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Chia et al. Hepatoma Res 2019;5:9  I  http://dx.doi.org/10.20517/2394-5079.2018.112                                               Page 3 of 14


               Table 1. Performance of various HCC diagnostic biomarkers and tools
                Biomarker         Sensitivity (%)  Specificity (%)           Note                   Ref.
                Ultrasonography       60           97             Meta-analysis on 14 studies        [4]
                CT                    68           93             Meta-analysis on 14 studies        [4]
                AFP                   55           87             n = 5,581                          [14]
                                      66           82             Early stage HCC, n = 836           [22]
                                      59           89             Early stage HCC, n = 1,100         [47]
                                      35           88             Meta-analysis on 19 studies        [75]
                                      41-65        80-94          Meta-analysis on 5 studies, cirrhotic patients  [139]
                                      97           40             n = 100                            [140]
                                      58           85             n = 4,217                          [52]
                AFP-L3                37           92             n = 372                            [21]
                                      57           64             Detect using microfluidic device   [23]
                DCP                   61           70             Early stage HCC, n = 836           [22]
                AFP-L3 + DCP          61           71             n = 372                            [21]
                                      78           62             Early stage HCC, n = 208           [22]
                AXL                   71           73             n = 584                            [43]
                AXL + AFP             84           92             n = 584                            [43]
                Thioredoxin           75           89             Early stage HCC, n = 1,100         [47]
                Thioredoxin + AFP     83           94             Early stage HCC, n = 1,100         [47]
                GP73                  75           97             n = 4,217                          [52]
                GP73 + AFP            89           85             n = 4,217                          [52]
                GPC3                  55           84             Meta-analysis on 19 studies        [75]
                                      55           97             Early stage HCC, meta-analysis on 19 studies  [75]
                OPN                   75           62             Early stage HCC, n = 312           [126]
                SCCA                  84           49             n = 961                            [141]
                Annexin A2            83           68             Early stage HCC, n = 224           [142]
                Annexin A2 + AFP      87           68             Early stage HCC, n = 224           [142]
                suPAR                 76           90             n = 267                            [143]
                MDK                   93           83             n = 100                            [140]
               CT: computed tomography; AFP: α-fetoprotein; GPC3: glypican 3; MDK: Midkine; OPN: osteopontin; SCCA: squamous cell carcinoma
               antigen; suPAR: soluble urokinase plasminogen activator receptor; DCP: des-gamma-carboxy prothrombin; HCC: hepatocellular
               carcinoma

                                                                                                        [22]
               sensitivity and specificity of only 57% and 64%, respectively. Comparing AFP-L3 with AFP, Marrero et al.
               concluded that AFP was more sensitive than AFP-L3 for detecting early HCC. Taken together, these results
               suggest that AFP-L3, despite having higher specificity, is inferior than AFP as an HCC biomarker. The low
               sensitivity of AFP encourages combining AFP with other biomarkers that are significantly overexpressed in
               HCC [Table 1]. Three of these biomarkers that have performed extraordinarily when used in combination
               with AFP are AXL, thioredoxin and GP73.

               AXL
                                                                                                   [24]
               AXL is a receptor tyrosine kinase that is expressed in a number of malignancies, including HCC , lung
                                                 [27]
                                                               [28]
                                    [26]
                     [25]
                                                                                                  [29]
               cancer , ovarian cancer , colon cancer , breast cancer  and pancreatic ductal adenocarcinoma  [Figure
               1]. AXL is stimulated by the vitamin K-dependent protein encoded by growth-arrest-specific gene 6. Stimulated
               AXL in turn activates the PI3K-AKT-mTOR, MEK-ERK, NF-κB and JAK/STAT signaling pathways that
               lead to tumour growth, immune escape and drug resistance [30-35] . AXL is also expressed in normal bone
               marrow stroma and myeloid cells to clear apoptotic material, suppress inflammatory responses and control
               natural killer cell activity [36,37] . Loss of AXL, therefore, leads to inflammation and autoimmunity [38,39] . AXL is
                                                                             [40]
               a key downstream target that drives YAP-dependent oncogenic functions . Knocking down AXL by RNAi
               decreased the ability of YAP-expressing MIHA and the primary HCC cell line to proliferate and invade.
               Furthermore, AXL also serves as a putative entry receptor for Zika Virus, Ebola Virus and West Nile Virus
               to infect the host cells . Activated AXL undergoes proteolytic processing to yield a soluble protein that
                                  [41]
                                        [42]
               can be detected in the serum . Detection of very early HCC (i.e., BCLC stage 0) by soluble AXL (sAXL)
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