational Modifications in Hepatocellular Carcinoma. J Clin Transl Hepatol 2023; 11:1192-1200. [PMID: 37577238 PMCID: PMC10412711 DOI: 10.14218/jcth.2022.00006s] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 02/03/2023] [Accepted: 02/21/2023] [Indexed: 07/03/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a common malignant tumor with high incidence and cancer mortality worldwide. Post-translational modifications (PTMs) of proteins have a great impact on protein function. Almost all proteins can undergo PTMs, including phosphorylation, acetylation, methylation, glycosylation, ubiquitination, and so on. Many studies have shown that PTMs are related to the occurrence and development of cancers. The findings provide novel therapeutic targets for cancers, such as glypican-3 and mucin-1. Other clinical implications are also found in the studies of PTMs. Diagnostic or prognostic value, and response to therapy have been identified. In HCC, it has been shown that glycosylated alpha-fetoprotein (AFP) has a higher detection rate for early liver cancer than conventional AFP. In this review, we mainly focused on the diagnostic and prognostic value of PTM, in order to provide new insights into the clinical implication of PTM in HCC.
Collapse
Affiliation(s)
- Jing Wang
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong, China
- China-America Cancer Research Institute, Key Laboratory for Epigenetics of Dongguan City, Guangdong Medical University, Dongguan, Guangdong, China
| | - Fangfang Wang
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong, China
- China-America Cancer Research Institute, Key Laboratory for Epigenetics of Dongguan City, Guangdong Medical University, Dongguan, Guangdong, China
| | - Ning Wang
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong, China
- China-America Cancer Research Institute, Key Laboratory for Epigenetics of Dongguan City, Guangdong Medical University, Dongguan, Guangdong, China
| | - Mei-Yin Zhang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China
| | - Hui-Yun Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China
| | - Guo-Liang Huang
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong, China
- China-America Cancer Research Institute, Key Laboratory for Epigenetics of Dongguan City, Guangdong Medical University, Dongguan, Guangdong, China
| |
Collapse
|
|
12
|
Kohansal-Nodehi M, Swiatek-de Lange M, Kroeniger K, Rolny V, Tabarés G, Piratvisuth T, Tanwandee T, Thongsawat S, Sukeepaisarnjaroen W, Esteban JI, Bes M, Köhler B, Chan HLY, Busskamp H. Discovery of a haptoglobin glycopeptides biomarker panel for early diagnosis of hepatocellular carcinoma. Front Oncol 2023; 13:1213898. [PMID: 37920152 PMCID: PMC10619681 DOI: 10.3389/fonc.2023.1213898] [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: 04/28/2023] [Accepted: 09/20/2023] [Indexed: 11/04/2023] Open
Abstract
Background There is a need for new serum biomarkers for early detection of hepatocellular carcinoma (HCC). Haptoglobin (Hp) N-glycosylation is altered in HCC, but the diagnostic value of site-specific Hp glycobiomarkers is rarely reported. We aimed to determine the site-specific glycosylation profile of Hp for early-stage HCC diagnosis. Method Hp glycosylation was analyzed in the plasma of patients with liver diseases (n=57; controls), early-stage HCC (n=50) and late-stage HCC (n=32). Hp phenotype was determined by immunoblotting. Hp was immunoisolated and digested into peptides. N-glycopeptides were identified and quantified using liquid chromatography-mass spectrometry. Cohort samples were compared using Wilcoxon rank-sum (Mann-Whitney U) tests. Diagnostic performance was assessed using receiver operating characteristic (ROC) curves and area under curve (AUC). Results Significantly higher fucosylation, branching and sialylation of Hp glycans, and expression of high-mannose glycans, was observed as disease progressed from cirrhosis to early- and late-stage HCC. Several glycopeptides demonstrated high values for early diagnosis of HCC, with an AUC of 93% (n=1), >80% (n=3), >75% (n=13) and >70% (n=11), compared with alpha-fetoprotein (AFP; AUC of 79%). The diagnostic performance of the identified biomarkers was only slightly affected by Hp phenotype. Conclusion We identified a panel of Hp glycopeptides that are significantly differentially regulated in early- and late-stage HCC. Some glycobiomarkers exceeded the diagnostic value of AFP (the most commonly used biomarker for HCC diagnosis). Our findings provide evidence that glycobiomarkers can be effective in the diagnosis of early HCC - individually, as a panel of glycopeptides or combined with conventional serological biomarkers.
Collapse
Affiliation(s)
| | | | | | - Vinzent Rolny
- Roche Diagnostics GmbH, Research and Development Core Lab, Penzberg, Germany
| | - Glòria Tabarés
- Roche Diagnostics GmbH, Research and Development Core Lab, Penzberg, Germany
| | - Teerha Piratvisuth
- NKC Institute of Gastroenterology and Hepatology, Songklanagarind Hospital, Prince of Songkla University, Hat Yai, Thailand
| | - Tawesak Tanwandee
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Satawat Thongsawat
- Department of Internal Medicine, Maharaj Nakorn Chiang Mai Hospital, Chiang Mai University, Chiang Mai, Thailand
| | | | | | - Marta Bes
- Transfusion Safety Laboratory, Banc de Sang i Teixits (BST), Barcelona, Spain
| | - Bruno Köhler
- Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany
- Liver Cancer Center Heidelberg, Heidelberg, Germany
| | - Henry Lik-Yuen Chan
- Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Holger Busskamp
- Roche Diagnostics GmbH, Research and Development Core Lab, Penzberg, Germany
| |
Collapse
|
|
13
|
Ugonabo O, Udoh UAS, Rajan PK, Reeves H, Arcand C, Nakafuku Y, Joshi T, Finley R, Pierre SV, Sanabria JR. The Current Status of the Liver Liquid Biopsy in MASH Related HCC: Overview and Future Directions. Biomolecules 2023; 13:1369. [PMID: 37759769 PMCID: PMC10526956 DOI: 10.3390/biom13091369] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 09/03/2023] [Accepted: 09/07/2023] [Indexed: 09/29/2023] Open
Abstract
Metabolic dysfunction-associated steatohepatitis (MASH) is one of the major risk factors for chronic liver disease and hepatocellular carcinoma (HCC). The incidence of MASH in Western countries continues to rise, driving HCC as the third cause of cancer-related death worldwide. HCC has become a major global health challenge, partly from the obesity epidemic promoting metabolic cellular disturbances but also from the paucity of biomarkers for its early detection. Over 50% of HCC cases are clinically present at a late stage, where curative measures are no longer beneficial. Currently, there is a paucity of both specific and sensitive biological markers for the early-stage detection of HCC. The search for biological markers in the diagnosis of early HCC in high-risk populations is intense. We described the potential role of surrogates for a liver biopsy in the screening and monitoring of patients at risk for nesting HCC.
Collapse
Affiliation(s)
- Onyinye Ugonabo
- Department of Medicine, Marshall University School of Medicine, Marshall University, Huntington, WV 25701, USA; (O.U.); (T.J.)
| | - Utibe-Abasi Sunday Udoh
- Marshall Institute for Interdisciplinary Research, Marshall University School of Medicine, Huntington, WV 25703, USA; (U.-A.S.U.); (P.K.R.); (Y.N.); (S.V.P.)
- Department of Surgery, Marshall University School of Medicine, Marshall University, Huntington, WV 25701, USA; (H.R.); (C.A.); (R.F.)
| | - Pradeep Kumar Rajan
- Marshall Institute for Interdisciplinary Research, Marshall University School of Medicine, Huntington, WV 25703, USA; (U.-A.S.U.); (P.K.R.); (Y.N.); (S.V.P.)
- Department of Surgery, Marshall University School of Medicine, Marshall University, Huntington, WV 25701, USA; (H.R.); (C.A.); (R.F.)
| | - Heather Reeves
- Department of Surgery, Marshall University School of Medicine, Marshall University, Huntington, WV 25701, USA; (H.R.); (C.A.); (R.F.)
| | - Christina Arcand
- Department of Surgery, Marshall University School of Medicine, Marshall University, Huntington, WV 25701, USA; (H.R.); (C.A.); (R.F.)
| | - Yuto Nakafuku
- Marshall Institute for Interdisciplinary Research, Marshall University School of Medicine, Huntington, WV 25703, USA; (U.-A.S.U.); (P.K.R.); (Y.N.); (S.V.P.)
- Department of Surgery, Marshall University School of Medicine, Marshall University, Huntington, WV 25701, USA; (H.R.); (C.A.); (R.F.)
| | - Tejas Joshi
- Department of Medicine, Marshall University School of Medicine, Marshall University, Huntington, WV 25701, USA; (O.U.); (T.J.)
| | - Rob Finley
- Department of Surgery, Marshall University School of Medicine, Marshall University, Huntington, WV 25701, USA; (H.R.); (C.A.); (R.F.)
| | - Sandrine V. Pierre
- Marshall Institute for Interdisciplinary Research, Marshall University School of Medicine, Huntington, WV 25703, USA; (U.-A.S.U.); (P.K.R.); (Y.N.); (S.V.P.)
| | - Juan Ramon Sanabria
- Marshall Institute for Interdisciplinary Research, Marshall University School of Medicine, Huntington, WV 25703, USA; (U.-A.S.U.); (P.K.R.); (Y.N.); (S.V.P.)
- Department of Surgery, Marshall University School of Medicine, Marshall University, Huntington, WV 25701, USA; (H.R.); (C.A.); (R.F.)
- Department of Nutrition and Metabolomic Core Facility, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
| |
Collapse
|
|
14
|
Li H, Liu H, Yan LJ, Ding ZN, Zhang X, Pan GQ, Han CL, Tian BW, Tan SY, Dong ZR, Wang DX, Yan YC, Li T. Performance of GALAD score and serum biomarkers for detecting NAFLD-related HCC: a systematic review and network meta-analysis. Expert Rev Gastroenterol Hepatol 2023; 17:1159-1167. [PMID: 37929312 DOI: 10.1080/17474124.2023.2279175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Accepted: 10/31/2023] [Indexed: 11/07/2023]
Abstract
INTRODUCTION The incidence of nonalcoholic fatty liver disease (NAFLD)-related hepatocellular carcinoma (HCC) is increasing globally. We aimed to assess the performance of alpha-fetoprotein (AFP), AFP-L3, des-gamma-carboxy prothrombin (DCP), and GALAD score in detecting NAFLD-related HCC. METHODS We searched the relevant literature in PubMed, Embase and Cochrane. Conventional and network meta-analyses were performed for sensitivity, specificity, Youden index (YI), and the area under the summary receiver operator characteristic curve (AUC). RESULTS Fifteen studies involving 2031 NAFLD participants were included in this meta-analysis. When detecting early-stage NAFLD-related HCC, GALAD score and DCP process excellent performance. The sensitivity and AUC of DCP (0.60, 0.74, respectively) were higher than AFP (0.34, 0.59, respectively). The network meta-analysis showed that DCP and GALAD score had similar performance. In detecting all-stage NAFLD-related HCC, GALAD score (sensitivity = 0.87; YI = 0.77) performed better than AFP (sensitivity = 0.56; YI = 0.50), AFP-L3 (sensitivity = 0.39; YI = 0.36) and DCP (sensitivity = 0.73; YI = 0.62). Network meta-analysis obtained consistent results with conventional meta-analysis. CONCLUSIONS Due to the lower cost-effectiveness, DCP was more suitable for detecting early NAFLD-related HCC. AFP could be used in detecting all-stage NAFLD-related HCC.
Collapse
Affiliation(s)
- Han Li
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Hui Liu
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Lun-Jie Yan
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Zi-Niu Ding
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Xiao Zhang
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Guo-Qiang Pan
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Cheng-Long Han
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Bao-Wen Tian
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Si-Yu Tan
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Zhao-Ru Dong
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Dong-Xu Wang
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Yu-Chuan Yan
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Tao Li
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| |
Collapse
|
|
15
|
McMahon B, Cohen C, Brown Jr RS, El-Serag H, Ioannou GN, Lok AS, Roberts LR, Singal AG, Block T. Opportunities to address gaps in early detection and improve outcomes of liver cancer. JNCI Cancer Spectr 2023; 7:pkad034. [PMID: 37144952 PMCID: PMC10212536 DOI: 10.1093/jncics/pkad034] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Accepted: 04/10/2023] [Indexed: 05/06/2023] Open
Abstract
Death rates from primary liver cancer (hepatocellular carcinoma [HCC]) have continued to rise in the United States over the recent decades despite the availability of an increasing range of treatment modalities, including new systemic therapies. Prognosis is strongly associated with tumor stage at diagnosis; however, most cases of HCC are diagnosed beyond an early stage. This lack of early detection has contributed to low survival rates. Professional society guidelines recommend semiannual ultrasound-based HCC screening for at-risk populations, yet HCC surveillance continues to be underused in clinical practice. On April 28, 2022, the Hepatitis B Foundation convened a workshop to discuss the most pressing challenges and barriers to early HCC detection and the need to better leverage existing and emerging tools and technologies that could improve HCC screening and early detection. In this commentary, we summarize technical, patient-level, provider-level, and system-level challenges and opportunities to improve processes and outcomes across the HCC screening continuum. We highlight promising approaches to HCC risk stratification and screening, including new biomarkers, advanced imaging incorporating artificial intelligence, and algorithms for risk stratification. Workshop participants emphasized that action to improve early detection and reduce HCC mortality is urgently needed, noting concern that many of the challenges we face today are the same or similar to those faced a decade ago and that HCC mortality rates have not meaningfully improved. Increasing the uptake of HCC screening was identified as a short-term priority while developing and validating better screening tests and risk-appropriate surveillance strategies.
Collapse
Affiliation(s)
- Brian McMahon
- Liver Disease and Hepatitis Program, Alaska Native Tribal Health Consortium, Anchorage, AK, USA
| | | | - Robert S Brown Jr
- Department of Medicine, Division of Gastroenterology and Hepatology, Weill Cornell Medicine, New York, NY, USA
| | - Hashem El-Serag
- Department of Medicine, Baylor College of Medicine, Houston, TX, USA
| | - George N Ioannou
- Department of Medicine, Division of Gastroenterology, VA Puget Sound Health Care System, Seattle, WA, USA
| | - Anna S Lok
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Lewis R Roberts
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Amit G Singal
- Department of Internal Medicine, Division of Digestive and Liver Diseases, UT Southwestern, Dallas, TX, USA
| | - Timothy Block
- Baruch S. Blumberg Institute and Hepatitis B Foundation, Doylestown, PA, USA
| |
Collapse
|
|
16
|
Tan Y, Zhu J, Gutierrez Reyes CD, Lin Y, Tan Z, Wu Z, Zhang J, Cano A, Verschleisser S, Mechref Y, Singal AG, Parikh ND, Lubman DM. Discovery of Core-Fucosylated Glycopeptides as Diagnostic Biomarkers for Early HCC in Patients with NASH Cirrhosis Using LC-HCD-PRM-MS/MS. ACS OMEGA 2023; 8:12467-12480. [PMID: 37033807 PMCID: PMC10077536 DOI: 10.1021/acsomega.3c00519] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Accepted: 03/09/2023] [Indexed: 06/19/2023]
Abstract
Aberrant changes in site-specific core fucosylation (CF) of serum proteins contribute to cancer development and progression, which enables them as potential diagnostic markers of tumors. An optimized data-dependent acquisition (DDA) workflow involving isobaric tags for relative and absolute quantitation-labeling and enrichment of CF peptides by lens culinaris lectin was applied to identify CF of serum proteins in a test set of patients with nonalcoholic steatohepatitis (NASH)-related cirrhosis (N = 16) and hepatocellular carcinoma (HCC, N = 17), respectively. A total of 624 CF peptides from 343 proteins, with 683 CF sites, were identified in our DDA-mass spectrometry (MS) analysis. Subsequently, 19 candidate CF peptide markers were evaluated by a target parallel reaction-monitoring-MS workflow in a validation set of 58 patients, including NASH-related cirrhosis (N = 29), early-stage HCC (N = 21), and late-stage HCC (N = 8). Significant changes (p < 0.01) were observed in four CF peptides between cirrhosis and HCC, where peptide LGSFEGLVn160LTFIHLQHNR from LUM in combination with AFP showed the best diagnostic performance in discriminating HCC from cirrhosis, with an area under curve (AUC) of 0.855 compared to AFP only (AUC = 0.717). This peptide in combination with AFP also significantly improved diagnostic performance in distinguishing early HCC from cirrhosis, with an AUC of 0.839 compared to AFP only (AUC = 0.689). Validation of this novel promising biomarker panel in larger cohorts should be performed.
Collapse
Affiliation(s)
- Yifei Tan
- Department
of Liver Surgery, Liver Transplantation Center, West China Hospital of Sichuan University, Chengdu 610017, China
- Department
of Surgery, University of Michigan Medical
Center, Ann Arbor, Michigan 48109, United
States
| | - Jianhui Zhu
- Department
of Surgery, University of Michigan Medical
Center, Ann Arbor, Michigan 48109, United
States
| | | | - Yu Lin
- Department
of Surgery, University of Michigan Medical
Center, Ann Arbor, Michigan 48109, United
States
| | - Zhijing Tan
- Department
of Surgery, University of Michigan Medical
Center, Ann Arbor, Michigan 48109, United
States
| | - Zuowei Wu
- Department
of Surgery, University of Michigan Medical
Center, Ann Arbor, Michigan 48109, United
States
| | - Jie Zhang
- Department
of Surgery, University of Michigan Medical
Center, Ann Arbor, Michigan 48109, United
States
| | - Alva Cano
- Department
of Internal Medicine, University of Texas
Southwestern Medical Center, Dallas, Texas 75390, United States
| | - Sara Verschleisser
- Department
of Internal Medicine, University of Texas
Southwestern Medical Center, Dallas, Texas 75390, United States
| | - Yehia Mechref
- Department
of Chemistry and Biochemistry, Texas Tech
University, Lubbock, Texas 79409, United States
| | - Amit G. Singal
- Department
of Internal Medicine, University of Texas
Southwestern Medical Center, Dallas, Texas 75390, United States
| | - Neehar D. Parikh
- Department
of Internal Medicine, University of Michigan
Medical Center, Ann Arbor, Michigan 48109, United States
| | - David M. Lubman
- Department
of Surgery, University of Michigan Medical
Center, Ann Arbor, Michigan 48109, United
States
| |
Collapse
|
|
17
|
In-Depth Analysis of the N-Glycome of Colorectal Cancer Cell Lines. Int J Mol Sci 2023; 24:ijms24054842. [PMID: 36902272 PMCID: PMC10003090 DOI: 10.3390/ijms24054842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 02/21/2023] [Accepted: 02/27/2023] [Indexed: 03/06/2023] Open
Abstract
Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the second leading cause of cancer deaths worldwide. A well-known hallmark of cancer is altered glycosylation. Analyzing the N-glycosylation of CRC cell lines may provide potential therapeutic or diagnostic targets. In this study, an in-depth N-glycomic analysis of 25 CRC cell lines was conducted using porous graphitized carbon nano-liquid chromatography coupled to electrospray ionization mass spectrometry. This method allows for the separation of isomers and performs structural characterization, revealing profound N-glycomic diversity among the studied CRC cell lines with the elucidation of a number of 139 N-glycans. A high degree of similarity between the two N-glycan datasets measured on the two different platforms (porous graphitized carbon nano-liquid chromatography electrospray ionization tandem mass spectrometry (PGC-nano-LC-ESI-MS) and matrix-assisted laser desorption/ionization time of flight-mass spectrometry (MALDI-TOF-MS)) was discovered. Furthermore, we studied the associations between glycosylation features, glycosyltransferases (GTs), and transcription factors (TFs). While no significant correlations between the glycosylation features and GTs were found, the association between TF CDX1 and (s)Le antigen expression and relevant GTs FUT3/6 suggests that CDX1 contributes to the expression of the (s)Le antigen through the regulation of FUT3/6. Our study provides a comprehensive characterization of the N-glycome of CRC cell lines, which may contribute to the future discovery of novel glyco-biomarkers of CRC.
Collapse
|
|
18
|
Lubman DM. David M. Lubman-The University of Michigan-A retrospective in research. MASS SPECTROMETRY REVIEWS 2023; 42:643-651. [PMID: 34289523 PMCID: PMC8903096 DOI: 10.1002/mas.21718] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 07/01/2021] [Accepted: 07/02/2021] [Indexed: 06/13/2023]
|
|
19
|
Oh MJ, Lee SH, Kim U, An HJ. In-depth investigation of altered glycosylation in human haptoglobin associated cancer by mass spectrometry. MASS SPECTROMETRY REVIEWS 2023; 42:496-518. [PMID: 34037272 DOI: 10.1002/mas.21707] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 04/28/2021] [Accepted: 05/12/2021] [Indexed: 05/08/2023]
Abstract
Serum haptoglobin (Hp), a highly sialylated biomolecule with four N-glycosylation sites, is a positive acute-phase response glycoprotein that acts as an immunomodulator. Hp has gained considerable attention due to its potential as a signature molecule that exhibits aberrant glycosylation in inflammatory disorders and malignancies. Its glycosylation can be analyzed qualitatively and quantitatively by various methods using mass spectrometry. In this review, we have provided a brief overview of Hp structure and biological function and described mass spectrometry-based techniques for analyzing glycosylation ranging from macroheterogeneity to microheterogeneity of Hp in diseases and cancer. The sugars on haptoglobin can be a sweet bridge to link the potential of cancer-specific biomarkers to clinically relevant applications.
Collapse
Affiliation(s)
- Myung Jin Oh
- Asia-Pacific Glycomics Reference Site, Daejeon, South Korea
- Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon, South Korea
| | - Sung Hyeon Lee
- Department of Biomedical Research Center, Korea University Guro Hospital, Seoul, South Korea
| | - Unyoung Kim
- Division of Bioanalysis, Biocomplete Inc., Seoul, South Korea
| | - Hyun Joo An
- Asia-Pacific Glycomics Reference Site, Daejeon, South Korea
- Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon, South Korea
| |
Collapse
|
|
20
|
Sun F, Suttapitugsakul S, Wu R. Systematic characterization of extracellular glycoproteins using mass spectrometry. MASS SPECTROMETRY REVIEWS 2023; 42:519-545. [PMID: 34047389 PMCID: PMC8627532 DOI: 10.1002/mas.21708] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Revised: 05/10/2021] [Accepted: 05/13/2021] [Indexed: 05/13/2023]
Abstract
Surface and secreted glycoproteins are essential to cells and regulate many extracellular events. Because of the diversity of glycans, the low abundance of many glycoproteins, and the complexity of biological samples, a system-wide investigation of extracellular glycoproteins is a daunting task. With the development of modern mass spectrometry (MS)-based proteomics, comprehensive analysis of different protein modifications including glycosylation has advanced dramatically. This review focuses on the investigation of extracellular glycoproteins using MS-based proteomics. We first discuss the methods for selectively enriching surface glycoproteins and investigating protein interactions on the cell surface, followed by the application of MS-based proteomics for surface glycoprotein dynamics analysis and biomarker discovery. We then summarize the methods to comprehensively study secreted glycoproteins by integrating various enrichment approaches with MS-based proteomics and their applications for global analysis of secreted glycoproteins in different biological samples. Collectively, MS significantly expands our knowledge of extracellular glycoproteins and enables us to identify extracellular glycoproteins as potential biomarkers for disease detection and drug targets for disease treatment.
Collapse
Affiliation(s)
| | | | - Ronghu Wu
- School of Chemistry and Biochemistry and the Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia 30332, USA
| |
Collapse
|
|
21
|
Yin H, Zhu J. Methods for quantification of glycopeptides by liquid separation and mass spectrometry. MASS SPECTROMETRY REVIEWS 2023; 42:887-917. [PMID: 35099083 PMCID: PMC9339036 DOI: 10.1002/mas.21771] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 11/14/2021] [Accepted: 01/13/2022] [Indexed: 05/05/2023]
Abstract
Recent advances in analytical techniques provide the opportunity to quantify even low-abundance glycopeptides derived from complex biological mixtures, allowing for the identification of glycosylation differences between healthy samples and those derived from disease states. Herein, we discuss the sample preparation procedures and the mass spectrometry (MS) strategies that have facilitated glycopeptide quantification, as well as the standards used for glycopeptide quantification. For sample preparation, various glycopeptide enrichment methods are summarized including the columns used for glycopeptide separation in liquid chromatography separation. For MS analysis strategies, MS1 level-based quantification and MS2 level-based quantification are described, either with or without labeling, where we have covered isotope labeling, TMT/iTRAQ labeling, data dependent acquisition, data independent acquisition, multiple reaction monitoring, and parallel reaction monitoring. The strengths and weaknesses of these methods are compared, particularly those associated with the figures of merit that are important for clinical biomarker studies and the pathological and functional studies of glycoproteins in various diseases. Possible future developments for glycopeptide quantification are discussed.
Collapse
Affiliation(s)
- Haidi Yin
- Shenzhen Bay Laboratory, Shenzhen, Guangdong, 518132, China
- Correspondence to: Haidi Yin, Shenzhen Bay Laboratory, A1201, Shenzhen, Guangdong, 518132, China. Phone: 0755-26849276. , Jianhui Zhu, Department of Surgery, University of Michigan, 1150 West Medical Center Drive, Building MSRB1, Rm A500, Ann Arbor, MI 48109-0656, USA. Tel: 734-615-2567. Fax: 734-615-2088.
| | - Jianhui Zhu
- Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA
- Correspondence to: Haidi Yin, Shenzhen Bay Laboratory, A1201, Shenzhen, Guangdong, 518132, China. Phone: 0755-26849276. , Jianhui Zhu, Department of Surgery, University of Michigan, 1150 West Medical Center Drive, Building MSRB1, Rm A500, Ann Arbor, MI 48109-0656, USA. Tel: 734-615-2567. Fax: 734-615-2088.
| |
Collapse
|
|
22
|
Li S, Zhu J, Lubman DM, Zhou H, Tang H. GlycoSLASH: Concurrent Glycopeptide Identification from Multiple Related LC-MS/MS Data Sets by Using Spectral Clustering and Library Searching. J Proteome Res 2023; 22:1501-1509. [PMID: 36802412 PMCID: PMC10164058 DOI: 10.1021/acs.jproteome.3c00066] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/23/2023]
Abstract
Liquid chromatography coupled with tandem mass spectrometry is commonly adopted in large-scale glycoproteomic studies involving hundreds of disease and control samples. The software for glycopeptide identification in such data (e.g., the commercial software Byonic) analyzes the individual data set and does not exploit the redundant spectra of glycopeptides presented in the related data sets. Herein, we present a novel concurrent approach for glycopeptide identification in multiple related glycoproteomic data sets by using spectral clustering and spectral library searching. The evaluation on two large-scale glycoproteomic data sets showed that the concurrent approach can identify 105%-224% more spectra as glycopeptides compared to the glycopeptide identification on individual data sets using Byonic alone. The improvement of glycopeptide identification also enabled the discovery of several potential biomarkers of protein glycosylations in hepatocellular carcinoma patients.
Collapse
Affiliation(s)
- Sujun Li
- Department of Blood Transfusion, The First Affiliated Hospital of Nanchang University, Nanchang 330000, China.,JiangXi Key Laboratory of Transfusion Medicine, Nanchang 330000, China.,Luddy School of Informatics, Computing and Engineering, Indiana University, Bloomington, Indiana 47408, United States
| | - Jianhui Zhu
- Department of Surgery, University of Michigan, Medical Center, Ann Arbor, Michigan 48109, United States
| | - David M Lubman
- Department of Surgery, University of Michigan, Medical Center, Ann Arbor, Michigan 48109, United States
| | - He Zhou
- Shenzhen Dengding Biopharma Co. Ltd., Shenzhen 518000, China
| | - Haixu Tang
- Luddy School of Informatics, Computing and Engineering, Indiana University, Bloomington, Indiana 47408, United States
| |
Collapse
|
|
23
|
Mechref Y, Peng W, Gautam S, Ahmadi P, Lin Y, Zhu J, Zhang J, Liu S, Singal AG, Parikh ND, Lubman DM. Mass spectrometry based biomarkers for early detection of HCC using a glycoproteomic approach. Adv Cancer Res 2022; 157:23-56. [PMID: 36725111 PMCID: PMC10014290 DOI: 10.1016/bs.acr.2022.07.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related mortality worldwide and 80%-90% of HCC develops in patients that have underlying cirrhosis. Better methods of surveillance are needed to increase early detection of HCC and the proportion of patients that can be offered curative therapies. Recent work in novel mass spec-based methods for glycomic and glycopeptide analysis for discovery and confirmation of markers for early detection of HCC versus cirrhosis is reviewed in this chapter. Results from recent work in these fields by several groups and the progress made in developing markers of early HCC which can outperform the current serum-based markers are described and discussed. Also, recent developments in isoform analysis of glycans and glycopeptides and in various mass spec fragmentation methods will be described and discussed.
Collapse
Affiliation(s)
- Yehia Mechref
- Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX, United States.
| | - Wenjing Peng
- Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX, United States
| | - Sakshi Gautam
- Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX, United States
| | - Parisa Ahmadi
- Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX, United States
| | - Yu Lin
- Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI, United States
| | - Jianhui Zhu
- Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI, United States
| | - Jie Zhang
- Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI, United States
| | - Suyu Liu
- Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Amit G Singal
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Neehar D Parikh
- Division of Gastroenterology and Hepatology, University of Michigan Medical Center, Ann Arbor, MI, United States
| | - David M Lubman
- Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI, United States.
| |
Collapse
|
|
24
|
Ueno M, Takeda H, Takai A, Seno H. Risk factors and diagnostic biomarkers for nonalcoholic fatty liver disease-associated hepatocellular carcinoma: Current evidence and future perspectives. World J Gastroenterol 2022; 28:3410-3421. [PMID: 36158261 PMCID: PMC9346451 DOI: 10.3748/wjg.v28.i27.3410] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 04/24/2022] [Accepted: 06/16/2022] [Indexed: 02/06/2023] Open
Abstract
High rates of excessive calorie intake diets and sedentary lifestyles have led to a global increase in nonalcoholic fatty liver disease (NAFLD). As a result, this condition has recently become one of the leading causes of hepatocellular carcinoma (HCC). Furthermore, the incidence of NAFLD-associated HCC (NAFLD-HCC) is expected to increase in the near future. Advanced liver fibrosis is the most common risk factor for NAFLD-HCC. However, up to 50% of NAFLD-HCC cases develop without underlying liver cirrhosis. Epidemiological studies have revealed many other risk factors for this condition; including diabetes, other metabolic traits, obesity, old age, male sex, Hispanic ethnicity, mild alcohol intake, and elevated liver enzymes. Specific gene variants, such as single-nucleotide polymorphisms of patatin-like phospholipase domain 3, transmembrane 6 superfamily member 2, and membrane-bound O-acyl-transferase domain-containing 7, are also associated with an increased risk of HCC in patients with NAFLD. This clinical and genetic information should be interpreted together for accurate risk prediction. Alpha-fetoprotein (AFP) is the only biomarker currently recommended for HCC screening. However, it is not sufficiently sensitive in addressing this diagnostic challenge. The GALAD score can be calculated based on sex, age, lectin-bound AFP, AFP, and des-carboxyprothrombin and is reported to show better diagnostic performance for HCC. In addition, emerging studies on genetic and epigenetic biomarkers have also yielded promising diagnostic potential. However, further research is needed to establish an effective surveillance program for the early diagnosis of NAFLD-HCC.
Collapse
Affiliation(s)
- Masayuki Ueno
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto 6068507, Japan
| | - Haruhiko Takeda
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto 6068507, Japan
| | - Atsushi Takai
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto 6068507, Japan
| | - Hiroshi Seno
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto 6068507, Japan
| |
Collapse
|
|
25
|
Advance of Serum Biomarkers and Combined Diagnostic Panels in Nonalcoholic Fatty Liver Disease. DISEASE MARKERS 2022; 2022:1254014. [PMID: 35811662 PMCID: PMC9259243 DOI: 10.1155/2022/1254014] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 05/31/2022] [Accepted: 06/02/2022] [Indexed: 02/06/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) affects approximately 25-30% population worldwide, which progresses from simple steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma, and has complications such as cardiovascular events. Liver biopsy is still the gold standard for the diagnosis of NAFLD, with some limitations, such as invasive, sampling deviation, and empirical judgment. Therefore, it is urgent to develop noninvasive diagnostic biomarkers. Currently, a large number of NAFLD-related serum biomarkers have been identified, including apoptosis, inflammation, fibrosis, adipokines, hepatokines, and omics biomarkers, which could effectively diagnose NASH and exclude patients with progressive fibrosis. We summarized serum biomarkers and combined diagnostic panels of NAFLD, to provide some guidance for the noninvasive diagnosis and further clinical studies.
Collapse
|
|
26
|
Lin Y, Zhu J, Zhang J, Dai J, Liu S, Arroyo A, Rose M, Singal AG, Parikh ND, Lubman DM. Glycopeptides with Sialyl Lewis Antigen in Serum Haptoglobin as Candidate Biomarkers for Nonalcoholic Steatohepatitis Hepatocellular Carcinoma Using a Higher-Energy Collision-Induced Dissociation Parallel Reaction Monitoring-Mass Spectrometry Method. ACS OMEGA 2022; 7:22850-22860. [PMID: 35811936 PMCID: PMC9261276 DOI: 10.1021/acsomega.2c02600] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Accepted: 06/13/2022] [Indexed: 06/15/2023]
Abstract
Nonalcoholic steatohepatitis (NASH) is the fastest growing cause of hepatocellular carcinoma (HCC) in the United States. Changes in N-glycosylation on specific glycosites of serum proteins have been investigated as potential markers for the early detection of NASH-related HCC. Herein, we report a glycopeptide with a Sialyl Lewis structure derived from serum haptoglobin (Hp) as a potential marker for NASH related HCCs among 95 patients with NASH, including 46 cirrhosis, 32 early-stage HCC, and 17 late-stage HCC. Hp immuno-isolated from patient serum was analyzed using LC-HCD-PRM-MS/MS followed by data analysis via Skyline software. Two glycopeptides involving site N184 and four glycopeptides involving site N241 were significantly changed in patients with HCC vs NASH cirrhosis (P < 0.05). The two-marker panel using N-glycopeptide N241_A4G4F2S4 showed the best performance for HCC detection when combined with α-fetoprotein (AFP), with an improved estimated area under the curve (AUC) = 0.898 (95% CI: 0.835, 0.951), compared to the AUC of 0.790(95% CI, 0.697 0.872) using AFP alone (P = 0.048). At 90% specificity, the combination of N241_A4G4F2S4 + AFP had an improved sensitivity of 63.3%, compared to the sensitivity of 52.3% using AFP alone. When using three markers, the panel of AFP + N241_A2G2F1S2 + N241_A4G4F2S4 yielded an estimated AUC of 0.928 (95% CI: 0.877, 0.970). Our findings indicated that N241_A4G4F2S4 may play an important role in distinguishing HCC from NASH cirrhosis.
Collapse
Affiliation(s)
- Yu Lin
- Department
of Surgery, University of Michigan Medical
Center, Ann Arbor, Michigan 48109, United States
| | - Jianhui Zhu
- Department
of Surgery, University of Michigan Medical
Center, Ann Arbor, Michigan 48109, United States
| | - Jie Zhang
- Department
of Surgery, University of Michigan Medical
Center, Ann Arbor, Michigan 48109, United States
| | - Jianliang Dai
- Department
of Biostatistics, University of Texas MD
Anderson Cancer Center, Houston, Texas 77030, United States
| | - Suyu Liu
- Department
of Biostatistics, University of Texas MD
Anderson Cancer Center, Houston, Texas 77030, United States
| | - Ana Arroyo
- Department
of Internal Medicine, University of Texas
Southwestern Medical Center, Dallas, Texas 75390, United States
| | - Marissa Rose
- Department
of Internal Medicine, University of Texas
Southwestern Medical Center, Dallas, Texas 75390, United States
| | - Amit G. Singal
- Department
of Internal Medicine, University of Texas
Southwestern Medical Center, Dallas, Texas 75390, United States
| | - Neehar D. Parikh
- Division
of Gastroenterology and Hepatology, University
of Michigan Medical Center, Ann Arbor, Michigan 48109, United States
| | - David M. Lubman
- Department
of Surgery, University of Michigan Medical
Center, Ann Arbor, Michigan 48109, United States
| |
Collapse
|
|
27
|
Liang Y, Fu B, Zhang Y, Lu H. Progress of proteomics-driven precision medicine: From a glycosylation view. RAPID COMMUNICATIONS IN MASS SPECTROMETRY : RCM 2022; 36:e9288. [PMID: 35261114 DOI: 10.1002/rcm.9288] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Revised: 02/23/2022] [Accepted: 02/26/2022] [Indexed: 05/08/2023]
Abstract
Currently, cancer is one of the leading causes of death worldwide, partially owing to the lack of early diagnosis methods and effective therapies. With the rapid development of various omics, the precision medicine strategy becomes a promising way to increase the survival rates by considering individual differences. Glycosylation is one of the most essential protein post-translational modifications and plays important roles in a variety of biological processes. Therefore, it is highly possible to acquire understanding of the molecular mechanisms as well as discover novel potential markers for diagnosis and prognosis based on glycoproteomics research. This review summarizes the recent glycoproteomics studies about N-glycosylation of several cancer types, mainly in the past 5 years. We also highlight corresponding mass spectrometry-based analytical methods to give a brief overview on the main techniques applied in glycoproteomics.
Collapse
Affiliation(s)
- Yuying Liang
- Shanghai Cancer Center and Department of Chemistry, Fudan University, Shanghai, People's Republic of China
| | - Bin Fu
- Shanghai Cancer Center and Department of Chemistry, Fudan University, Shanghai, People's Republic of China
| | - Ying Zhang
- Shanghai Cancer Center and Department of Chemistry, Fudan University, Shanghai, People's Republic of China
- Institutes of Biomedical Sciences and NHC Key Laboratory of Glycoconjugates Research, Fudan University, Shanghai, People's Republic of China
| | - Haojie Lu
- Shanghai Cancer Center and Department of Chemistry, Fudan University, Shanghai, People's Republic of China
- Institutes of Biomedical Sciences and NHC Key Laboratory of Glycoconjugates Research, Fudan University, Shanghai, People's Republic of China
| |
Collapse
|
|
28
|
Wang J, Wang X, Li J, Xia Y, Gao M, Zhang X, Huang LH. A novel hydrophilic MOFs-303-functionalized magnetic probe for the highly efficient analysis of N-linked glycopeptides. J Mater Chem B 2022; 10:2011-2018. [PMID: 35244662 DOI: 10.1039/d1tb02827h] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
The effective analysis of glycoproteomics in clinical complex samples is of vital importance for the diagnosis and therapy of diseases. In this study, a hydrophilic MOFs-303-functionalized magnetic probe (GO@Fe3O4@MOF-303) is designed and fabricated to profile N-linked glycopeptides. Owing to its strong magnetic property, large surface area (845 m2 g-1), excellent hydrophilicity and suitable porous structure, the GO@Fe3O4@MOF-303 probe exhibits an ultralow detection limit (0.1 fmol μL-1), perfect size-exclusion effect (HRP digests/BSA protein/HRP protein, 1 : 1000 : 1000, w/w/w), a high binding capacity (200 mg g-1) and excellent reusability in the capture of standard N-linked glycopeptides. More excitingly, the GO@Fe3O4@MOF-303 probe also shows remarkable performance in practical applications, where 274 N-linked glycopeptides from 101 glycoproteins were identified in total for healthy controls, while a total of 265 N-linked glycopeptides from 102 glycoproteins were identified in serum (1 μL) with hepatocellular carcinoma (HCC). In addition, we discovered 4 up-regulated and 19 down-regulated serum glycoproteins in HCC patients by the hierarchical clustering heatmap. All results demonstrated that the reusable GO@Fe3O4@MOF-303 probe has great potential in profiling different N-linked glycopeptides in complex clinical samples. This study not only developed a novel probe for the highly effective capture of N-linked glycopeptides but also contributed to further understanding the mechanism of HCC and provides guidance for the development of novel clinical diagnostic methods.
Collapse
Affiliation(s)
- Jiaxi Wang
- Shanghai Key Laboratory of Metabolic Remodeling and Health, Department of Chemistry and Institute of Metabolism and Integrative Biology, Fudan University, Shanghai 200032, China. .,Shanghai Qi Zhi Institute, Shanghai 200030, China
| | - Xinmei Wang
- Shanghai Key Laboratory of Metabolic Remodeling and Health, Department of Chemistry and Institute of Metabolism and Integrative Biology, Fudan University, Shanghai 200032, China.
| | - Jie Li
- Shanghai Key Laboratory of Metabolic Remodeling and Health, Department of Chemistry and Institute of Metabolism and Integrative Biology, Fudan University, Shanghai 200032, China.
| | - Yan Xia
- Shanghai Key Laboratory of Metabolic Remodeling and Health, Department of Chemistry and Institute of Metabolism and Integrative Biology, Fudan University, Shanghai 200032, China.
| | - Mingxia Gao
- Shanghai Key Laboratory of Metabolic Remodeling and Health, Department of Chemistry and Institute of Metabolism and Integrative Biology, Fudan University, Shanghai 200032, China.
| | - Xiangmin Zhang
- Shanghai Key Laboratory of Metabolic Remodeling and Health, Department of Chemistry and Institute of Metabolism and Integrative Biology, Fudan University, Shanghai 200032, China.
| | - Li-Hao Huang
- Shanghai Key Laboratory of Metabolic Remodeling and Health, Department of Chemistry and Institute of Metabolism and Integrative Biology, Fudan University, Shanghai 200032, China.
| |
Collapse
|
|
29
|
Lin Y, Zhang J, Arroyo A, Singal AG, Parikh ND, Lubman DM. A Fucosylated Glycopeptide as a Candidate Biomarker for Early Diagnosis of NASH Hepatocellular Carcinoma Using a Stepped HCD Method and PRM Evaluation. Front Oncol 2022; 12:818001. [PMID: 35372033 PMCID: PMC8970044 DOI: 10.3389/fonc.2022.818001] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Accepted: 02/21/2022] [Indexed: 12/19/2022] Open
Abstract
Aberrant specific N-glycosylation, especially the increase in fucosylation on specific peptide sites of serum proteins have been investigated as potential markers for diagnosis of nonalcoholic steatohepatitis (NASH)-related HCC. We have combined a workflow involving broad scale marker discovery in serum followed by targeted marker evaluation of these fucosylated glycopeptides. This workflow involved an LC-Stepped HCD-DDA-MS/MS method coupled with offline peptide fractionation for large-scale identification of N-glycopeptides directly from pooled serum samples (each n=10) as well as differential determination of N-glycosylation changes between disease states. We then evaluated the fucosylation level of the glycoprotein ceruloplasmin among 62 patient samples (35 cirrhosis, 27 early-stage NASH HCC) by LC-Stepped HCD-PRM-MS/MS to quantitatively analyze 18 targeted glycopeptides. Of these targets, we found the ratio of fucosylation of a tri-antennary glycopeptide from site N762, involving N762_ HexNAc(5)Hex(6)Fuc(2)NeuAc(3) (P=0.0486), increased significantly from cirrhosis to early HCC. This fucosylation ratio of a tri-antennary glycopeptide in CERU could be a potential biomarker for further validation in a larger sample set and could be a promising candidate for early detection of NASH HCC.
Collapse
Affiliation(s)
- Yu Lin
- Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI, United States
| | - Jie Zhang
- Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI, United States
| | - Ana Arroyo
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Amit G. Singal
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Neehar D. Parikh
- Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI, United States
| | - David M. Lubman
- Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI, United States
| |
Collapse
|
|
30
|
Ramachandran P, Xu G, Huang HH, Rice R, Zhou B, Lindpaintner K, Serie D. Serum Glycoprotein Markers in Nonalcoholic Steatohepatitis and Hepatocellular Carcinoma. J Proteome Res 2022; 21:1083-1094. [PMID: 35286803 PMCID: PMC8981307 DOI: 10.1021/acs.jproteome.1c00965] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Fatty liver disease progresses through stages of fat accumulation and inflammation to nonalcoholic steatohepatitis (NASH), fibrosis and cirrhosis, and eventually hepatocellular carcinoma (HCC). Currently available diagnostic tools for HCC lack sensitivity and specificity. In this study, we investigated the use of circulating serum glycoproteins to identify a panel of potential prognostic markers that may be indicative of progression from the healthy state to NASH and further to HCC. Serum samples were processed and analyzed using a novel high-throughput glycoproteomics platform. Our initial dataset contained healthy, NASH, and HCC serum samples. We analyzed 413 glycopeptides, representing 57 abundant serum proteins, and compared among the three phenotypes. We studied the normalized abundance of common glycoforms and found 40 glycopeptides with statistically significant differences in abundances in NASH and HCC compared to controls. Summary level relative abundances of core-fucosylated, sialylated, and branched glycans containing glycopeptides were higher in NASH and HCC as compared to controls. We replicated some of our findings in an independent set of samples of individuals with benign liver conditions and HCC. Our results may be of value in the management of liver diseases. Data generated in this work can be downloaded from MassIVE (https://massive.ucsd.edu) with identifier MSV000088809.
Collapse
Affiliation(s)
| | - Gege Xu
- InterVenn Biosciences, South San Francisco, California 94080, United States
| | - Hector H Huang
- InterVenn Biosciences, South San Francisco, California 94080, United States
| | - Rachel Rice
- InterVenn Biosciences, South San Francisco, California 94080, United States
| | - Bo Zhou
- InterVenn Biosciences, South San Francisco, California 94080, United States
| | - Klaus Lindpaintner
- InterVenn Biosciences, South San Francisco, California 94080, United States
| | - Daniel Serie
- InterVenn Biosciences, South San Francisco, California 94080, United States
| |
Collapse
|
|
31
|
Islam Khan MZ, Tam SY, Law HKW. Advances in High Throughput Proteomics Profiling in Establishing Potential Biomarkers for Gastrointestinal Cancer. Cells 2022; 11:973. [PMID: 35326424 PMCID: PMC8946849 DOI: 10.3390/cells11060973] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 03/05/2022] [Accepted: 03/08/2022] [Indexed: 12/24/2022] Open
Abstract
Gastrointestinal cancers (GICs) remain the most diagnosed cancers and accounted for the highest cancer-related death globally. The prognosis and treatment outcomes of many GICs are poor because most of the cases are diagnosed in advanced metastatic stages. This is primarily attributed to the deficiency of effective and reliable early diagnostic biomarkers. The existing biomarkers for GICs diagnosis exhibited inadequate specificity and sensitivity. To improve the early diagnosis of GICs, biomarkers with higher specificity and sensitivity are warranted. Proteomics study and its functional analysis focus on elucidating physiological and biological functions of unknown or annotated proteins and deciphering cellular mechanisms at molecular levels. In addition, quantitative analysis of translational proteomics is a promising approach in enhancing the early identification and proper management of GICs. In this review, we focus on the advances in mass spectrometry along with the quantitative and functional analysis of proteomics data that contributes to the establishment of biomarkers for GICs including, colorectal, gastric, hepatocellular, pancreatic, and esophageal cancer. We also discuss the future challenges in the validation of proteomics-based biomarkers for their translation into clinics.
Collapse
Affiliation(s)
| | | | - Helen Ka Wai Law
- Department of Health Technology and Informatics, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Hung Hom, Hong Kong, China; (M.Z.I.K.); (S.Y.T.)
| |
Collapse
|
|
32
|
Chen F, Wang J, Wu Y, Gao Q, Zhang S. Potential Biomarkers for Liver Cancer Diagnosis Based on Multi-Omics Strategy. Front Oncol 2022; 12:822449. [PMID: 35186756 PMCID: PMC8851237 DOI: 10.3389/fonc.2022.822449] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 01/17/2022] [Indexed: 12/11/2022] Open
Abstract
Liver cancer is the fourth leading cause of cancer-related death worldwide. Hepatocellular carcinoma (HCC) accounts for about 85%-90% of all primary liver malignancies. However, only 20-30% of HCC patients are eligible for curative therapy mainly due to the lack of early-detection strategies, highlighting the significance of reliable and accurate biomarkers. The integration of multi-omics became an important tool for biomarker screening and unique alterations in tumor-associated genes, transcripts, proteins, post-translational modifications and metabolites have been observed. We here summarized the novel biomarkers for HCC diagnosis based on multi-omics technology as well as the clinical significance of these potential biomarkers in the early detection of HCC.
Collapse
Affiliation(s)
- Fanghua Chen
- Center for Tumor Diagnosis & Therapy, Jinshan Hospital, Fudan University, Shanghai, China
- Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Junming Wang
- Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Yingcheng Wu
- Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Qiang Gao
- Center for Tumor Diagnosis & Therapy, Jinshan Hospital, Fudan University, Shanghai, China
- Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Shu Zhang
- Center for Tumor Diagnosis & Therapy, Jinshan Hospital, Fudan University, Shanghai, China
- Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
- *Correspondence: Shu Zhang,
| |
Collapse
|
|
33
|
Feng X, Shu H, Zhang S, Peng Y, Zhang L, Cao X, Wei L, Lu H. Relative Quantification of N-Glycopeptide Sialic Acid Linkage Isomers by Ion Mobility Mass Spectrometry. Anal Chem 2021; 93:15617-15625. [PMID: 34779613 DOI: 10.1021/acs.analchem.1c02803] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Sialic acids decorate the surface of glycoproteins and play important roles in a variety of pathological processes. Although the mass spectrometry (MS) based linkage-specific analysis of sialylated N-glycopeptide is developing rapidly, quantitative analysis of these isomers still remains a challenge. Herein, we reported a novel quantitative strategy that can unambiguously identify and relatively quantify linkage-specific N-glycopeptides using ion mobility mass spectrometry (IM-MS). Without the assistance of derivatization, this method can relatively quantify sialic acid isomers of intact glycopeptides by using their characteristic fragment ions in IM-MS. Moreover, good linearity (R2 > 0.99) of relative quantification within a dynamic range of 2 orders of magnitude and high reproducibility (coefficient of variation (CV) < 10%, n = 3) were demonstrated. Finally, our results illustrated the aberrant sialylation of haptoglobin (Hp) in hepatocellular carcinoma (HCC), where the ratios of α2,3 to α2,6 sialylation of seven N-glycopeptides were found to be significantly altered (p < 0.01) in HCC individuals (n = 27) compared with healthy controls (n = 27).
Collapse
Affiliation(s)
- Xiaoxiao Feng
- Institutes of Biomedical Sciences & Shanghai Cancer Center, Fudan University, Shanghai 200032, People's Republic of China
| | - Hong Shu
- Department of Clinical Laboratory, Cancer Hospital of Guangxi Medical University, Nanning, Guangxi 530021, People's Republic of China
| | - Shu Zhang
- Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai 200032, People's Republic of China
| | - Ye Peng
- Institutes of Biomedical Sciences & Shanghai Cancer Center, Fudan University, Shanghai 200032, People's Republic of China
| | - Lei Zhang
- Institutes of Biomedical Sciences & Shanghai Cancer Center, Fudan University, Shanghai 200032, People's Republic of China
| | - Xinyi Cao
- Institutes of Biomedical Sciences & Shanghai Cancer Center, Fudan University, Shanghai 200032, People's Republic of China
| | - Liming Wei
- Institutes of Biomedical Sciences & Shanghai Cancer Center, Fudan University, Shanghai 200032, People's Republic of China.,Department of Chemistry & NHC Key Laboratory of Glycoconjugates Research, Fudan University, Shanghai 200032, People's Republic of China
| | - Haojie Lu
- Institutes of Biomedical Sciences & Shanghai Cancer Center, Fudan University, Shanghai 200032, People's Republic of China.,Department of Chemistry & NHC Key Laboratory of Glycoconjugates Research, Fudan University, Shanghai 200032, People's Republic of China
| |
Collapse
|
|
34
|
Lai Z, Zhang M, Zhou J, Chen T, Li D, Shen X, Liu J, Zhou J, Li Z. Fe 3O 4@PANI: a magnetic polyaniline nanomaterial for highly efficient and handy enrichment of intact N-glycopeptides. Analyst 2021; 146:4261-4267. [PMID: 34105527 DOI: 10.1039/d1an00580d] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Glycosylation of proteins plays important roles in the occurrence and development of chronic diseases. In this study, we report an enrichment method of intact N-glycopeptides using a magnetic polyaniline nanomaterial (Fe3O4@PANI). Under the synergistic effect of hydrogen bonding and electrostatic adsorption, Fe3O4@PANI can rapidly and easily enrich N-glycopeptides derived from standard protein (bovine fetuin and transferrin) tryptic digests and serum haptoglobin tryptic digests. Finally we have detected 63 glycopeptides in the glycosylation sites of both N204 and N211 from the serum haptoglobin beta chain using MALDI FTICR MS. Compared with non-magnetic materials, Fe3O4@PANI can achieve complete separation from complex biological samples, meeting the requirement of the high purity of samples for mass spectrometric detection. Overall, Fe3O4@PANI exhibits great application potential in the highly efficient enrichment of intact N-glycopeptides due to its stability and convenient preparation.
Collapse
Affiliation(s)
- Zhizhen Lai
- Department of Biophysics and Structural Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine, Peking Union Medical College, 5 Dongdan San Tiao, Beijing 100005, China.
| | | | | | | | | | | | | | | | | |
Collapse
|
|
35
|
Zhang R, Zhu J, Lubman DM, Mechref Y, Tang H. GlycoHybridSeq: Automated Identification of N-Linked Glycopeptides Using Electron Transfer/High-Energy Collision Dissociation (EThcD). J Proteome Res 2021; 20:3345-3352. [PMID: 34010560 PMCID: PMC8185882 DOI: 10.1021/acs.jproteome.1c00245] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
![]()
Glycosylation is
one of the most common post-translational modifications
(PTM) occurring in a large variety of proteins with important biological
functions in human and other higher organisms. Liquid chromatography
tandem mass spectrometry (LC-MS/MS) has been routinely used to characterize
site-specific protein glycosylation at high throughput in complex
glycoproteomic samples. Recently, electron transfer/high-energy collision
dissociation (EThcD) was introduced for glycopeptide identification,
which offers rich structural information on glycopepides with the
fragment ions from the cleavages of both the glycan and the peptide
backbone. Herein, we present the software GlycoHybridSeq for automated
interpretation of EThcD-MS/MS spectra from glycoproteomic data using
a customized scoring function, which enables the functionalities of
identifying glycopeptides, characterizing glycosylation sites, and
distinguishing some isomeric glycans. We evaluate GlycoHybridSeq on
glycoproteomic data collected for cancer biomarker discovery. The
results showed that it achieved comparable or better performance than
that of Byonic and MSFragger. GlycoHybridSeq is released as an open
source software and is ready to be used in large-scale glycoproteomic
data analyses.
Collapse
Affiliation(s)
- Rui Zhang
- Department of Computer Science, Luddy School of Informatics, Computing, and Engineering, Indiana University, Bloomington, Indiana 47405, United States
| | - Jianhui Zhu
- Department of Surgery, University of Michigan Medical Center, Ann Arbor, Michigan 48109, United States
| | - David M Lubman
- Department of Surgery, University of Michigan Medical Center, Ann Arbor, Michigan 48109, United States
| | - Yehia Mechref
- Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, Texas 79409, United States
| | - Haixu Tang
- Department of Computer Science, Luddy School of Informatics, Computing, and Engineering, Indiana University, Bloomington, Indiana 47405, United States
| |
Collapse
|
|
36
|
Lin Y, Zhu J, Pan L, Zhang J, Tan Z, Olivares J, Singal AG, Parikh ND, Lubman DM. A Panel of Glycopeptides as Candidate Biomarkers for Early Diagnosis of NASH Hepatocellular Carcinoma Using a Stepped HCD Method and PRM Evaluation. J Proteome Res 2021; 20:3278-3289. [PMID: 33929864 DOI: 10.1021/acs.jproteome.1c00175] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Changes in N-glycosylation on specific peptide sites of serum proteins have been investigated as potential markers for diagnosis of nonalcoholic steatohepatitis (NASH)-related HCC. To accomplish this work, a novel workflow involving broad-scale marker discovery in serum followed by targeted marker evaluation of these glycopeptides were combined. The workflow involved an LC-Stepped HCD-DDA-MS/MS method coupled with offline peptide fractionation for large-scale identification of N-glycopeptides directly from pooled serum samples (each n = 10) as well as differential determination of N-glycosylation changes between disease states. We then evaluated several potentially diagnostic N-glycopeptides among 78 individual patient samples (40 cirrhosis, 28 early stage NASH HCC, and 10 late-stage NASH HCC) by LC-Stepped HCD-PRM-MS/MS to quantitatively analyze 65 targeted glycopeptides from 7 glycoproteins. Of these targets, we found site-specific N-glycopeptides n169GSLFAFR_HexNAc(4)Hex(5)NeuAc(2) and n242ISDGFDGIPDNVDAALALPAHSYSGR_HexNAc(5)Hex(6)Fuc(1)NeuAc(3) from VTNC were significantly increased comparing samples from patients with NASH cirrhosis and NASH HCC (p < 0.05). When combining results of these 2 glycopeptides with AFP, the ROC curve analysis demonstrated the AUC value increased to 0.834 (95% CI, 0.748-0.921) and 0.847 (95% CI, 0.766-0.932), respectively, as compared to that of AFP alone (AUC = 0.791, 95% CI, 0.690-0.892). These 2 glycopeptides may serve as potential biomarkers for early HCC diagnosis in patients with NASH related cirrhosis.
Collapse
Affiliation(s)
- Yu Lin
- Department of Surgery, University of Michigan Medical Center, Ann Arbor, Michigan 48109, United States
| | - Jianhui Zhu
- Department of Surgery, University of Michigan Medical Center, Ann Arbor, Michigan 48109, United States
| | - Lingyun Pan
- Department of Surgery, University of Michigan Medical Center, Ann Arbor, Michigan 48109, United States
| | - Jie Zhang
- Department of Surgery, University of Michigan Medical Center, Ann Arbor, Michigan 48109, United States
| | - Zhijing Tan
- Department of Surgery, University of Michigan Medical Center, Ann Arbor, Michigan 48109, United States
| | - Jocelyn Olivares
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States
| | - Amit G Singal
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States
| | - Neehar D Parikh
- Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan 48109, United States
| | - David M Lubman
- Department of Surgery, University of Michigan Medical Center, Ann Arbor, Michigan 48109, United States
| |
Collapse
|
|
37
|
Chen Z, Yu Q, Yu Q, Johnson J, Shipman R, Zhong X, Huang J, Asthana S, Carlsson C, Okonkwo O, Li L. In-depth Site-specific Analysis of N-glycoproteome in Human Cerebrospinal Fluid and Glycosylation Landscape Changes in Alzheimer's Disease. Mol Cell Proteomics 2021; 20:100081. [PMID: 33862227 PMCID: PMC8724636 DOI: 10.1016/j.mcpro.2021.100081] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 04/02/2021] [Accepted: 04/03/2021] [Indexed: 01/22/2023] Open
Abstract
As the body fluid that directly interchanges with the extracellular fluid of the central nervous system (CNS), cerebrospinal fluid (CSF) serves as a rich source for CNS-related disease biomarker discovery. Extensive proteome profiling has been conducted for CSF, but studies aimed at unraveling site-specific CSF N-glycoproteome are lacking. Initial efforts into site-specific N-glycoproteomics study in CSF yield limited coverage, hindering further experimental design of glycosylation-based disease biomarker discovery in CSF. In the present study, we have developed an N-glycoproteomic approach that combines enhanced N-glycopeptide sequential enrichment by hydrophilic interaction chromatography (HILIC) and boronic acid enrichment with electron transfer and higher-energy collision dissociation (EThcD) for large-scale intact N-glycopeptide analysis. The application of the developed approach to the analyses of human CSF samples enabled identifications of a total of 2893 intact N-glycopeptides from 511 N-glycosites and 285 N-glycoproteins. To our knowledge, this is the largest site-specific N-glycoproteome dataset reported for CSF to date. Such dataset provides molecular basis for a better understanding of the structure-function relationships of glycoproteins and their roles in CNS-related physiological and pathological processes. As accumulating evidence suggests that defects in glycosylation are involved in Alzheimer's disease (AD) pathogenesis, in the present study, a comparative in-depth N-glycoproteomic analysis was conducted for CSF samples from healthy control and AD patients, which yielded a comparable N-glycoproteome coverage but a distinct expression pattern for different categories of glycoforms, such as decreased fucosylation in AD CSF samples. Altered glycosylation patterns were detected for a number of N-glycoproteins including alpha-1-antichymotrypsin, ephrin-A3 and carnosinase CN1 etc., which serve as potentially interesting targets for further glycosylation-based AD study and may eventually lead to molecular elucidation of the role of glycosylation in AD progression.
Collapse
Affiliation(s)
- Zhengwei Chen
- Department of Chemistry, University of Wisconsin, Madison, Wisconsin, USA
| | - Qinying Yu
- School of Pharmacy, University of Wisconsin, Madison, Wisconsin, USA
| | - Qing Yu
- School of Pharmacy, University of Wisconsin, Madison, Wisconsin, USA
| | - Jillian Johnson
- School of Pharmacy, University of Wisconsin, Madison, Wisconsin, USA
| | - Richard Shipman
- Department of Applied Science, University of Wisconsin-Stout, Menomonie, Wisconsin, USA
| | - Xiaofang Zhong
- School of Pharmacy, University of Wisconsin, Madison, Wisconsin, USA
| | - Junfeng Huang
- School of Pharmacy, University of Wisconsin, Madison, Wisconsin, USA
| | - Sanjay Asthana
- School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, USA
| | - Cynthia Carlsson
- School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, USA
| | - Ozioma Okonkwo
- School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, USA
| | - Lingjun Li
- Department of Chemistry, University of Wisconsin, Madison, Wisconsin, USA; School of Pharmacy, University of Wisconsin, Madison, Wisconsin, USA.
| |
Collapse
|
|
38
|
Guan MC, Wang MD, Liu SY, Ouyang W, Liang L, Pawlik TM, Xu QR, Huang DS, Shen F, Zhu H, Yang T. Early diagnosis and therapeutic strategies for hepatocellular carcinoma: From bench to bedside. World J Gastrointest Oncol 2021; 13:197-215. [PMID: 33889272 PMCID: PMC8040062 DOI: 10.4251/wjgo.v13.i4.197] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 01/14/2021] [Accepted: 03/11/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related deaths worldwide. The prognosis of patients with HCC remains poor largely due to the late diagnosis and lack of effective treatments. Despite being widely used, alpha-fetoprotein serology and ultrasonography have limited diagnostic performance for early-stage HCC. The emergence of omics strategies has contributed to significant advances in the development of non-invasive biomarkers for the early diagnosis of HCC including proteins, metabolites, circulating tumor deoxyribonucleic acid, and circulating non-coding ribonucleic acid. Early diagnosis is beneficial to patients as it increases the proportion who can be treated with curative treatment, thus prolonging survival outcomes. Currently, multiple clinical trials involving locoregional, systemic therapies, and combinations of these modalities are changing therapeutic strategies for different stage HCC. Success in several preclinical trials that involve immunotherapeutic innovations has created the potential to complement and enforce other treatment strategies in the future. This review summarizes the most recent advances in non-invasive early molecular detection, current therapy strategies, and potential immunotherapeutic innovations of HCC.
Collapse
Affiliation(s)
- Ming-Cheng Guan
- Department of Medical Oncology, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu Province, China
| | - Ming-Da Wang
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital (Navy Medical University), Second Military Medical University, Shanghai 200438, China
| | - Si-Yu Liu
- Department of Laboratory, Lishui Municipal Central Hospital, Lishui 323000, Zhejiang Province, China
| | - Wei Ouyang
- Department of Medical Oncology, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu Province, China
| | - Lei Liang
- Department of Hepatobiliary, Pancreatic and Minimal Invasive Surgery, Zhejiang Provincial People’s Hospital (People’s Hospital of Hangzhou Medical College), Hangzhou 310000, Zhejiang Province, China
- Department of Hepatobiliary, Pancreatic and Minimal Invasive Surgery, Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Hangzhou 310000, Zhejiang Province, China
| | - Timothy M Pawlik
- Department of Surgery, Ohio State University, Wexner Medical Center, Columbus, OH 43210, United States
| | - Qiu-Ran Xu
- Department of Hepatobiliary, Pancreatic and Minimal Invasive Surgery, Zhejiang Provincial People’s Hospital (People’s Hospital of Hangzhou Medical College), Hangzhou 310000, Zhejiang Province, China
- Department of Hepatobiliary, Pancreatic and Minimal Invasive Surgery, Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Hangzhou 310000, Zhejiang Province, China
| | - Dong-Sheng Huang
- Department of Hepatobiliary, Pancreatic and Minimal Invasive Surgery, Zhejiang Provincial People’s Hospital (People’s Hospital of Hangzhou Medical College), Hangzhou 310000, Zhejiang Province, China
- Department of Hepatobiliary, Pancreatic and Minimal Invasive Surgery, Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Hangzhou 310000, Zhejiang Province, China
| | - Feng Shen
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital (Navy Medical University), Second Military Medical University, Shanghai 200438, China
| | - Hong Zhu
- Department of Medical Oncology, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu Province, China
| | - Tian Yang
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital (Navy Medical University), Second Military Medical University, Shanghai 200438, China
- Department of Hepatobiliary, Pancreatic and Minimal Invasive Surgery, Zhejiang Provincial People’s Hospital (People’s Hospital of Hangzhou Medical College), Hangzhou 310000, Zhejiang Province, China
- Department of Hepatobiliary, Pancreatic and Minimal Invasive Surgery, Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Hangzhou 310000, Zhejiang Province, China
| |
Collapse
|
|
39
|
Pont L, Kuzyk V, Benavente F, Sanz-Nebot V, Mayboroda OA, Wuhrer M, Lageveen-Kammeijer GSM. Site-Specific N-Linked Glycosylation Analysis of Human Carcinoembryonic Antigen by Sheathless Capillary Electrophoresis-Tandem Mass Spectrometry. J Proteome Res 2021; 20:1666-1675. [PMID: 33560857 PMCID: PMC8023805 DOI: 10.1021/acs.jproteome.0c00875] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
![]()
With 28 potential N-glycosylation sites, human
carcinoembryonic antigen (CEA) bears an extreme amount of N-linked glycosylation, and approximately 60% of its molecular
mass can be attributed to its carbohydrates. CEA is often overexpressed
and released by many solid tumors, including colorectal carcinomas.
CEA displays an impressive heterogeneity and variability in sugar
content; however, site-specific distribution of carbohydrate structures
has not been reported so far. The present study investigated CEA samples
purified from human colon carcinoma and human liver metastases and
enabled the characterization of 21 out of 28 potential N-glycosylation sites with respect to their occupancy. The coverage
was achieved by a multienzymatic digestion approach with specific
enzymes, such as trypsin, endoproteinase Glu-C, and the nonspecific enzyme, Pronase, followed by analysis using
sheathless CE-MS/MS. In total, 893 different N-glycopeptides
and 128 unique N-glycan compositions were identified.
Overall, a great heterogeneity was found both within (micro) and in
between (macro) individual N-glycosylation sites.
Moreover, notable differences were found on certain N-glycosylation sites between primary adenocarcinoma and metastatic
tumor in regard to branching, bisection, sialylation, and fucosylation.
Those features, if further investigated in a targeted manner, may
pave the way toward improved diagnostics and monitoring of colorectal
cancer progression and recurrence. Raw mass spectrometric data and
Skyline processed data files that support the findings of this study
are available in the MassIVE repository with the identifier MSV000086774
[DOI: 10.25345/C5Z50X].
Collapse
Affiliation(s)
- Laura Pont
- Department of Chemical Engineering and Analytical Chemistry, University of Barcelona, 08007 Barcelona, Spain
| | - Valeriia Kuzyk
- Center for Proteomics and Metabolomics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.,Division of Bioanalytical Chemistry, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands
| | - Fernando Benavente
- Department of Chemical Engineering and Analytical Chemistry, University of Barcelona, 08007 Barcelona, Spain
| | - Victoria Sanz-Nebot
- Department of Chemical Engineering and Analytical Chemistry, University of Barcelona, 08007 Barcelona, Spain
| | - Oleg A Mayboroda
- Center for Proteomics and Metabolomics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
| | - Manfred Wuhrer
- Center for Proteomics and Metabolomics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
| | | |
Collapse
|
|
40
|
Moldogazieva NT, Mokhosoev IM, Zavadskiy SP, Terentiev AA. Proteomic Profiling and Artificial Intelligence for Hepatocellular Carcinoma Translational Medicine. Biomedicines 2021; 9:biomedicines9020159. [PMID: 33562077 PMCID: PMC7914649 DOI: 10.3390/biomedicines9020159] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 01/27/2021] [Accepted: 02/02/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary cancer of the liver with high morbidity and mortality rates worldwide. Since 1963, when alpha-fetoprotein (AFP) was discovered as a first HCC serum biomarker, several other protein biomarkers have been identified and introduced into clinical practice. However, insufficient specificity and sensitivity of these biomarkers dictate the necessity of novel biomarker discovery. Remarkable advancements in integrated multiomics technologies for the identification of gene expression and protein or metabolite distribution patterns can facilitate rising to this challenge. Current multiomics technologies lead to the accumulation of a huge amount of data, which requires clustering and finding correlations between various datasets and developing predictive models for data filtering, pre-processing, and reducing dimensionality. Artificial intelligence (AI) technologies have an enormous potential to overcome accelerated data growth, complexity, and heterogeneity within and across data sources. Our review focuses on the recent progress in integrative proteomic profiling strategies and their usage in combination with machine learning and deep learning technologies for the discovery of novel biomarker candidates for HCC early diagnosis and prognosis. We discuss conventional and promising proteomic biomarkers of HCC such as AFP, lens culinaris agglutinin (LCA)-reactive L3 glycoform of AFP (AFP-L3), des-gamma-carboxyprothrombin (DCP), osteopontin (OPN), glypican-3 (GPC3), dickkopf-1 (DKK1), midkine (MDK), and squamous cell carcinoma antigen (SCCA) and highlight their functional significance including the involvement in cell signaling such as Wnt/β-catenin, PI3K/Akt, integrin αvβ3/NF-κB/HIF-1α, JAK/STAT3 and MAPK/ERK-mediated pathways dysregulated in HCC. We show that currently available computational platforms for big data analysis and AI technologies can both enhance proteomic profiling and improve imaging techniques to enhance the translational application of proteomics data into precision medicine.
Collapse
Affiliation(s)
- Nurbubu T. Moldogazieva
- Laboratory of Bioinformatics, Institute of Translational Medicine and Biotechnology, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia
- Correspondence: or
| | - Innokenty M. Mokhosoev
- Department of Biochemistry and Molecular Biology, N.I. Pirogov Russian National Research Medical University, 117997 Moscow, Russia; (I.M.M.); (A.A.T.)
| | - Sergey P. Zavadskiy
- Department of Pharmacology, A.P. Nelyubin Institute of Pharmacy, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia;
| | - Alexander A. Terentiev
- Department of Biochemistry and Molecular Biology, N.I. Pirogov Russian National Research Medical University, 117997 Moscow, Russia; (I.M.M.); (A.A.T.)
| |
Collapse
|