Page 145 - Read Online

Zacharakis et al. Hepatoma Res 2018;4:65 I http://dx.doi.org/10.20517/2394-5079.2018.76 Page 7 of 15

[77]
genes during HCC pathogenesis . There are several types of miRNAs being tested as diagnostic and
prognostic markers for HCC. To date, most common methods used for detection are the microarray, PCR and
[78]
gene sequencing . As a prognostic factor, low level and down-regulation of miRNA-542 and miRNA-139 are
associated with poor prognosis as vascular invasion, larger tumor size and metastatic disease [79,80] . Expression
of miRNA profile in the histopathological analysis after HCC resection can predict the risk of HCC recurrence
[82]
[81]
within the Milan criteria , HCC miRNAs expression varies between cirrhotic and non-cirrhotic HCC .
Remarkably, miRNAs like miR503HG suppress metastasis and inhibit malignant cell migration. Therefore,
downregulation is associated with a higher risk of metastatic disease. This discovery may act as a template
[83]
for future pharmacological targeted treatment . Several studies compared them with the conventional HCC
biomarkers such as AFP, DCP, AFP-L3 or used along with these biomarkers and the results demonstrated that
a single miRNA or even better combination of different miRNAs were more sensitive than AFP, DCP, and
AFP-L3%. However, the miRNA expression profiles in HCC patients could vary significantly according to the
tumor stages. Subsequently, it was difficult to distinguish between patients with different tumor stages. This
was a limitation of the diagnostic utility of miRNAs as serological biomarkers.

Later, a panel of circulating miRNAs was developed, with the advances in miRNA screening techniques and
the development of new bioinformatics tools achieved higher sensitivity and specificity in HCC diagnosis.
Indeed, a miRNA panel, with cutoff 20 ng/mL, showed better diagnostic sensitivity than AFP and similar
specificity to AFP especially for the detection of small and early-stage tumors Also, this miRNA panel could be
used as a prognostic score to improve the treatment outcome of HCC patients.

In conclusion, miRNAs are the promising biomarkers in the field of HCC diagnosis, prognosis, and potential
therapeutic targets. However, they do not yet fit for the routine clinical setting.

lncRNAs
lncRNA are a unique class which are defined as transcripts of more than 200 nucleotides that present in
genome-wide analysis of mammalian transcriptome. Accumulating evidence showed that dysregulated
lncRNA had been involved in the pathogenesis of HCC [84,85] . Lately, IncRNA has been recognized as
important regulators for carbohydrate and lipid metabolism; this has led to discovering a novel biomarker
“IncRNA Ftx” which stimulate HCC progression and glycolysis. Therefore, IncRNA Ftx may act as a
[86]
prototype for further research in targeted therapy for HCC . A recent prospective study suggested
combining lncRNA and AFP measurement may be a novel useful marker for HCC regarding diagnosis and
[87]
prognosis . Expression of RP11-466I1 in the serum and HCC tissue is associated with poor features like
[88]
tumor capsule invasion .
CTCs
One of the most adverse prognostic features of HCC is the presence of vascular invasion which leads to
hematological spread and distant metastasis of malignant cells. Therefore, detection of CTCs has strategic
clinical value in predicting HCC recurrence and monitoring treatment response [89,90] . Detection of CTCs
[91]
is associated with poor overall survival and relapse-free survival . In addition to that, CTCs positivity
is significantly correlated with serum AFP level, vascular invasion and TNM stage which can reflect the
[92]
histopathological status of HCC . According to a recent meta-analysis of more than 20 studies, the CTC is
[92]
not used as a sole indicator for diagnosis instead associated with poor clinical and pathological features .
cfDNA
Dysregulated levels of cfDNA have a role in diagnosis, monitoring of treatment response, and even outcome
prediction for cancer diseases [93-95] . Furthermore, single-nucleotide polymorphism of cfDNA such as Ser249
p53 mutation which is commonly found in the plasma DNA, unfortunately, is detected in HCC and non-
[96]
HHC individuals . However, differential methylation signatures identified in cfDNA, precede the occurrence