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Page 10 of 15 Zacharakis et al. Hepatoma Res 2018;4:65 I http://dx.doi.org/10.20517/2394-5079.2018.76

HCC biomarkers that might be used as therapeutic targets
As explained previously, GPC3 is a membrane-associated heparan sulfate proteoglycan that can be used
as biomarker for HCC. However, recent studies have shown that it plays a role in cancer pathogenesis and
proliferation and therefore it can be used as a therapeutic target to stop the progress and proliferation of tumor
cells [125,126] .

Another biomarker and possible therapeutic target is the kinesin family member C1 (KIFC1). Recent studies
showed that KIFC1 is overexpressed in HCC tumor tissues compared with non-tumor tissues, therefore, it
[127]
might be used as a predictor for HCC . Moreover, in vitro KIFC1 knockdown could effectively decrease the
viability of HCC tumor cells, and induce apoptosis and cell death. This highlights that KIFC1 might be used as
[127]
a biomarker and a therapeutic target for HCC .

Serum marker panels for HCC
Aspartate aminotransferase to platelet ratio index
Aspartate aminotransferase to platelet ratio index (APRI) has been used to assess the risk of fibrosis and
cirrhosis among hepatitis C patients. APRI has been recently investigated to predict the risk of cirrhosis-
[128]
dependent and independent HCC in HBV patients . A recent study showed that APRI can predict response
[129]
to transarterial chemoembolization treatment before starting the therapy .
Fibrosis-4 index
A Korean study evaluating the role of Fibrosis-4 (FIB-4) index in predicting HCC among HBsAg
positive individuals; they found that FIB‐4 has a better predictive of HCC incidence, compared to that of
[130]
ultrasonographic liver cirrhosis (C‐index: 0.775 vs. 0.701; P = 0.040) . On the other hand, some reports show
that liver fibrosis index (FIB-4) is not reliable for the prediction of HCC .
[131]
Forns test
A study of liver fibrosis indices (APRI, FIB-4 index, and Forns index) showed that Forns index performed
before HCV antiviral therapy was a predictor to identify patients with low likelihood of developing HCC after
[132]
achieving a sustained virologic response . Morevoer, Forns index was found to predict the recurrence and
[133]
death of patients with hepatitis B-related HCC after curative resection .
CONCLUSION
No biomarker combination is reliable enough to diagnose a lesion as HCC without confirmatory histological
or radiological features. None of the new tumor markers outperform the conventional ones in such a way that
it has been widely adopted in clinical practice. The diagnostic accuracy, particularly for early-stage HCC, can
be improved by combining two or more biomarkers to reach an acceptable (> 80%) sensitivity with a modest
[49]
decrement in specificity . For this purpose, the accuracy can also be improved by measuring the overtime
variability of the marker. However, all these proposals are waiting for prospective and external validations, and
there are no recommended recall policies based on biomarker combinations or variability for the surveillance
of patients at risk of developing HCC.

In terms of response to HCC treatment, AFP levels can predict response to ramucirumab treatment; an
elevated AFP is a poor prognostic factor for ramucirumab survival benefit. However, future research should
develop useful biomarkers for monitoring treatment activity, detecting early resistance to treatment and
identifying patients who would more likely benefit from treatment.

DECLARATIONS
Authors’ contributions
Reviewed the literature and wrote the manuscript: Zacharakis G, Aleid A, Aldossari KK