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used as a serological biomarker due to its ability to accurately distinguish between patients with small, well-
[57]
differentiated HCC tumors and those with cirrhosis . This marker is similar to AFP, showed high specificity
[58]
but low sensitivity . Even if it is combined with miRNAs, such as miR-21, only a slight improvement in
[59]
performance was shown compared with AFP .
Other markers used in combination with GPC3 include HSP70 and GS. HSP70 belongs to a class of genes
(heat shock proteins) abundantly overexpressed in advanced HCC as compared to early HCC, and in early
[61]
[60]
HCC as compared to precancerous lesions . Also, a study by Osada et al. showed a stepwise increase in GS
immunoreactivity from precancerous lesions to early and advanced HCC suggested that GS has a role in HCC.
In CPG jointly published by EASL-EORTC recommend that GPC3 could be used alone or in combination with
HSP70 and GS to distinguish well-differentiated HCC (early and grade 1) from dysplastic nodules of cirrhosis.

NOVEL BIOMARKERS FOR HCC
There is an unmet clinical need to discover better biomarkers for HCC that (1) fully correlate with the tumor
stage; (2) can be detected in early HCC; and (3) allow for tumor surveillance and evaluation of therapeutic
efficacy. Therefore, the research into novel HCC biomarkers continues. In this section, we briefly discuss the
novel biomarkers for HCC, all are under investigation in clinical trials and are not currently used in clinical
practice.

CK19
CK19 is a novel HCC biomarker associated with poor prognostic factors in HCC patients due to high risk of
microvascular invasion and distant metastasis, as well as worse treatment outcome [62-64] .

GP73
GP73 is a transmembrane protein localized in the Golgi complex. Although it is absent in normal hepatocytes,
[65]
abundantly overexpressed in HCC patients, compared with cirrhotic patients . GP73 could be used as a
marker in early-stage [66,67] .

OPN
[68]
OPN is a glycoprotein, an extracellular matrix protein expressed in HCC cells and other various types
[69]
of malignancies . OPN, although, it has a higher sensitivity in the discrimination of early HCC than AFP
[70]
according to the clinical study of Shang et al. . The low specificity can be explained by its relationship
[71]
with more than 30 types of cancers . Therefore a combination with AFP is necessary to optimize its
[70]
performance .
SCCA
SCCA is a serine protease inhibitor. It is found in squamous epithelium. The use of SCCA as an additional
[72]
diagnostic marker with AFP for HCC has been well documented . Also, it might play a role as a biomarker
[73]
for response to treatment as there is an inverse correlation with the treatment response for HCC . Finally, the
combination of AFP and SCCA should be investigated in future studies to validate the diagnostic role of SCCA
as a predictor for the risk of HCC in patients with chronic liver disease.

Annexin A2
Annexin A2 is a calcium-dependent, phospholipid-binding protein. It is present in the cell surface, and it seems
[74]
to be implicated in the development and metastasis of HCC . It has been used as a serological biomarker for
[75]
diagnosis and prognosis of early-stage HCC patients with higher sensitivity and specificity than AFP .
miRNA
miRNAs are small non-coding endogenous RNAs that have been implicated in various biological roles at the
[76]
cellular level including apoptosis and oncogenesis . Some types of miRNAs act as controllers of different