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Rojas et al. Hepatoma Res 2018;4:31 I http://dx.doi.org/10.20517/2394-5079.2018.60 Page 9 of 17

patients compared to controls, showing that both lncRNAs could be potential biomarkers for HCC and
HBV screening (P < 0.001). HCC patients compared with normal group showed an AUC value for lncRNA-
uc003wbd: 0.86 (95% CI: 0.82-0.91) and for lncRNA-AF085935 was 0.96 (95% CI: 0.93-0.99). Authors suggest
[106]
that both lncRNAs may serve as potential biomarkers for the detection of HCC and HBV . Long intergenic
non-protein coding RNA 974 (Linc00974F-1) was increased in serum of HCC patients and it was useful as a
tumor marker to improve the prognosis of HCC. The combination of Linc00974F-1 and CYFRA21-1 showed
an AUC: 0.866, indicating a significant predictor of tumor growth and metastasis [107] . In addition, SPRY4-IT1
expression was upregulated in the plasma from HCC patients suggesting this one to be a good diagnostic
biomarker. Combination of SPRY4-IT1 and AFP (the cut-off value of AFP was at 200 ng/mL) possessed
a moderate ability for discrimination between HCC patients and controls; the area was equal to 0.80 [108] .
Highly upregulated in liver cancer (HULC) lncRNA has been implicated in the regulation of hepatoma
cell proliferation, since it induces HCC cells to activate EMT and then promotes tumor progression
and metastasis through the miR-200a/ZEB1 signalling pathway [109] . Furthermore, HULC lncRNA was
upregulated in the plasma of HCC patients compared to healthy controls (HULC was detected in 63%
(19/30) of the HCC patients and 10% in the healthy control group (2/20) and with a positive correlation to
Edmondson grades (the detection rates were 14%, 62%, and 100% for Edmondson grades I-II, II-III, and III-
IV, respectively) [110] . The lncRNA DANCR activates the Wnt pathway, one of the most important pathways
responsible of HCC development [111] . DANCR was up-regulated in tumor tissues and plasma of patients with
HCC, and its expression was highly correlated with microvascular and liver capsule invasion of HCC. The
results showed that AUC for plasma DANCR was 0.868 which was higher than that for AFP (AUC = 0.744)
when differentiating patients with HCC from non-HCC patients [112] . Besides these circulating lncRNAs,
JPX, UCA1 and WRAP53 were found increased in HCC patients [106,113,114] alone or in combination with other
lncRNAs, miRNAs or serum biomarkers [115] . Many reports have indicated that the deregulation of lncRNAs
plays important roles in occurrence and progression of HCC however further studies are needed in order to
use these as biomarkers.

Circulating miRNAs
Numerous studies have shown that circulating miRNAs are closely associated with tumor development and
progression. In spite of these findings, miRNAs are considered good biomarkers for differentiating between
HCC and healthy people.

For instance, miR-122 is a liver-specific miRNA whose role is to maintain the liver homeostasis. The loss
of its expression contributes to the malignant phenotype of HCC cells and it has been described as the
miRNA responsible to develop HCC in HCV infection [116] . However, controversial results about miR-
122 were reported due to the underlying aetiology and active ongoing necroinflammatory changes. miR-
122 was found significantly downregulated in HBV-related HCC [117] and Xu et al. [118] found it increased in
serum from patients with HCC and chronic hepatitis B together with miR-21 and miR-223. A positive linear
correlation was present between serum ALT and serum miR-122 levels in mouse models of alcoholic liver
[100]
disease (r = 0.893; P < 0.001) and it was postulated to be a key regulator of alpha-fetoprotein expression
and it could influence the aggressiveness of the HCC in an in vitro model [119] . Using panels of miRNAs may
provide a high diagnostic accuracy of HCC regardless of the disease status, and it can also differentiate
HCC from healthy controls and chronic liver injury [120,121] . These were hsa-miR-206, hsa-miR-141-3p, hsa-
miR-433-3p, hsa-miR-1228-5p, hsa-miR-199a-5p, hsa-miR-122-5p, hsa-miR-192-5p, and hsa-miR-26a-5p. The
diagnostic accuracy using these miRNAs, as measured by AUC, was 0.665, 0.68, 0.607, 0.534, 0.609, 0.729, 0.69
[121]
and 0.677, respectively [120] . Ali et al. showed that miR-122, miR-21 and miR-222 had the highest sensitivity
and specificity, in discriminating HCC from healthy controls (miR-122: 94.3% and 92.9% respectively; miR-
21: 80% and 92.9% respectively, and miR-222: 82.9% and 78.6%, respectively).

Another study demonstrated that serum miR-122, miR-885-5p, miR-221, miR-22 in association with AFP
showed a high diagnostic accuracy for early detection of HCC in a cohort of cirrhotic patients (AUC = 0.982),