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Figure 1. Cartoon depicting structures of cadherin-17 (CDH17), Trop2, glypican 3 (GPC3) and AXL

showed an area under the curve (AUC) of 0.848 upon receiver operating characteristic curve analysis. The
sensitivity and specificity of the detection was 76.9% and 69.2%, respectively. The accuracy of the detection
was increased to 0.936 by the combined use of sAXL and AFP. Interestingly, sAXL combined with AFP
could differentiate very early HCC from liver cirrhosis with an accuracy of 0.901, of which the sensitivity
[43]
and specificity was 88.5% and 76.7%, respectively . Nevertheless, multicenter clinical studies are needed to
validate these findings.

Thioredoxin
Thioredoxin, together with thioredoxin reductase, forms a ubiquitous oxidoreductase system that plays
an important role in regulating intracellular redox environment, controlling cellular proliferation and
[44]
providing defense mechanism against oxidative stress . Thioredoxin expression is detected in HCC, non-
small cell lung cancer and colorectal cancer [45,46] . It is generally associated with a more aggressive tumour
[47]
phenotype, poor prognosis and a lower survival rate. As a sole early stage HCC biomarker, Li et al.
found that thioredoxin (sensitivity, 75%; specificity, 89%) surprisingly outperformed AFP (sensitivity, 70%;
specificity, 79%) in their study. When used in combination, they could detect early HCC with an impressive
sensitivity and specificity of 83% and 94%, respectively. This supports the idea that an ideal combination of
biomarkers can outperform a single biomarker in giving both lower false positive and false negative rates.

GP73
GP73 is a 400 amino acid, type II Golgi-specific membrane glycoprotein normally expresses on epithelial
[48]
cells of liver and kidney . GP73 resides within the cis-Golgi complex but it can be secreted into the
[49]
extracellular space by cleavage at the proprotein convertase site . In fact, soluble GP73 was detected in the
medium cultured with HeLa, foreskin fibroblasts (HCA) and osteosarcoma (MG63) cell lines, suggesting
[50]
that it may have some functions in the extracellular environment . A number of studies noted elevated
[52]
level of serum GP73 in HCC patients [49,51] . Mao et al. compared serum GP73 and AFP biomarkers in 4,217
subjects with a mixture of healthy adults, HBV carriers and patients with cirrhosis, HCC or others cancers.
They found GP73 to be a superior biomarker (sensitivity: 75%, specificity: 97%) than AFP (sensitivity 58%,
specificity 85%). The combination of both biomarkers improved the sensitivity further to 89% but with a
drop-in specificity down to 85%.

Annexin A2
Annexin A2 (ANXA2), a member of the annexin family, is a 36-kDa calcium-dependent phospholipid-
binding protein that plays a role in immune responses, phospholipase A2 regulation and anti-inflammation.
The serum ANXA2 was found to be elevated in HCC patients (n = 50) as compared with patients with
[53]
chronic disease (n = 30) or healthy subjects (n = 20) by ELISA . In the same study, follistatin, a potential
serological HCC biomarker, was found elevated in both HCC patients and patients with chronic liver