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  • Review Article
  • OPEN ACCESS

Diagnostic and Prognostic Value of Protein Post-translational Modifications in Hepatocellular Carcinoma

  • Jing Wang1,2,
  • Fangfang Wang1,2,
  • Ning Wang1,2,
  • Mei-Yin Zhang3,
  • Hui-Yun Wang3,*  and
  • Guo-Liang Huang1,2,* 
 Author information  Cite
Journal of Clinical and Translational Hepatology   2023;11(5):1192-1200

doi: 10.14218/JCTH.2022.00006S

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.

Keywords

Diagnosis, Hepatocellular carcinoma, Post-translational modification, Prognosis

Introduction

About 80% of primary liver cancers are hepatocellular carcinomas (HCCs), which are malignant neoplasms of hepatocytes. One of the leading causes of cancer-related mortality around the world is HCC.1 In developing countries, the incidence of HCC is higher compared with developed countries. HCC occurs mainly in East Asia, Southeast Asia, and Africa.2 There is an association between chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection and approximately 80% of cases of HCC.3,4 Additionally, alcoholism, aflatoxin infection, smoking, and various metabolic diseases all contribute to HCC risk. However, the causes of liver cancer are gradually changing from viral and alcoholic liver disease to obesity, type 2 diabetes mellitus and nonalcoholic fatty liver disease (NAFLD).5 The resulting molecular and signal transduction network disturbances, genomic instability, and microenvironmental differences account for HCC heterogeneity. Various therapies have been developed for the treatment of liver cancer, including local area therapy, systemic chemotherapy, hormone therapy, molecular targeted therapy, immune checkpoint therapy, surgical resection, and liver transplantation.6,7 Although these methods can be used to treat HCC, the side effects of various drugs, high recurrence rate after treatment, and low rate of transplantation all lead to a low HCC cure rate.8–10

During translation, proteins undergo a series of chemical modifications. These post-translational modifications (PTMs) have a great impact on protein function, including enzyme activation and inactivation, protein stability, subcellular localization, interaction, and PTM crosstalk.11 At present, many studies have shown that the development of a wide range of diseases is linked to PTMs, such as tumors, neurological diseases, metabolic diseases, and immune diseases.12–15 Currently, approximately 400 types of PTMs are known to exist. Almost all proteins can undergo PTMs, including phosphorylation, acetylation, methylation, glycosylation, ubiquitination, and so on.16,17 Phosphorylation is one of the most common and well-studied PTMs. Protein phosphorylation is a reversible process. Protein kinase can covalently transfer a phosphate group to an amino acid residue, while protein phosphatase removes the phosphate group.18 Phosphorylation of proteins can further lead to activation of some signaling pathways, which then affect downstream molecules and promote the occurrence, proliferation, migration, and invasion of tumors.19 Acetylation modification of proteins mainly includes histone and nonhistone acetylation modification. At present, histone acetylation is more studied in liver cancer than nonhistone acetylation.20 A balance exists between histone acetyltransferases (HATs) and histone deacetylase (HDAC) activities that regulate histone acetylation. Gene silencing occurs through histone deacetylation induced by HDAC, while histone acetylation induced by HAT is linked to gene transcription.21 Protein acetylations have been reported to be abnormally expressed in HCC tumor tissues and have shown a connection with clinical stage, prognosis, and survival. Tumor cells with altered glycosylation are common in humans and the heterogeneity and functional diversity of tumor molecules are mainly derived from the diversity of glycosylation.22 At least nine basic amino acid residues can have their structure changed by sugar groups. There are two main protein glycosylation pathways, namely N-linked and O-linked. The most common glycosidic bond in nature is N-glycosylation and the part of the asparagine (Asn) part of the protein that is linked to the carbohydrate is the N-glycosidic bond.23 O-glycosylation usually refers to the ligation of O-glycans to Ser or Thr residues on proteins by enzymatic reactions.24 Altered glycosylation profiles have been proved to associated with many cancers including liver, breast, and lung.

PTM studies provide new insights into the diagnosis, prognosis, and therapy of cancers. The clinical implication of PTMs in HCC have been identified in a number of articles. The glycoprotein, alpha-fetoprotein (AFP), has been used widely as a biomarker for HCC. The clinical utility of AFP has been recently reviewed.25–28 Glypican-3 (GPC3), as a member of the proteoglycan family, is a promising therapeutic target and biomarker for the diagnosis and prognosis of HCC. Further discussion of the clinical value of GPC3 in HCC can be found in several reviews.29–32 This review provides an overview of the diagnostic and prognostic value of major types of PTM in HCC.

Diagnostic value of PTM in HCC

A set of glycoproteins, including AFP, AFP-L3, Golgi phosphoprotein 73 (GP73), GPC3, Fuc-GP73 and fucosylated paraoxonase 1 (Fuc-PON1), are considered to be diagnostic markers for HCC.

AFP and its fucosylation

AFP, as a glycoprotein, is the most widely used serum biomarker for the diagnosis of HCC worldwide. However, the elevation of AFP is not detected in many HCC patients, and AFP may be elevated in cirrhosis or hepatitis cases.33 Many studies aim to search for meaningful diagnostic markers in patients with liver cancer whose AFP is negative.34 The N-glycosylated isoform of AFP (AFP-L3), which contains core fucosylation on its N-linked glycans, shows potential ability for diagnosing AFP-negative HCC. Zhang et al.35 detected AFP-L3 in the serum of 50% patients with liver cancer, only 3.33% of patients with other liver diseases, and 2.00% of healthy participants. Studies shown that AFP-L3 promoted the proliferation of cancer cells by activating the Wnt-β-catenin pathway and promoted the invasion and metastasis of liver cancer cells by activating the downstream TGF-β and VEGF pathways.36

GP73 and its fucosylation

GP73, a transmembrane glycoprotein, was detected in 66% of AFP-negative HCC, 10% of non-HCC participants, and 0% of healthy participants.35 Hu et al.37 measured serum levels of GP73 in a hepatitis B-endemic Asian population and showed the area under the curve of the receiver operating characteristic (AUROC) was 0.89. GP73 downregulation led to the accumulation of matrix metalloproteinase-2 (MMP2), which inhibited the activation of AAPK/JNK and P53-P21 pathways, and attenuated cell invasion. The two pathways also regulated MMP2 activity by a negative feedback mechanism.38 Fucosylation is a type of glycosylation. Zhao et al.39 found that the AUROC of fucosylated GP73 (Fuc-GP73) for diagnosis of HCC was 0.885, with a specificity of 95% and a sensitivity of 82%.

APOH, ORM2, and C3

Cao et al.40 designed a straightforward and highly efficient scheme to identify glycoprotein biomarkers using a nonglycopeptide-based mass spectrometry pipeline. The diagnostic sensitivities were 0.901 for APOH, 0.945 for ORM2, 0.944 for C3, while the diagnostic sensitivity of AFP was only 0.633. The results showed that three glycoproteins, β-2-glycoprotein 1 (APOH), α-1-acid glycoprotein 2 (ORM2), and complement C3 (C3) could be used as biomarkers to distinguish HCC patients from healthy individuals. APOH interacted with hepatitis B surface antigen (HBsAg) to activate the NF-κB pathway, thus promoting tumor cell proliferation.41 Fang et al.42 reported that ORM2 was regulated by CCAAT/enhancer-binding protein β and inhibited the progression of liver cancer. Glycosylation of C3 affected various biological functions of C3. C3 activated the P38-MAPK signaling pathway, thus inhibiting the secretion of cytotoxic T cells and leading to tumor cell proliferation.43

Glycosylation of α-1-acid glycoprotein (AGP)

AGP, with an official name of orosomucoid (ORM), is also known as AAP. Tanabe et al.44 assessed glycopeptides obtained from serum proteins of 42 HCC patients and 80 controls by liquid chromatography time-of-flight mass spectrometry and revealed that AGP with multifucosylated tetra-antennary N-glycans was higher in HCC patients. High levels of sialylated and fucosylated peptides from AGP were reported in HCC patients compared to controls. The diagnostic potential of these glycopeptides was reported to differentiate HCC patients from cirrhosis participants with AUCs greater than 0.9.45

Fucosylated paraoxonase 1 (Fuc-PON1)

Zhang et al.46 used an ELISA index to assess the fucosylation level of PON1. The utility of Fuc-PON1 in distinguishing HCC from liver cirrhosis was indicated by an AUC of 0.803, sensitivity of 80% and specificity of 64.4%. In addition, the data showed a better AUROC curve and higher sensitivity and specificity in AFP-negative patients.

Fucosylation of alpha-1-antitrypsin (A1AT)

Glycosylation of A1AT increases with the development of HCC, and there are five major isoforms. A patient cohort of 458 patients was used to evaluate the lever of fucosylated A1AT compared with 375 patients with other liver diseases and 20 with no evidence of liver disease. Core fucosylation was observed only in patients with HCC. The AUROC of fucosylated A1AT was 0.871, suggesting core fucosylation of A1AT had the ability to be used as a diagnostic biomarker for HCC.47

Glycosylation of haptoglobin (Hp)

Hp is an acute-phase response protein secreted by the liver. Various types of glycosylation of Hp were reported to be higher in HCC. Ang et al.48 performed a systematic analysis of serum concentrations of Hp and its glycosylation in HCC patients and chronic liver diseases. Using Hp for HCC diagnosis, the sensitivity could be 79% with the specificity of 95%. Serum Hp concentrations of hypersialylated fucosylated and hyposialylated fucosylated species were significantly increased in patients with advanced HCC. Five N-glycopeptides at sites N184 and N241 of Hp were found to be significantly increased during the progression of cirrhosis to HCC. The glycopeptides had a diagnostic potential in detection of HCC, with an AUC greater than AFP.49 In addition, a total of 26 complete O-glyopeptides that could be used to distinguish HCC from liver cirrhosis were discovered on Hp using mass spectrometry.50

C3, CE, HRG, CD14, HGF

Ceruloplasmin (CE), a glycoprotein, played an important role in iron homeostasis. In liver cancer cells, the absence of CE promoted the accumulation of lipid reactive oxygen species, which led to ferroptosis.51 In the presence of tumor necrosis factor receptor 1 (TNFR1), HRG bound to TNFR1 to promote apoptosis and inhibit the activation of NF-κB signaling pathway and the expression of survival-promoting genes.52 In addition, it was reported that HRG inhibited cell proliferation by inhibiting FGF-ERK1/2 phosphorylation.53 Liu et al.54 developed an integrated platform to discover glycoprotein biomarkers in early HCC. The data indicated C3, CE, histidine-rich glycoprotein (HRG), CD14, and hepatocyte growth factor (HGF) were biomarker candidates for distinguishing early-stage HCC from cirrhosis. The combination of the five proteins had an AUROC of 0.811 and the AUROC curve of each glycoprotein were better than AFP of 0.661.

Combination of biomarkers

Meta-analyses and studies of combinations of biomarkers or patient characteristics were applied to investigate the diagnosis of HCC. AFP-L3 % is the ratio of AFP-L3 to total AFP in serum. Marrero et al.55 performed a phase 2 biomarker case-control study with 836 patients at seven academic medical centers. The results showed that the AUC of AFP was better than that of AFP-L3% in ROC analysis for the diagnosis of early-stage HCC.55 However, Leerapun et al.56 found that when AFP-L3% was greater than 35%, the specificity reached 100% for HCC patients with AFP values of 10–200 ng/ml.56 In a meta-analysis that included 2,447 patients, Zhou et al.57 reported that AFP-L3% had a high pooled specificity (92%), low pooled sensitivity (34%), and moderate AUC of the summary ROC curve (0.755) for HCC diagnosis. The results suggested that AFP-L3% could be used as an adjunct biomarker for HCC diagnosis. In a recent prospective phase III biomarker study of 534 patients. Tayob et al.58 showed that GALAD (a combination of Gender, Age, AFP-L3, AFP, and DCP) significantly improved the sensitivity of HCC detection, but with an increasement in the false-positive rate.58 The results of two meta-analyses indicate that a combination of AFP and GP73 had the best AUCs in the diagnosis of HCC among AFP, AFP-L3, GP73, and DCP alone or combined.59,60 The combination of AGP and AFP had an AUC of 0.943, whereas AFP and AAG had AUCs of 0.750 and 0.907 respectively, to differentiate HCC from chronic liver disease. The data indicate that combining of AAG and AFP improved the diagnostic potential of HCC.61

H2A.Z acetylation and ALDOA phosphorylation

In addition to glycoproteins, other types of posttranslational modifications of protein are involved in HCC development and be potential biomarkers. Histone variant H2A.Z is involved in the proliferation, cell cycle, apoptosis, and metastasis of HCC cells. Acetylated HA2.Z inhibited the transcription of downstream target genes and thus affected various tumor behaviors. Yuan et al.62 measured the acetylation level of H2A.Z and found that it was elevated in HCC cells and tissue samples. The results indicate that H2A.Z and its acetylation had diagnostic potential for HCC. Gao et al.63 conducted a proteogenomic study of HBV-associated HCC. The results showed that in CTNNB1-mutated tumors, glucose metabolism was regulated by Ser36 phosphorylation of ALDOA and further affected cell proliferation. Increased Ser36 phosphorylation of ALDOA was found in CTNNB1-mutated tumors and was used as a potential diagnostic biomarker for such tumors.63

Prognostic value of PTM in HCC

Phosphorylation of p53 at serine 15 (p53 Ser15-P)

Phosphorylation of p53 at serine 15 (p53 Ser15-P) may be a prognostic marker of HCC. P53 Ser15-P was found to inhibit tumor progression by binding with p21 to stop cell cycle progression. Yang et al.64 performed an immunohistochemistry analysis to determine the prognostic value of PCNA, p53, p53 phosphorylation at serine 15 (p53 Ser15-P) and Ser392 (p53 Ser392-P) in 199 patients with HCC. The results showed that the levels of p53 Ser15-P, but not p53 or p53 Ser392-P, were correlated with 5-year survival of HCC. Moreover, patients with positive PCNA and negative p53 Ser15-P had worse survival outcomes than those with positive PCNA and positive p53 Ser15-P. The results indicate that p53 Ser15-P was a prognosis marker not only of overall HCC but also of patients with positive PCNA.64 Identification of poor survival groups by monitoring p53 Ser15-P in PCNA-positive patients may contribute to the treatment of liver cancer, especially in PCNA-positive patients.

Phosphorylation of PCK1, INSIG1, and INSIG2

Phosphorylated PCK1 was shown to reduce binding of INSIG1/2 to SCAP, leading to translocation of the SCAP/SREBP complex to the Golgi. Activation of SREBP proteins was related to transcription of downstream lipid-related genes, tumor cell proliferation, and tumorigenesis in mice. Xu et al.65 reported the phosphorylation at Ser90 of phosphoenolpyruvate carboxykinase 1(PCK1), Ser207 of INSIG1, and Ser151 of INSIG2 was positively correlated with nuclear accumulation of SREBP1 in HCC samples. IHC analysis showed that increased levels of phosphorylation of PCK1 Ser90 and INSIG1 Ser207/INSIG2 Ser151 were associated with reduced overall survival in 90 HCC patients.

Androgen receptor (AR) phosphorylation at Ser96

Ren et al.66 performed IHC staining on human steatosis liver tissue and HCC samples using anti-ARpS96 antibodies. High AR S96 phosphorylation was found in human liver adipose tissue and HCC tissue. Survival analysis showed that p-AR S96 expression was associated with HCC survival and was an independent risk factor for OS in HCC patients. MTOR signaling stimulated AR phosphorylation. Phosphorylation at Ser96 increased the stability and transcriptional activity of AR and activated downstream SREBP signaling, which enhanced liver steatosis and hepatocarcinogenesis in mice.66

Recombinant Human Eukaryotic Translation Initiation Factor 4E-Binding Protein 1 (4E-BP1) phosphorylation at Thr46

HCC with early formation of portal vein tumor thrombosis (PVTT) had a higher risk of metastasis. Lin et al.67 performed a phosphorylated proteomic analysis and identified a total of 1,745 phosphoproteins in HCC tissues, normal tissues, and PVTT tissues. The results showed that HCC and PVTT tissues had higher phosphorylation levels of 4E-BP1 than surrounding noncancerous tissues. The expression of phosphorylated 4E-BP1 in patients who relapsed within 1 year was significantly higher than that in patients who relapsed after 3 years. The reduction of mTOR signal stimulated phosphorylation of 4EBP1. Phosphorylation of 4E-BP1 weaken its binding to eukaryotic translation initiation factor 4E, thereby promoting the initiation of protein translation and promoting tumor cell proliferation. Therefore, the prediction of early recurrence of HCC may be assisted by 4E-BP1 with phosphorylation at Thr46 as a reliable biomarker.67

Acetylation of AFP

Acetylation at lysines 194, 211, and 242 of AFP were reported to enhance the protein stability of AFP and strengthen its oncogenic function by inhibition of binding to the phosphatase PTEN and the pro-apoptotic protein caspase-3. Results of the immunostaining of 70 HCC liver specimens showed that patients with higher levels of AcK194-AFP, AcK211-AFP, and AcK242-AFP had poorer progression-free and overall survival. Moreover, elevated acetylation levels of AFP were correlated with metastasis and HBV infection. The data suggest that acetylation of AFP played a vital role in HCC development and could serve as a novel potential marker for the prognosis of HCC.68

Acetylation and methylation of histone

Histone-related modifications also have an important role in tumors. Acetylation of lysine 120 on histone H2B (H2BK120ac), lysine 18 on histone H3.3 (H3.3K18ac), and lysine 77 on histone H4 (H4K77ac) was upregulated in HCCs compared with paracancerous or normal liver tissues. Patients with high acetylation levels of all three histones had obviously worse OS than patients with low acetylation levels.69 He et al.70 performed immunohistochemical experiments and statistical analysis to assess the expression and clinicopathologic association of methylation of lysine 4 in histone H3 (H3K4me3) in two cohorts of HCC patients. The results revealed that high expression of H3K4me3 was associated with worse survival in both the testing cohort and validation cohort. However, high level of H3K4me3 discriminated differences in OS for the subset of patients with TNM stage III/IV only in the testing cohort. Multivariate analysis was carried out to indicate that the expression of H3K4me3 was a significant independent prognosis factor for poor overall survival in both the testing cohort and validation cohort.

Mac-2-binding protein glycosylation isomer (M2BPGi)

Serum Mac-2-binding protein glycosylation isomer (M2BPGi) is a novel glycoprotein biomarker for liver fibrosis or cirrhosis. M2BPGi enhanced the migration and invasion of HCC via the mTOR signaling pathway.71 Tak et al.72 studied the serum M2BPGi levels of 226 HCC patients received transcatheter arterial chemoembolization (TACE). The study demonstrated that patients with low M2BPGi levels had significantly better OS and PFS than those with high M2BPGi levels. The hepatoma arterial embolization prognostic (HAP) score is a prognostic tool based on albumin, bilirubin, AFP, levels, and tumor size.73 Combination of serum M2BPGi and the HAP score increased the prognostic ability. Serum M2BPGi level is a useful prognostic indicator for survival of HCC patients treated with TACE.

Human C3

Human C3 in HCC plasma was reported to have high-mannose and hybrid glycoforms at Asn85 with the utility of post-proteomic site-specific N-glycan analysis. The level of plasma mannose-5 or mannose-6 glycoform at Asn85 of C3 was significantly associated with the HCC tumor grade. Low tumor recurrence and mortality rates were found in the plasma of HCC patients with C3 with a hybrid glycoform at Asn85. The results suggest that specific plasma N-glycoproteins are potential noninvasive markers of HCC prognosis.74

Conclusions and perspectives

PTM of proteins affects the biology of almost all normal cells and the pathogenesis of various diseases. Differences in PTMs provide novel insights into the clinical of HCC. In this review, various PTMs, mainly including phosphorylation, glycosylation, acetylation, and methylation of proteins that had diagnostic and prognostic value for HCC were summarized (Fig. 1, Tables 1 and 235,37,39,40,44-50,54,57,59,60,64-70,72,74). Some PTMs had clinical value for the therapy of HCC. GPC3, as a member of the proteoglycan family, was a promising therapeutic target of HCC. A total of 33 GPC3-targeted CAR-T trials were registered at ClinicalTrials.gov (https://clinicaltrials.gov/ ) as of December 21, 2022. The initial safety of CAR-GPC3 T cell therapy has been demonstrated in phase I Trials.75 Phase II clinical trials for two GPC3-targeted therapies for HCC are presently underway. One patient with advanced HCC had complete tumor resolution 30 days after intratumoral injection of anti-GPC3-7 × 19 CAR-T (a CAR-T cell expressing IL7 and CCL19).76 Wu et al.77 constructed a mouse model to demonstrate the potential of sorafenib in combination with GPC3-targeted CAR-T cells for the treatment of HCC. Meanwhile, because of the shedding of GPC3 from the cell surface, the content of GPC3 in the serum of HCC patients is high. Sun et al.78 found that shed GPC3 competed with GPC3 on the cell membrane for CAR-T binding, thus contributing to immune escape of HCC cells. Further discussion on the clinical value of GPC3 in HCC can be found in r reecent views.29,30 Mucin 1 (MUC 1), as a tumor-associated antigen with high glycosylation, is highly expressed in HCC. Currently, a few promising clinical trials of immunotherapies targeting MUC 1 are ongoing.79 A phase I clinical trial of MUC1-targeting TILs/CAR-TILs cells treatment for HCC was initiated in 2021. In addition, some targets have clinical therapeutic potential, but have not yet entered the clinical trial stage. Animal studies have found that the interaction between phosphorylated p62 and Keap1 can inhibit tumor development, and thus inhibitors of this process have the potential to be used as therapeutic drugs for human HCC.80 Inhibition of NF-κBp65 phosphorylation might inhibit the occurrence of HCC, suggesting that NF-κBp65 phosphorylation as a new therapeutic target for HCC.81 In a study by Li et al.,82 computer-aided screening and inhibition assays were used to identify inhibitors of CD147 glycosylation, and finally, compound 72 (methyl 3′-(4-chlorophenyl)-4′,5′-dihydro-[3,5′-biisoxazole]-5-carboxylate), was the best candidate for CD147 inhibition, which provided new ideas for the design of CD147 glycosylation targeting drugs in HCC treatment.82

The mechanisms affecting tumor behavior by diagnostic and prognostic PTMs in HCC.
Fig. 1  The mechanisms affecting tumor behavior by diagnostic and prognostic PTMs in HCC.

PTM, post-translational modification; HCC, hepatocellular carcinoma.

Table 1

Diagnostic value of post-translational modification of proteins in hepatocellular carcinoma

ProteinModified typeNo. of sampleSensitivitySpecificityAUCReference
AFP-L3Glycosylation13050.0%97.5%–35
GP73Glycoprotein13066.0%96.2%–35
Fuc-GP73Fucosylation12477.4%83.9%0.8937
Fuc-GP73Fucosylation15082%95%0.88539
APOHGlycoprotein6290.1%–Combination of the three glycoproteins and AFP was 0.97840
ORM2Glycoprotein6294.5%–
C3Glycoprotein6294.4%–
AGPGlycosylation12293%86%0.9844
AGPSialylation and fucosylation259––Over than 0.945
Fuc-PON1Fucosylation18080%64.4%0.80346
A1ATFucosylation85370%86%0.87147
HpFucosylation9679%95%0.73348
HpGlycosylation at sites N184 and N247073%70%0.733, 0.77549
HpGlycosylation158–––50
C3, CE, HRG, CD14, HGFGlycoprotein7472%79%Combination of five proteins was 0.81154
AFP-L3%Glycoprotein2,44734%92%0.75557
AFP+GP73Glycoprotein28 articlesThe sum of sensitivity and specificity was 1.760.9359
AFP+GP73Glycoprotein40 articles––0.94360

AFP, Alpha-fetoprotein; AFP-L3, N-glycosylated isoform of AFP; AGP, α-1-acid glycoprotein; APOH: β-2-glycoprotein 1; AUROC, area under the curve of receiver operating characteristic; A1AT, Alpha-1-antitrypsin; CE, ceruloplasmin; C3, complement C3; Fuc-GP73, fucosylated GP73; Fuc-PON1, fucosylated paraoxonase 1; GP73, Golgi phosphoprotein 73; HCC, hepatocellular carcinoma; HGF, hepatocyte growth factor; Hp, haptoglobin; HRG, histidine-rich glycoprotein; ORM2, α-1-acid glycoprotein 2.

Table 2

Prognostic value of post-translational modification of proteins in hepatocellular carcinoma

ProteinModified typeNo. of sampleP values for OSHR(95%CI)Other significanceReference
P53Phosphorylation at Ser151990.0160.614 (0.418–0.902)Correlation with 5-year survival of patients (p=0.013)64
PCK1; INSIG1; INSIG2Phosphorylation at Ser90; Ser207; Ser151900.0064; 0.0069––65
ARPhosphorylation at Ser961400.0382.385 (1.162–4.893)Correlated with tumor size (p=0.045) and tumor pathological grade (p=0.028). An independent risk factors for OS in patients with HCC (p=0.018)66
4E-BP1Phosphorylation at Thr4620––Higher in patients with late recurrence than that in early recurrence67
AFPAcetylation at Lys194, 211, 242700.0007; 0.0004; 0.0002–Correlated with high T classification, high TNM classification, metastasis, and HBV infection68
Histone H2B Histone H3.3 Histone H4Acetylation at Lys120; Acetylation at Lys18; Acetylation at Lys7750.007; 0.029; 0.034–Poor differentiation (p=0.002). Microvascular invasion (p=0.031). Elevated alpha-fetoprotein (p=0.035), larger tumors (p=0.017) and microvascular invasion (p=0.047).69
Histone H3Methylation at Lys4168<0.00013.592 (2.302–5.605)An independent prognostic factor for poor OS (p < 0.001)70
M2BPGiGlycosylation2260.0111.858 (1.144–3.018)An independent predictor of PFS in patients undergoing TACE. An independent factor of OS and recurrence.72
C3Glycosylation at Asn85315C3-Man5 p=0.004; C3-Man6 p=0.007; C3-hybridp=0.0021.499 (1.030–2.183); 1.473 (0.998–2.174); 0.579 (0.371–0.902)C3-Man5 and C3-hybrid were independent factors for the recurrent HCC (p=0.046, 0.034)74

4E-BP1, 4E-binding protein 1; AFP, alpha-fetoprotein; AR, androgen receptor; CCA, cholangiocarcinoma; C3, complement C3; DFS, disease-free survival; HCC, hepatocellular carcinoma; IHC, immunohistochemistry; INSIG1, insulin induced gene 1; INSIG2, Insulin induced gene 2; M2BPGi, mac-2-binding protein glycosylation isomer; OS, overall survival; PCK1, phosphoenolpyruvate carboxykinase 1; PVTT, portal vein tumor thrombosis; TACE, transcatheter arterial chemoembolization.

In addition, many enzymes that regulate PTMs are promising targets for HCC treatment. Protein arginase methyltransferase 5 (PRMT5), a protein methyltransferase, had an important role in carcinogenesis. A novel PRMT5 inhibitor, DW14800, suppressed tumor growth in vitro and in vivo by promoting the transcription of HNF4α.83 Luo et al.84 found that another inhibitor of PRMT5, GSK3326595, increased the infiltration of immune cells in tumors of mouse models and improved therapeutic effects in HCC. In the treatment of cancer, drug resistance is a major problem. Therefore, improving the drug sensitivity of tumors is an important research direction. HDAC was found to deacetylate histones and to have an important role in chromosome structural modification and gene expression regulation. Bi et al.85 found that patients treated with sorafenib therapy with low levels of HDAC11 had an increased OS. In addition, various cytological and mouse experiments have demonstrated that HDAC11 could protect HCC cells from sorafenib-induced cytotoxicity, providing a new target for addressing sorafenib resistance during HCC treatment. 5-FU is a substrate of organic anion transporter 2 (OAT2). HDAC inhibitor SAHA reversed the histone deacetylation status of OAT2 and enhanced its interaction with 5-FU, thereby increasing the sensitivity of liver cancer cells to 5-FU.86 The ubiquitin-specific protease (USP)family is the largest class of deubiquitination enzymes and is related to a variety of signaling pathways in biological processes. USP7 inhibitor P22077 could inhibit tumor growth in nude mice.87 Ubiquitin-conjugating enzyme UBE2S was found to promote the development of HCC by accelerating the cell cycle. Zhang et al.88 demonstrated that the small-molecule cephalomannine attenuate the malignant progression of HCC by inhibiting the expression of UBE2S both in vitro and in vivo.

There are also some post-translational modification protein-targeting drugs in clinical trials in cancer types other than HCC. CD52 is an anchor glycoprotein mainly distributed on lymphocytes and lymphoid tumor cells. Anti-CD52 monoclonal antibodies (Campath and Lemtreda) have been approved for the treatment of chronic B-cell leukemias and multiple sclerosis in the USA and the European Union. CD47 is an important tumor antigen that is involved in the occurrence and development of various cancers. The anti-CD47 monoclonal antibody CC-90002 was investigated in a phase I study in patients with relapsed/refractory acute myeloid leukemia and high-risk myelodysplastic syndromes.89 SRF231, a fully human IgG4 anti-CD47 antibody, has completed phase I clinical trials in advanced solid and hematologic cancers (NCT03512340). Currently, there are a total of 32 CD70-targeting agents in clinical trials, mainly for renal cell carcinoma and hematological tumors. Although these targets were not reported in HCC, these therapeutics might also provide insight into HCC.

In addition to the PTMs described in this review, there are some modification types with certain clinical implications in HCC. S-nitrosylation of endothelial proteins may regulate angiogenesis, adhesion of tumor cells to the endothelium, intra- and extravasation of tumor cells, and contribute to metastasis.90 Khan et al.91 used anti-SNO-cysteine for immunoblotting and identified a novel and biologically relevant post-translational modification of CYB5A thiol only in HCC specimens. Two other nuclear envelope proteins, ATP synthase subunit beta (ATPB) and hemoglobin subunit beta (HBB) were found to be nitrosylated in HCC. S-nitrosylation of mitochondrial chaperone TRAP1 led to loss of S-nitrosoglutathione reductase (GSNOR) and increased succinate dehydrogenase (SDH) levels and activity. Thus, S-nitrosylation of mitochondrial chaperone TRAP1 enhanced the sensitivity of HCC cells to succinate dehydrogenase inhibitors.92 S-palmitoylation is is the attachment of fatty acids (lipidylation), such as palmitic acid, to cysteine of proteins. Oncoproteins such as RAS-family GTPases require palmitoylation to promote tumor formation.93 Sun et al.94 designed a peptide containing a mutant site to compete for S-palmitoylation of PCSK9 in vivo, and confirmed that the inhibitor enhanced the inhibitory effect of sorafenib on hepatoma cells by both in vivo and in vitro experiments.94 The data suggest that some uncommon PTMs may also have clinical significance in HCC.

Because of the diversity and dynamics of the immune system and the heterogeneity between and within tumors, to receive a sustained response for cancer therapy in all patients is challenging.95 Single-cell technologies, including single-cell proteomics, make it possible to assess the heterogeneity of tumor, microenvironmental cell type composition, and cell state transitions that influence therapeutic response.96 Krieg et al.97 determined subsets of immune cells in peripheral blood samples from patients with metastatic melanoma before and after 12 weeks of immunotherapy against PD-1 using high-dimensional single-cell mass cytometry. With this single-cell proteomic profiling, a class of monocyte was identified that was associated with better treatment response and patient survival prior to anti-PD-1 therapy. With the advancement of single-cell proteomics, the clinical value of single-cell PTM is achievable.

There have been many studies on post-translational modification of liver cancer, but there are still few biomarkers or drugs available for clinical use. It is important to identify novel PTM biomarkers of diagnosis or prognosis and to conduct clinical trials to test the clinical value of the present studies. Finding abnormal PTM of molecular targets in cancer and understanding the mechanisms of the modification after translation is helpful to reveal the process of tumor progression and provide novel target of therapy.

Abbreviations

AFP: 

alpha-fetoprotein

AFP-L3: 

N-glycosylated isoform of AFP

AGP: 

α-1-acid glycoprotein

APOH: 

β-2-glycoprotein 1

AR: 

androgen receptor

Asn: 

asparagine

ATPB: 

ATP synthase subunit beta

AUROC: 

area under the curve of receiver operating characteristic

A1AT: 

Alpha-1-antitrypsin

CCA: 

cholangiocarcinoma

CE: 

ceruloplasmin

C3: 

complement C3

DFS: 

disease-free survival

Fuc-GP73: 

fucosylated GP73

Fuc-PON1: 

fucosylated paraoxonase 1

GPC3: 

glypican-3

GP73: 

Golgi phosphoprotein 73

HAT: 

histone acetyltransferase

HBB: 

hemoglobin subunit beta

HBsAg: 

hepatitis B surface antigen

HBV: 

hepatitis B virus

HCC: 

hepatocellular carcinoma

HCV: 

hepatitis C virus

HDAC: 

histone deacetylase

HGF: 

hepatocyte growth factor

Hp: 

haptoglobin

HRG: 

histidine-rich glycoprotein

IHC: 

immunohistochemistry

MMP2: 

matrix metalloproteinase-2

MUC 1: 

mucin 1

M2BPGi: 

Mac-2-binding protein glycosylation isomer

NAFLD: 

Nonalcoholic fatty liver disease

ORM: 

orosomucoid

ORM2: 

α-1-acid glycoprotein 2

OS: 

overall survival

PCK1: 

phosphoenolpyruvate carboxykinase 1

PRMT5: 

protein arginase methyltransferase 5

PTM: 

post-translational modification

PVTT: 

Portal vein tumor thrombosis

SDH: 

succinate dehydrogenase

TACE: 

transcatheter arterial chemoembolization

TNFR1: 

tumor necrosis factor receptor 1

USP: 

ubiquitin-specific protease

4E-BP1: 

4E-Binding Protein 1

Declarations

Funding

This research was funded by National Natural Science Foundation of China (81772982), the Special Innovation Fund of Department of Education of Guangdong Province (2019KTSCX049), Discipline Construction Project of Guangdong Medical University (4SG23034G), and Talent Development Foundation of The First Dongguan Affiliated Hospital of Guangdong Medical University (PF100-2-03).

Conflict of interest

The authors have no conflict of interests related to this publication.

Authors’ contributions

Writing of the manuscript (JW), revision of the manuscript (FFW, NW and MYZ), and developing the idea for the article and critically reviewing it (HYW and GLH). All authors read and approved the final version of the manuscript.

References

  1. El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 2007;132(7):2557-2576 View Article PubMed/NCBI
  2. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 2021;71(3):209-249 View Article PubMed/NCBI
  3. Jia L, Gao Y, He Y, Hooper JD, Yang P. HBV induced hepatocellular carcinoma and related potential immunotherapy. Pharmacol Res 2020;159:104992 View Article PubMed/NCBI
  4. Razavi H. Global Epidemiology of Viral Hepatitis. Gastroenterol Clin North Am 2020;49(2):179-189 View Article PubMed/NCBI
  5. Marengo A, Rosso C, Bugianesi E. Liver Cancer: Connections with Obesity, Fatty Liver, and Cirrhosis. Annu Rev Med 2016;67:103-117 View Article PubMed/NCBI
  6. Shiani A, Narayanan S, Pena L, Friedman M. The Role of Diagnosis and Treatment of Underlying Liver Disease for the Prognosis of Primary Liver Cancer. Cancer Control 2017;24(3):1073274817729240 View Article PubMed/NCBI
  7. Vogel A, Cervantes A, Chau I, Daniele B, Llovet JM, Meyer T, et al. Hepatocellular carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2018;29(Suppl 4):iv238-iv255 View Article PubMed/NCBI
  8. Zheng Y, Wang S, Cai J, Ke A, Fan J. The progress of immune checkpoint therapy in primary liver cancer. Biochim Biophys Acta Rev Cancer 2021;1876(2):188638 View Article PubMed/NCBI
  9. Vogel A, Saborowski A. Medical therapy of HCC. J Hepatol 2022;76(1):208-210 View Article PubMed/NCBI
  10. Dikilitas M. Why Adjuvant and Neoadjuvant Therapy Failed in HCC. Can the New Immunotherapy Be Expected to Be Better?. J Gastrointest Cancer 2020;51(4):1193-1196 View Article PubMed/NCBI
  11. Song L, Luo ZQ. Post-translational regulation of ubiquitin signaling. J Cell Biol 2019;218(6):1776-1786 View Article PubMed/NCBI
  12. Brackett CM, Blagg BSJ. Current Status of SUMOylation Inhibitors. Curr Med Chem 2021;28(20):3892-3912 View Article PubMed/NCBI
  13. Barrett PJ, Timothy Greenamyre J. Post-translational modification of α-synuclein in Parkinson’s disease. Brain Res 2015;1628(Pt B):247-253 View Article PubMed/NCBI
  14. Brunmeir R, Xu F. Functional Regulation of PPARs through Post-Translational Modifications. Int J Mol Sci 2018;19(6):1738 View Article PubMed/NCBI
  15. Liu J, Qian C, Cao X. Post-Translational Modification Control of Innate Immunity. Immunity 2016;45(1):15-30 View Article PubMed/NCBI
  16. Drazic A, Myklebust LM, Ree R, Arnesen T. The world of protein acetylation. Biochim Biophys Acta 2016;1864(10):1372-1401 View Article PubMed/NCBI
  17. Schjoldager KT, Narimatsu Y, Joshi HJ, Clausen H. Global view of human protein glycosylation pathways and functions. Nat Rev Mol Cell Biol 2020;21(12):729-749 View Article PubMed/NCBI
  18. Humphrey SJ, James DE, Mann M. Protein Phosphorylation: A Major Switch Mechanism for Metabolic Regulation. Trends Endocrinol Metab 2015;26(12):676-687 View Article PubMed/NCBI
  19. Wong TH, Dickson FH, Timmins LR, Nabi IR. Tyrosine phosphorylation of tumor cell caveolin-1: impact on cancer progression. Cancer Metastasis Rev 2020;39(2):455-469 View Article PubMed/NCBI
  20. Rajan PK, Udoh UA, Sanabria JD, Banerjee M, Smith G, Schade MS, et al. The Role of Histone Acetylation-/Methylation-Mediated Apoptotic Gene Regulation in Hepatocellular Carcinoma. Int J Mol Sci 2020;21(23):8894 View Article PubMed/NCBI
  21. Ropero S, Esteller M. The role of histone deacetylases (HDACs) in human cancer. Mol Oncol 2007;1(1):19-25 View Article PubMed/NCBI
  22. Clerc F, Reiding KR, Jansen BC, Kammeijer GS, Bondt A, Wuhrer M. Human plasma protein N-glycosylation. Glycoconj J 2016;33(3):309-343 View Article PubMed/NCBI
  23. Ben-Dor S, Esterman N, Rubin E, Sharon N. Biases and complex patterns in the residues flanking protein N-glycosylation sites. Glycobiology 2004;14(2):95-101 View Article PubMed/NCBI
  24. Yang S, Onigman P, Wu WW, Sjogren J, Nyhlen H, Shen RF, et al. Deciphering Protein O-Glycosylation: Solid-Phase Chemoenzymatic Cleavage and Enrichment. Anal Chem 2018;90(13):8261-8269 View Article PubMed/NCBI
  25. Reig M, Forner A, Rimola J, Ferrer-Fàbrega J, Burrel M, Garcia-Criado Á, et al. BCLC strategy for prognosis prediction and treatment recommendation: The 2022 update. J Hepatol 2022;76(3):681-693 View Article PubMed/NCBI
  26. Hanif H, Ali MJ, Susheela AT, Khan IW, Luna-Cuadros MA, Khan MM, et al. Update on the applications and limitations of alpha-fetoprotein for hepatocellular carcinoma. World J Gastroenterol 2022;28(2):216-229 View Article PubMed/NCBI
  27. Turshudzhyan A, Wu GY. Persistently Rising Alpha-fetoprotein in the Diagnosis of Hepatocellular Carcinoma: A Review. J Clin Transl Hepatol 2022;10(1):159-163 View Article PubMed/NCBI
  28. Hu X, Chen R, Wei Q, Xu X. The Landscape Of Alpha Fetoprotein In Hepatocellular Carcinoma: Where Are We?. Int J Biol Sci 2022;18(2):536-551 View Article PubMed/NCBI
  29. Zhou F, Shang W, Yu X, Tian J. Glypican-3: A promising biomarker for hepatocellular carcinoma diagnosis and treatment. Med Res Rev 2018;38(2):741-767 View Article PubMed/NCBI
  30. Haruyama Y, Kataoka H. Glypican-3 is a prognostic factor and an immunotherapeutic target in hepatocellular carcinoma. World J Gastroenterol 2016;22(1):275-283 View Article PubMed/NCBI
  31. Filmus J, Capurro M. Glypican-3: a marker and a therapeutic target in hepatocellular carcinoma. FEBS J 2013;280(10):2471-2476 View Article PubMed/NCBI
  32. Allegretta M, Filmus J. Therapeutic potential of targeting glypican-3 in hepatocellular carcinoma. Anticancer Agents Med Chem 2011;11(6):543-548 View Article PubMed/NCBI
  33. Wang T, Zhang KH. New Blood Biomarkers for the Diagnosis of AFP-Negative Hepatocellular Carcinoma. Front Oncol 2020;10:1316 View Article PubMed/NCBI
  34. Luo P, Wu S, Yu Y, Ming X, Li S, Zuo X, et al. Current Status and Perspective Biomarkers in AFP Negative HCC: Towards Screening for and Diagnosing Hepatocellular Carcinoma at an Earlier Stage. Pathol Oncol Res 2020;26(2):599-603 View Article PubMed/NCBI
  35. Zhang Z, Zhang Y, Wang Y, Xu L, Xu W. Alpha-fetoprotein-L3 and Golgi protein 73 may serve as candidate biomarkers for diagnosing alpha-fetoprotein-negative hepatocellular carcinoma. Onco Targets Ther 2016;9:123-129 View Article PubMed/NCBI
  36. Ahn KS, O’Brien DR, Kim YH, Kim TS, Yamada H, Park JW, et al. Associations of Serum Tumor Biomarkers with Integrated Genomic and Clinical Characteristics of Hepatocellular Carcinoma. Liver Cancer 2021;10(6):593-605 View Article PubMed/NCBI
  37. Hu JS, Wu DW, Liang S, Miao XY. GP73, a resident Golgi glycoprotein, is sensibility and specificity for hepatocellular carcinoma of diagnosis in a hepatitis B-endemic Asian population. Med Oncol 2010;27(2):339-345 View Article PubMed/NCBI
  38. Liu Y, Zhang X, Zhou S, Shi J, Xu Y, He J, et al. Knockdown of Golgi phosphoprotein 73 blocks the trafficking of matrix metalloproteinase-2 in hepatocellular carcinoma cells and inhibits cell invasion. J Cell Mol Med 2019;23(4):2399-2409 View Article PubMed/NCBI
  39. Zhao Y, Zhang L, Huo L, Pei L, Li Q, Li H, et al. Clinical significance of fucosylated GP73 in the differential diagnosis of hepatocellular carcinoma. Int J Biol Markers 2018;33(4):439-446 View Article PubMed/NCBI
  40. Cao WQ, Jiang BY, Huang JM, Zhang L, Liu MQ, Yao J, et al. Straightforward and Highly Efficient Strategy for Hepatocellular Carcinoma Glycoprotein Biomarker Discovery Using a Nonglycopeptide-Based Mass Spectrometry Pipeline. Anal Chem 2019;91(19):12435-12443 View Article PubMed/NCBI
  41. Jing X, Tian Z, Gao P, Xiao H, Qi X, Yu Y, et al. HBsAg/β2GPI activates the NF-κB pathway via the TLR4/MyD88/IκBα axis in hepatocellular carcinoma. Oncol Rep 2018;40(2):1035-1045 View Article PubMed/NCBI
  42. Fang T, Cui M, Sun J, Ge C, Zhao F, Zhang L, et al. Orosomucoid 2 inhibits tumor metastasis and is upregulated by CCAAT/enhancer binding protein β in hepatocellular carcinomas. Oncotarget 2015;6(18):16106-16119 View Article PubMed/NCBI
  43. Wang N, Tan HY, Lu Y, Chan YT, Wang D, Guo W, et al. PIWIL1 governs the crosstalk of cancer cell metabolism and immunosuppressive microenvironment in hepatocellular carcinoma. Signal Transduct Target Ther 2021;6(1):86 View Article PubMed/NCBI
  44. Tanabe K, Kitagawa K, Kojima N, Iijima S. Multifucosylated Alpha-1-acid Glycoprotein as a Novel Marker for Hepatocellular Carcinoma. J Proteome Res 2016;15(9):2935-2944 View Article PubMed/NCBI
  45. Zhang D, Huang J, Luo D, Feng X, Liu Y, Liu Y. Glycosylation change of alpha-1-acid glycoprotein as a serum biomarker for hepatocellular carcinoma and cirrhosis. Biomark Med 2017;11(5):423-430 View Article PubMed/NCBI
  46. Zhang S, Jiang K, Zhang Q, Guo K, Liu Y. Serum fucosylated paraoxonase 1 as a potential glycobiomarker for clinical diagnosis of early hepatocellular carcinoma using ELISA Index. Glycoconj J 2015;32(3-4):119-125 View Article PubMed/NCBI
  47. Comunale MA, Rodemich-Betesh L, Hafner J, Wang M, Norton P, Di Bisceglie AM, et al. Linkage specific fucosylation of alpha-1-antitrypsin in liver cirrhosis and cancer patients: implications for a biomarker of hepatocellular carcinoma. PLoS One 2010;5(8):e12419 View Article PubMed/NCBI
  48. Ang IL, Poon TC, Lai PB, Chan AT, Ngai SM, Hui AY, et al. Study of serum haptoglobin and its glycoforms in the diagnosis of hepatocellular carcinoma: a glycoproteomic approach. J Proteome Res 2006;5(10):2691-2700 View Article PubMed/NCBI
  49. Zhu J, Huang J, Zhang J, Chen Z, Lin Y, Grigorean G, et al. Glycopeptide Biomarkers in Serum Haptoglobin for Hepatocellular Carcinoma Detection in Patients with Nonalcoholic Steatohepatitis. J Proteome Res 2020;19(8):3452-3466 View Article PubMed/NCBI
  50. Shu H, Zhang L, Chen Y, Guo Y, Li L, Chen F, et al. Quantification of Intact O-Glycopeptides on Haptoglobin in Sera of Patients With Hepatocellular Carcinoma and Liver Cirrhosis. Front Chem 2021;9:705341 View Article PubMed/NCBI
  51. Shang Y, Luo M, Yao F, Wang S, Yuan Z, Yang Y. Ceruloplasmin suppresses ferroptosis by regulating iron homeostasis in hepatocellular carcinoma cells. Cell Signal 2020;72:109633 View Article PubMed/NCBI
  52. Zou X, Zhang D, Song Y, Liu S, Long Q, Yao L, et al. HRG switches TNFR1-mediated cell survival to apoptosis in Hepatocellular Carcinoma. Theranostics 2020;10(23):10434-10447 View Article PubMed/NCBI
  53. Zhang Q, Jiang K, Li Y, Gao D, Sun L, Zhang S, et al. Histidine-rich glycoprotein function in hepatocellular carcinoma depends on its N-glycosylation status, and it regulates cell proliferation by inhibiting Erk1/2 phosphorylation. Oncotarget 2015;6(30):30222-30231 View Article PubMed/NCBI
  54. Liu Y, He J, Li C, Benitez R, Fu S, Marrero J, et al. Identification and confirmation of biomarkers using an integrated platform for quantitative analysis of glycoproteins and their glycosylations. J Proteome Res 2010;9(2):798-805 View Article PubMed/NCBI
  55. Marrero JA, Feng Z, Wang Y, Nguyen MH, Befeler AS, Roberts LR, et al. Alpha-fetoprotein, des-gamma carboxyprothrombin, and lectin-bound alpha-fetoprotein in early hepatocellular carcinoma. Gastroenterology 2009;137(1):110-118 View Article PubMed/NCBI
  56. Leerapun A, Suravarapu SV, Bida JP, Clark RJ, Sanders EL, Mettler TA, et al. The utility of Lens culinaris agglutinin-reactive alpha-fetoprotein in the diagnosis of hepatocellular carcinoma: evaluation in a United States referral population. Clin Gastroenterol Hepatol 2007;5(3):394-402 View Article PubMed/NCBI
  57. Zhou JM, Wang T, Zhang KH. AFP-L3 for the diagnosis of early hepatocellular carcinoma: A meta-analysis. Medicine (Baltimore) 2021;100(43):e27673 View Article PubMed/NCBI
  58. Tayob N, Kanwal F, Alsarraj A, Hernaez R, El-Serag HB. The Performance of AFP, AFP-3, DCP as Biomarkers for Detection of Hepatocellular Carcinoma (HCC): A Phase 3 Biomarker Study in the United States. Clin Gastroenterol Hepatol 2023;21(2):415-423.e4 View Article PubMed/NCBI
  59. Fang YS, Wu Q, Zhao HC, Zhou Y, Ye L, Liu SS, et al. Do combined assays of serum AFP, AFP-L3, DCP, GP73, and DKK-1 efficiently improve the clinical values of biomarkers in decision-making for hepatocellular carcinoma? A meta-analysis. Expert Rev Gastroenterol Hepatol 2021;15(9):1065-1076 View Article PubMed/NCBI
  60. Hu B, Tian X, Sun J, Meng X. Evaluation of individual and combined applications of serum biomarkers for diagnosis of hepatocellular carcinoma: a meta-analysis. Int J Mol Sci 2013;14(12):23559-23580 View Article PubMed/NCBI
  61. Bachtiar I, Santoso JM, Atmanegara B, Gani RA, Hasan I, Lesmana LA, et al. Combination of alpha-1-acid glycoprotein and alpha-fetoprotein as an improved diagnostic tool for hepatocellular carcinoma. Clin Chim Acta 2009;399(1-2):97-101 View Article PubMed/NCBI
  62. Yuan Y, Cao W, Zhou H, Qian H, Wang H. H2A.Z acetylation by lincZNF337-AS1 via KAT5 implicated in the transcriptional misregulation in cancer signaling pathway in hepatocellular carcinoma. Cell Death Dis 2021;12(6):609 View Article PubMed/NCBI
  63. Gao Q, Zhu H, Dong L, Shi W, Chen R, Song Z, et al. Integrated Proteogenomic Characterization of HBV-Related Hepatocellular Carcinoma. Cell 2019;179(2):561-577.e22 View Article PubMed/NCBI
  64. Yang T, Choi Y, Joh JW, Cho SK, Kim DS, Park SG. Phosphorylation of p53 Serine 15 Is a Predictor of Survival for Patients with Hepatocellular Carcinoma. Can J Gastroenterol Hepatol 2019;2019:9015453 View Article PubMed/NCBI
  65. Xu D, Wang Z, Xia Y, Shao F, Xia W, Wei Y, et al. The gluconeogenic enzyme PCK1 phosphorylates INSIG1/2 for lipogenesis. Nature 2020;580(7804):530-535 View Article PubMed/NCBI
  66. Ren QN, Zhang H, Sun CY, Zhou YF, Yang XF, Long JW, et al. Phosphorylation of androgen receptor by mTORC1 promotes liver steatosis and tumorigenesis. Hepatology 2022;75(5):1123-1138 View Article PubMed/NCBI
  67. Lin X, Huang Y, Sun Y, Tan X, Ouyang J, Zhao B, et al. 4E-BP1(Thr46) Phosphorylation Association with Poor Prognosis in Quantitative Phosphoproteomics of Portal Vein Tumor Thrombus Revealed that 4E-BP1Thr46 Phosphorylation is Associated with Poor Prognosis in HCC. Cancer Manag Res 2020;12:103-115 View Article PubMed/NCBI
  68. Xue J, Cao Z, Cheng Y, Wang J, Liu Y, Yang R, et al. Acetylation of alpha-fetoprotein promotes hepatocellular carcinoma progression. Cancer Lett 2020;471:12-26 View Article PubMed/NCBI
  69. Chai X, Guo J, Dong R, Yang X, Deng C, Wei C, et al. Quantitative acetylome analysis reveals histone modifications that may predict prognosis in hepatitis B-related hepatocellular carcinoma. Clin Transl Med 2021;11(3):e313 View Article PubMed/NCBI
  70. He C, Xu J, Zhang J, Xie D, Ye H, Xiao Z, et al. High expression of trimethylated histone H3 lysine 4 is associated with poor prognosis in hepatocellular carcinoma. Hum Pathol 2012;43(9):1425-1435 View Article PubMed/NCBI
  71. Dolgormaa G, Harimoto N, Ishii N, Yamanaka T, Hagiwara K, Tsukagoshi M, et al. Mac-2-binding protein glycan isomer enhances the aggressiveness of hepatocellular carcinoma by activating mTOR signaling. Br J Cancer 2020;123(7):1145-1153 View Article PubMed/NCBI
  72. Tak KY, Jang B, Lee SK, Nam HC, Sung PS, Bae SH, et al. Use of M2BPGi in HCC patients with TACE. J Gastroenterol Hepatol 2021;36(10):2917-2924 View Article PubMed/NCBI
  73. Kadalayil L, Benini R, Pallan L, O’Beirne J, Marelli L, Yu D, et al. A simple prognostic scoring system for patients receiving transarterial embolisation for hepatocellular cancer. Ann Oncol 2013;24(10):2565-2570 View Article PubMed/NCBI
  74. Chang TT, Cheng JH, Tsai HW, Young KC, Hsieh SY, Ho CH. Plasma proteome plus site-specific N-glycoprofiling for hepatobiliary carcinomas. J Pathol Clin Res 2019;5(3):199-212 View Article PubMed/NCBI
  75. Shi D, Shi Y, Kaseb AO, Qi X, Zhang Y, Chi J, et al. Chimeric Antigen Receptor-Glypican-3 T-Cell Therapy for Advanced Hepatocellular Carcinoma: Results of Phase I Trials. Clin Cancer Res 2020;26(15):3979-3989 View Article PubMed/NCBI
  76. Pang N, Shi J, Qin L, Chen A, Tang Y, Yang H, et al. IL-7 and CCL19-secreting CAR-T cell therapy for tumors with positive glypican-3 or mesothelin. J Hematol Oncol 2021;14(1):118 View Article PubMed/NCBI
  77. Wu X, Luo H, Shi B, Di S, Sun R, Su J, et al. Combined Antitumor Effects of Sorafenib and GPC3-CAR T Cells in Mouse Models of Hepatocellular Carcinoma. Mol Ther 2019;27(8):1483-1494 View Article PubMed/NCBI
  78. Sun L, Gao F, Gao Z, Ao L, Li N, Ma S, et al. Shed antigen-induced blocking effect on CAR-T cells targeting Glypican-3 in Hepatocellular Carcinoma. J Immunother Cancer 2021;9(4):e001875 View Article PubMed/NCBI
  79. Kumar AR, Devan AR, Nair B, Nair RR, Nath LR. Biology, Significance and Immune Signaling of Mucin 1 in Hepatocellular Carcinoma. Curr Cancer Drug Targets 2022;22(9):725-740 View Article PubMed/NCBI
  80. Ichimura Y, Waguri S, Sou YS, Kageyama S, Hasegawa J, Ishimura R, et al. Phosphorylation of p62 activates the Keap1-Nrf2 pathway during selective autophagy. Mol Cell 2013;51(5):618-631 View Article PubMed/NCBI
  81. Xu X, Lei Y, Chen L, Zhou H, Liu H, Jiang J, et al. Phosphorylation of NF-κBp65 drives inflammation-mediated hepatocellular carcinogenesis and is a novel therapeutic target. J Exp Clin Cancer Res 2021;40(1):253 View Article PubMed/NCBI
  82. Li W, Wang D, Ge Y, Zhang L, Wu J, Liu D. Discovery and Biological Evaluation of CD147 N-Glycan Inhibitors: A New Direction in the Treatment of Tumor Metastasis. Molecules 2020;26(1):33 View Article PubMed/NCBI
  83. Zheng BN, Ding CH, Chen SJ, Zhu K, Shao J, Feng J, et al. Targeting PRMT5 Activity Inhibits the Malignancy of Hepatocellular Carcinoma by Promoting the Transcription of HNF4α. Theranostics 2019;9(9):2606-2617 View Article PubMed/NCBI
  84. Luo Y, Gao Y, Liu W, Yang Y, Jiang J, Wang Y, et al. Myelocytomatosis-Protein Arginine N-Methyltransferase 5 Axis Defines the Tumorigenesis and Immune Response in Hepatocellular Carcinoma. Hepatology 2021;74(4):1932-1951 View Article PubMed/NCBI
  85. Bi L, Ren Y, Feng M, Meng P, Wang Q, Chen W, et al. HDAC11 Regulates Glycolysis through the LKB1/AMPK Signaling Pathway to Maintain Hepatocellular Carcinoma Stemness. Cancer Res 2021;81(8):2015-2028 View Article PubMed/NCBI
  86. Wang Y, Zhu Q, Hu H, Zhu H, Yang B, He Q, et al. Upregulation of histone acetylation reverses organic anion transporter 2 repression and enhances 5-fluorouracil sensitivity in hepatocellular carcinoma. Biochem Pharmacol 2021;188:114546 View Article PubMed/NCBI
  87. Zhang W, Zhang J, Xu C, Zhang S, Bian S, Jiang F, et al. Ubiquitin-specific protease 7 is a drug-able target that promotes hepatocellular carcinoma and chemoresistance. Cancer Cell Int 2020;20:28 View Article PubMed/NCBI
  88. Zhang RY, Liu ZK, Wei D, Yong YL, Lin P, Li H, et al. UBE2S interacting with TRIM28 in the nucleus accelerates cell cycle by ubiquitination of p27 to promote hepatocellular carcinoma development. Signal Transduct Target Ther 2021;6(1):64 View Article PubMed/NCBI
  89. Zeidan AM, DeAngelo DJ, Palmer J, Seet CS, Tallman MS, Wei X, et al. Phase 1 study of anti-CD47 monoclonal antibody CC-90002 in patients with relapsed/refractory acute myeloid leukemia and high-risk myelodysplastic syndromes. Ann Hematol 2022;101(3):557-569 View Article PubMed/NCBI
  90. Sharma V, Fernando V, Letson J, Walia Y, Zheng X, Fackelman D, et al. S-Nitrosylation in Tumor Microenvironment. Int J Mol Sci 2021;22(9):4600 View Article PubMed/NCBI
  91. Khan R, Zahid S, Wan YJ, Forster J, Karim AB, Nawabi AM, et al. Protein expression profiling of nuclear membrane protein reveals potential biomarker of human hepatocellular carcinoma. Clin Proteomics 2013;10(1):6 View Article PubMed/NCBI
  92. Rizza S, Montagna C, Cardaci S, Maiani E, Di Giacomo G, Sanchez-Quiles V, et al. S-nitrosylation of the Mitochondrial Chaperone TRAP1 Sensitizes Hepatocellular Carcinoma Cells to Inhibitors of Succinate Dehydrogenase. Cancer Res 2016;76(14):4170-4182 View Article PubMed/NCBI
  93. Ko PJ, Dixon SJ. Protein palmitoylation and cancer. EMBO Rep 2018;19(10):e46666 View Article PubMed/NCBI
  94. Sun Y, Zhang H, Meng J, Guo F, Ren D, Wu H, et al. S-palmitoylation of PCSK9 induces sorafenib resistance in liver cancer by activating the PI3K/AKT pathway. Cell Rep 2022;40(7):111194 View Article PubMed/NCBI
  95. Li L, Yan S, Lin B, Shi Q, Lu Y. Single-Cell Proteomics for Cancer Immunotherapy. Adv Cancer Res 2018;139:185-207 View Article PubMed/NCBI
  96. Davis-Marcisak EF, Deshpande A, Stein-O’Brien GL, Ho WJ, Laheru D, Jaffee EM, et al. From bench to bedside: Single-cell analysis for cancer immunotherapy. Cancer Cell 2021;39(8):1062-1080 View Article PubMed/NCBI
  97. Krieg C, Nowicka M, Guglietta S, Schindler S, Hartmann FJ, Weber LM, et al. High-dimensional single-cell analysis predicts response to anti-PD-1 immunotherapy. Nat Med 2018;24(2):144-153 View Article PubMed/NCBI
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  • Journal of Clinical and Translational Hepatology
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Diagnostic and Prognostic Value of Protein Post-translational Modifications in Hepatocellular Carcinoma

Jing Wang, Fangfang Wang, Ning Wang, Mei-Yin Zhang, Hui-Yun Wang, Guo-Liang Huang
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