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Page 10 of 17 Rojas et al. Hepatoma Res 2018;4:31 I http://dx.doi.org/10.20517/2394-5079.2018.60

in the meantime that miR-122, miR-885-5p and miR-29b in association with AFP showed a high diagnostic
accuracy for early detection of HCC in general population (AUC = 1) [122] . The combination of lncRNA and
miRNAs has been also studied. lncRNA-CTBP, miR-16-2, miR-21-5p and LAMP2 had high sensitivities
(91%, 92.3%, 93.6% and 92.3% respectively) for discriminating HCC from healthy subjects and also from
chronic hepatitis C patients (75%, 88.9%, 88.9% and 94.9% respectively) [123] . miR-224 was highly expressed in
HCC tissue and plasma, and after surgery the levels were normalized suggesting that miR-224 could reflect
tumor dynamisms. There was an association between plasma miR-224 level, tumor size (P = 0.0005) and
the incidence of recurrence (P = 0.0027). However no significant correlation were found with AFP serum
levels [124] .

In addition, miR-21 was found upregulated in plasma from HCC patients compared to healthy volunteers.
The combination of miR-21 and AFP increased its diagnostic value (more than 90%) suggesting its potential
use as a biomarker of HCC diagnosis [125] . A systematic review and meta-analysis concluded that circulating
miRNAs, particularly miR-21 and miR-122 are promising biomarkers for the early diagnosis of HCC [126] .
In addition, miR-21 (oncogene) and miR-182 (tumor suppressor gene) were related with the development of
metastasis [127,128] .

Due to the diversity showed in the results, numerous profiling studies are ongoing in order to report miRNA
profiles based on sequencing microarrays to examine circulating miRNAs as HCC-associated biomarkers.

Tumor-associated circulating microparticles
Large cells membrane-derived extracellular vesicles (EVs), known as microparticles (MPs) and microvesicles
(MVs), have been reported to play a role in the horizontal communication between cells [129] .

Hepatocytes secrete exosomes, MPs and MVs, and their production can change quantitatively and
qualitatively in response to cellular stimulation and under different disease conditions [130] . It was shown
that tumors prepare their own tumor niches via the release of EVs including a possible suppression of the
immune system and the activation of tumor neo-angiogenesis [131] . MPs are between 100 and 1000 nm in
size and bear on their surface the antigenic markers of the parent cell. They are formed and released during
cellular activation or in early stages of apoptosis into the extracellular space. MPs can be isolated from whole
blood, plasma and serum [132] .

Proteomic analysis revealed the presence of ~251 proteins in EVs derived from primary rat hepatocytes [133] .
Something that we have to be in account is that exosomes do not carry cell surface markers of their origin
cells however MPs carry the surface signature of their cell of origin and the quantification of MP subsets
using FACS sorting allows a non-invasive assessment of cell specific pathologies. Nowadays, there are many
studies which focus is to identify the most efficient surface markers of tumor associated MPs (taMPs) and
liver disease [134-136] .

A recent study showed that EpCAM and CD147 double positive taMPs could be a biomarker to compare
colorectal carcinoma (CRC), non-small cell lung carcinoma (NSCLC) and pancreas carcinoma with healthy
subjects. In all three types of tumor entities, EmCAM+CD147+ taMPs were found increased (AUROC:
0.8597, 0.8700 and 0.9000 respectively) indicating cancer presence. In addition, EpCAM+CD147+ taMPs
were significantly correlating with CRC tumor volume (r = 0.7288, P < 0.0001). Furthermore, EpCAM+
taMPs were found decreased after tumor resection in serum of CRC patients suggesting a close dependence
with tumor presence [134] . They conclude that EpCAM+ and EpCAM+CD147+ taMPs might serve as an early
indicator of cancer growth and monitor successful anti-tumour therapy and might be used as important
liquid biopsy tool to differentiate between therapy responders and non-responders [134] .

Regarding HCC the role of circulating MPs as potential biomarkers is under intensive investigation. Abbate
and colleagues showed that HepPar1-MPs are increased in the blood of subjects with HCC compared to