Table 8. Summary of proteomic studies that were reviewed.
| Protein (key role) | UniProt ID | Biofluid | Relation to HCC (↑, ↓) | HCC LB rate | Cohort sizes | Aetiology | AUROC | Fold change | Platform | Reference |
|---|---|---|---|---|---|---|---|---|---|---|
| AGP1 (AP: Transport) | P02763 | Plasma | ↑ HCC:CON | No information | *10 HCC; 30 controls (healthy/LC/HBV) | HBV | 0.73 | 1.6* | Lectin MRM–UPLC–ESI–MS | Ahn et al, 2012a, 2012b* |
| Plasma | ↓ HCC:LC | No information | Disc: 10 HCC/2 HCON Val: 18 HCC, 10 HCON | No information | 0.65 | — | nUPLC–ESI–QTOF–MS and QQQ | Lee et al, 2011 | ||
| Serum | ↑ HCC:LC | 100% ALL | Disc: 9 HCC/9 LC Val: 52 HCC/40 LC | HBV | — | 1.8† | ICAT–LC–ESI–MS/MS | Kang et al, 2010 | ||
| A1AT (AP: Protease inhibitor) | P01009 | Plasma | ↑ HCC:CON | Disc 24.2% Val 4.8% | Disc: 120 HCC, 99 LC, 120 HCON Val: 21 HCC, 6 LC, 18 ASC, 10 HCON | HBV/aflatoxin | 0.84 | — | QTOF–LC–MS, ELISA | Fye et al, 2013 |
| Plasma | ↑ HCC:CON | No information | *10 HCC; 30 controls (healthy/LC/HBV) | HBV | 0.92 | 2.4** | Lectin MRM–UPLC–ESI–MS | Ahn et al, 2012a, 2012b* | ||
| Serum | ↑ HCC:CON | No information | Disc: 20 HCC, 20 HBV, 20 HCON Val: 20 HCC, 20 HBV, 20 HCON | HBV | — | — | MALDI–TOF–MS/MS, 2DE | Feng et al, 2005 | ||
| A2M (Protease inhibitor) | P01023 | Plasma | ↑ HCC:CON | Disc 24.2% Val 4.8% | Disc: 120 HCC, 99 LC, 120 HCON Val: 21 HCC, 6 LC, 18 ASC, 10 HCON | HBV/aflatoxin | — | 1.13* | QTOF–nUPLC–ESI–MS | Fye et al, 2013 |
| Serum | ↓ HCC:LC | 100% of HCCs | Disc: 9 HCC/9 LC Val: 52 HCC/40 LC | HBV | — | 0.26† | ICAT–LC–ESI–MS/MS | Kang et al, 2010 | ||
| AACT (AP: Protease inhibitor) | P01011 | Plasma | ↑ HCC:CON | No information | *10 HCC; 30 controls (healthy/LC/HBV) | HBV | 0.93 | 3.7** | Lectin MRM–UPLC–ESI–MS | Ahn et al, 2012a, 2012b* |
| Plasma | ↑ HCC:CON | No information | 6 HCC, 3 HCON | No information | — | 5.3* | 2D LC–MALDI–TOF/TOF | Ishihara et al, 2011 | ||
| AFM (Vitamin transport) | P43652 | Plasma | ↑ HCC:CON | No information | 6 HCC, 3 HCON | No information | — | 33.1† | 2D LC–MALDI–TOF/TOF | Ishihara et al, 2011 |
| Plasma | ↓ HCC:CON | No information | 28 HCC, 10 HCON | No information | 0.72 | — | nUPLC–ESI–QTOF–MS and QQQ | Lee et al, 2011 | ||
|
Apolipoproteins | ||||||||||
| Apo A1 (Cholesterol metabolism) | P02647 | Plasma | ↓ HCC:CON | Disc 24.2% Val 4.8% | Disc: 120 HCC, 99 LC, 120 HCON Val: 21 HCC, 6 LC, 18 ASC, 10 HCON | HBV/aflatoxin | 0.83 | — | QTOF–nUPLC–ESI–MS | Fye et al, 2013 |
| Serum | ↓ HCC:CON | 100% of HCCs | 20 HCC, 20 HCON | No information | — | −3.59* | 2DE-coupled MALDI–TOF–MS | Sun et al, 2010b | ||
| Serum | ↓ HCC:CON | 100% of HCCs | 8 HCC, 21 HBV, 7 HCON | HBV | — | −3.10† | 2DE-coupled MALDI–TOF–MS | Steel et al, 2003 | ||
| Apo B-100 (Cholesterol metabolism) | P04114 | Plasma | ↓ HCC:CON | No information | 6 HCC, 3 HCON | No information | — | −3.7* | 2D LC–MALDI–TOF/TOF | Ishihara et al, 2011 |
| Apo L1 (Cholesterol metabolism) | O14791 | Plasma | ↓ HCC:CON | No information | *10 HCC; 30 controls (healthy/LC/HBV) | HBV | 0.68 | 0.5ns | Lectin MRM–UPLC–ESI–MS | Ahn et al, 2012a, 2012b* |
| B2M (Immunity) | P61769 | Plasma | ↑ HCC:CON | No information | 6 HCC, 16 LC/HBV/HCV, 8 HCON | HCV/HBV | — | — | SELDI–TOF–MS | Nakatsura, 2010 |
| Serum | ↑HCC:pre-HCC | Some Histo. % not stated | 38 Pre-HCC; 35 samples upon clinical diagnosis of HCC; 18 samples post treatment (longitudinal collection) | HCV | — | 1.82** | SELDI–TOF–MS | Ward et al, 2006 | ||
| C4B-α (Complement pathway) | P04003 | Plasma | ↑ HCC:CON | Disc 24.2% Val 4.8% | Disc: 120 HCC, 99 LC, 120 HCON Val: 21 HCC, 6 LC, 18 ASC, 10 HCON | HBV/aflatoxin | — | 1.25ns | QTOF–nUPLC–ESI–MS | Fye et al, 2013 |
| ↑ HCC:CON | No information | *10 HCC; 30 HCON/LC/HBV | HBV | 0.66 | 1.3ns | Lectin MRM–UPLC–ESI–MS | Ahn et al, 2012a, 2012b* | |||
| CC3 (Complement pathway) | P01024 | Plasma | ↑ HCC:CON | No information | 10 HCC; 30 HCON/LC/HBV | HBV | 0.67 | 2.0ns | Lectin MRM–ESI–UPLC–MS | Ahn et al, 2012b |
| Plasma | ↑ HCC:LC | Disc 24.2% Val 4.8% | Disc: 120 HCC, 99 LC, 120 HCON Val: 21 HCC, 6 LC, 18 ASC, 10 HCON | HBV/aflatoxin | 0.70 | — | QTOF–nUPLC–ESI–MS, ELISA | Fye et al, 2013 | ||
| Serum | ↓ HCC:CON | 100% of HCCs | 8 HCC, 21 HBV, 7 HCON | HBV | — | −1.87** | 2DE-coupled MALDI–TOF–MS | Steel et al, 2003 | ||
| CC3-α | Serum | ↑HCC:CLD/CON | No LBs done | 45 HCC, 42 CLD, 21 HCON | HCV | 0.70 | — | SELDI–TOF–MS | Kanmura et al, 2010 | |
| ↑HCC:CLD/CON | No information | 28 HCC, 10 HCON | HCV | — | n/r but P of Δ 0.00001 | SELDI–TOF–MS, WB | Lee et al, 2006 | |||
| CERU (Cu/ion transport) | P00450 | Plasma | ↑ HCC:CON | No information | 10 HCC; 30 HCON/LC/HBV) | HBV | 0.77 | 1.5** | Lectin MRM–UPLC–ESI–MS | Ahn et al, 2012b |
| Plasma | ↑ HCC:CON | No information | 6 HCC, 3 HCON | No information | — | 6.8† | 2D LC–MALDI–TOF/TOF | Ishihara et al, 2011 | ||
| Serum | HCC only | 100% of HCCs | 5 HCC, 5 HCON | HCV/HBV | — | — | nanoHPLC–ESI–MS/MS | Yang et al, 2007a | ||
| Serum | ↑ HCC:CON | No information | Disc: 20 HCC, 20 HBV, 20 HCON Val: 20 HCC, 20 HBV, 20 HCON | HBV | — | — | 2DE and MALDI–TOF–MS/MS | Feng et al, 2005 | ||
| CLU (apoptosis/complement pathway) | P10909 | Plasma/serum | ↓ HCC:CON | No information | No information | No information | — | — | SID–MRM–MS | Zhao et al, 2010 |
| Plasma | ↓ HCC:CON | Disc 24.2% Val 4.8% | Disc: 120 HCC, 99 LC, 120 HCON Val: 21 HCC, 6 LC, 18 ASC, 10 HCON | HBV/aflatoxin | — | 0.59* | QTOF–nUPLC–ESI–MS | Fye et al, 2013 | ||
| Plasma | ↓ HCC:CON | No information | 10 HCC; 30 HCON/LC/HBV | HBV | 0.70 | 0.8ns | Lectin MRM–UPLC–ESI–MS | Ahn et al, 2012a, 2012b | ||
| Serum | ↑ HCC:CON | No information | Disc: 20 HCC, 20 HBV, 20 HCON Val: 20 HCC, 20 HBV, 20 HCON | HBV | — | — | 2DE and MALDI–TOF–MS/MS | Feng et al, 2005 | ||
| ERBB3 (Signalling pathway) | P21860 | Serum | ↑HCC:LC/CON | Disc and Val 1–100% Val 2; Unclear | Disc: 10 total, HCC and non-HCC Val 1: 113 HCC, 47 LC, 64 HBV/HCV Val 2: 57 HCC, 35 HBV/HCV | HBV/HCV | 0.93/0.71 | — | MALDI–TOF–MS, WB, ELISA | Hsieh et al, 2011 |
| GFAP (cell differentiation/regeneration) | P14136 | Serum | ↑ HCC:CON | 100% HCCs | Disc: 20 HCC, 20 HCON Val: 5 HCC, 5 HCON | No information | — | — | 2DE-coupled MALDI–TOF, WB | Wu et al, 2012 |
| hCE1 (response to toxins) | P23141 | Plasma | ↑ HCC:CON | No information | 24 HCC, 14 LC, 7 CH, 8 CCa, 15 stomach cancer, 16 pancreatic cancer | No information | 0.80 | — | 2DE MALDI–TOF/TOF, nano-LC MS/MS, WB | Na et al, 2009 |
| HP (AP: Immunity and Fe homoeostasis) | P00738 | Serum | ↑ HCC:CON | 100% of HCCs | 5 HCC, 5 HCON | HCV/HBV | — | — | 2DE LC–ESI–MS/MS | Yang et al, 2007a |
| Serum | ↑ HCC:CLD | 100% of HCCs | 56 HCC, 40 CLD | No information | 0.73 | 2.57** | ELISA | Ang et al, 2006 | ||
| Serum | ↑ HCC:CON | No information | Disc: 20 HCC, 20 HBV, 20 HCON Val: 20 HCC, 20 HBV, 20 HCON | HBV | — | — | 2DE and MALDI–TOF–MS/MS | Feng et al, 2005 | ||
| Serum | ↑ HCC:CON | 100% of HCCs | 20 HCC, 20 HCON | No information | — | 5.10** | 2DE-coupled MALDI–TOF–MS | Sun et al, 2010b | ||
| Plasma | ↑ CON:LC | Disc 24.2% Val 4.8% | Disc: 120 HCC, 99 LC, 120 HCON Val: 21 HCC, 6 LC, 18 ASC, 10 HCON | HBV/aflatoxin | — | 1.35* | QTOF–nUPLC–ESI–MS | Fye et al, 2013 | ||
| HPR (metabolic process) | P00739 | Serum | ↑ HCC:CON | 100% of HCCs | 5 HCC, 5 HCON | HCV/HBV | — | — | 2DE LC–ESI–MS/MS | Yang et al, 2007a |
| Plasma | ↓ HCC:CON | Disc 24.2% Val 4.8% | Disc: 120 HCC, 99 LC, 120 HCON Val: 21 HCC, 6 LC, 18 ASC, 10 HCON | HBV/aflatoxin | — | 0.65* | QTOF–nUPLC–ESI–MS | Fye et al, 2013 | ||
| HPX (Fe homoeostasis) | P02790 | Plasma | ↑ HCC:CON | No information | 10 HCC; 30 HCON/LC/HBV | HBV | 0.61 | 1.2ns | Lectin MRM–UPLC–ESI–MS | Ahn et al, 2012b |
| Plasma | ↑ CON:LC | Disc 24.2% Val 4.8% | Disc: 120 HCC, 99 LC, 120 HCON Val: 21 HCC, 6 LC, 18 ASC, 10 HCON | HBV/aflatoxin | 0.81 | — | QTOF–nUPLC–ESI–MS | Fye et al, 2013 | ||
| Fu-HPX | Plasma | ↑ HCC:CON | Some Histo. % not stated | 72 HCC, 32 LC, 33 HBV, 133 HCV, 62 other liver diseases, 20 CON | HCV/HBV | 0.95 | 1.4** | Lectin LC–MS/MS | Comunale, 2009 | |
| HSP90 (stress response) | P08238 | Serum | ↑ HCC:CON | 100% of HCCs | 20 HCC, 20 HCON | No information | — | 7.04** | MALDI–TOF–MS, ELISA | Sun et al, 2010b |
| OPN (biomineralisation/cell adhesion) | P10451 | Plasma | ↑HCC:CLD/CON | Val: None | Disc: 17 HCC, 18 LC Val: 131 HCC, 76 LC, 52 CHCV/HBV, 53 HCON | HCV/HBV | 0.76 | — | LC–ESI–MS/MS with 2D nHPLC-coupled LTQ OrbiTrap | Shang et al, 2012 |
| Plasma | ↑HCC:CON/LC | Some Histo. % not stated | 30 HCC, 30 LC, 20 HCON | HCV | 0.92 | 4.33† | ELISA | El-Din Bessa et al, 2010 | ||
| PON-1 (antioxidant/hydrolase) | P27169 | Serum | ↑ HCC:CON | 100% of HCCs | 5 HCC, 5 HCON | HCV/HBV | — | — | 2DE LC–ESI–MS/MS | Yang et al, 2007a |
| Plasma | ↓ HCC:CON | Disc 24.2% Val 4.8% | Disc: 120 HCC, 99 LC, 120 HCON Val: 21 HCC, 6 LC, 18 ASC, 10 HCON | HBV/aflatoxin | — | 0.63** | QTOF–nUPLC–ESI–MS | Fye et al, 2013 | ||
| Prx-II (antioxidant/oxidoreductase/peroxidase) | P32119 | Plasma | ↑ LC:CON | 100% of cases | Disc: 27 HBV, 7 HCON Val: 68 HBV, 42 HCON | HBV | 1.00 | — | MALDI–TOF–MS | Lu et al, 2010 |
| Tissue | ↑ HCC:CON | 100% of HCCs | 6 HCC, 6 non-malignant adjacent tissue | HBV | — | 2.1† | 2DE-coupled MALDI–TOF–MS | Matos et al, 2009 | ||
| SAA (AP and innate response/cell adhesion) | P0DJI8 | Serum | ↑ HCC:CON | No information | 67 HCC, 53 CHBV, 44 HCON | HBV | — | 4.5† | 2DE MALDI–TOF–MS, SELDI–TOF–MS | He et al, 2008 |
| Serum | HCC only | 100% of HCCs | 5 HCC, 5 HCON | HCV/HBV | — | — | 2DE LC ESI–MS/MS | Yang et al, 2007a | ||
| SGP-2 (cell death) | Q6LDQ3 | Serum | ↑ HCC:CON | 100% HCCs | Disc: 20 HCC, 20 HCON Val: 5 HCC, 5 HCON | No information | — | — | 2DE MALDI–TOF–MS, WB | Wu et al, 2012 |
| TGM2 (apoptosis/transferase) | P21980 | Tissue/serum | ↑ HCC:CON | ALL: 100% of HCCs | Tissue disc: 61 HCC, 61 adjacent non-tumour tissue Val: 109 HCC, 42 HCON | HBV/HCV | — | — | LTQ–FT–MS/MS, ELISA | Sun et al, 2008 |
| TTR (Transport) | P02766 | Serum | ↓ HCC:CON | No information | Disc: 20 HCC, 20 HBV, 20 HCON Val: 20 HCC, 20 HBV, 20 HCON | HBV | — | — | 2DE and MALDI–TOF–MS/MS | Feng et al, 2005 |
| Serum | ↓ HCC:CON | 100% of HCCs | 5 HCC, 5 HCON | HCV/HBV | — | — | 2DE LC–ESI–MS/MS | Yang et al, 2007a | ||
| VIM (host-virus interaction) | P08670 | Tissue/serum | ↑HCC:LC/CON | Disc: 100% of HCCs Val: No information | Disc (tissue): 40 HCC, 36 CON Val: 88 HCC, 64 CON | HBV | 0.69 | 3.27† | 2DE MALDI–TOF/TOF, ELISA | Sun et al, 2010a |
| VIT (cell adhesion) | P04004 | Serum | ↑ HCC:LC | 91% of HCCs | 44 HCC, 38 LC | No information | 0.85 | — | SELDI–TOF–MS | Paradis et al, 2005 |
| Serum | ↓ HCC:CON | No information | 10 HCC, 10 HCON | No information | — | — | SID–MRM–MS | Zhao et al, 2010 | ||
| Plasma | ↑ HCC:CON | No information | 10 HCC; 30 HCON/LC/HBV | HBV | 0.54 | 1.1ns | Lectin MRM–UPLC–ESI–MS | Ahn et al, 2012b | ||
| Plasma | ↓ HCC:CON | No information | 28 HCC, 10 HCON | No information | 0.98 | — | nUPLC–ESI–QTOF–MS and QQQ | Lee et al, 2011 | ||
Abbreviations: 2D=two dimensional; 2DE=two-dimensional electrophoresis; ASC=asymptomatic carrier; AUROC=area under receiver operating characteristics; CCa=cholangiocarcinoma; CHBV/CHCV=chronic HBV or HCV; CLD=chronic liver disease; ELISA=enzyme-linked immunosorbent assay; ESI=electrospray ionisation; HBV=hepatitis B virus; HCC=hepatocellular carcinoma; HCON=healthy control; HCV=hepatitis C virus; Histo=histology; ICAT=isotope-coded affinity tag; LB=liver biopsy; LC=liquid chromatography; MALDI=matrix-assisted laser desorption/ionization; MRM=multiple reaction monitoring; MS=mass spectrometry; n/r=not recorded; nanoHPLC=nano high-performance liquid chromatography; nUPLC=nano ultra-performance liquid chromatography; QQQ=triple quadropole mass spectrometer; qTOF=quadrupole time of flight; WB=western blot; SELDI=surface-enhanced laser desorption/ionization; TOF=time-of-flight. *P<0.05; **P<0.01; ns, non-significant; †, no P-value reported.