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Guerriero et al. Hepatoma Res 2019;5:6 I http://dx.doi.org/10.20517/2394-5079.2018.108 Page 15 of 22

LNCRNAS
lncRNAs are a class of > 200 nt RNA transcripts linked to the modulation of several pathways through
various different molecular mechanisms [90,91] . Their expression differs between cancer and non-cancer tissues
and their role in cancer biology is well recognized [92,93] . Expression deregulation of several lncRNAs has been
[94]
reported in HCC and abnormal levels of an increasing number of lncRNAs are being found in serum/
plasma of HCC patients, suggesting their potential use as circulating tumor biomarkers. Table 5 summarizes
the studies that have linked circulating lncRNAs to HCC. Technologies for detection and quantification of
lncRNAs in biological samples are the same previously described for miRNAs.

A number of studies demonstrated that circulating lncRNAs could discriminate HCC from healthy controls
or patients with non-malignant chronic liver diseases. In several cases, the studies involved detection of
early HCCs, a crucial factor for the application of curative strategies. lncRNAs were evaluated either as
single biomarkers or in combination. As single biomarkers, results indicated a sensitivity ranging from 51%
[95]
[96]
to 92%. In this experimental setting, lncRNA - uc003wbd , ENSG00000258332.1 , small nucleolar RNA
[97]
[98]
host gene 1 (SNHG1) , zinc finger antisense 1 (ZFAS1) were able to differentiate HCC patients from
chronic hepatitis B virus (HBV) patients or healthy controls, urothelial carcinoma associated-1 (UCA1) or
[99]
WRAP53 were significantly higher in HCC patients’ sera in comparison with chronic hepatitis C virus
(HCV) patients or healthy volunteers. Diagnostic accuracy improved when lncRNAs were combined among
them or with AFP and DCP. Combination of the lncRNAs plasmacytoma variant translocation 1 (PVT1) and
[100]
uc002mbe.2 could discriminate early HCC patients from either HBV or HCV positive patients . ZFAS1 [98]
or the expressed neighbor of XIST (Enox or JPX) [101] levels in combination with AFP could discriminate
HCC from healthy individuals or chronic liver diseases patients with a better accuracy than each biomarker
considered individually. The same was found for the combination of serum lncRNA uc007biz.1 (LRB1) with
[100]
[102]
AFP and DCP biomarkers or the combination of PVT1 and uc002mbe.2 with AFP .
Many circulating lncRNAs were also found to correlate with unfavourable pathologic features [96,97,100-105]
[106]
and their association with prognosis was also evaluated. The increased levels of UCA1 or differentiation
[102]
[105]
antagonizing non-protein coding RNA (DANCR) or LRB1 were all associated to a poorer OS. Some of
the studies investigated the combination of lncRNAs. The combined up-regulation of ENSG00000258332.1
[101]
[96]
[106]
and LINC00635 , or of SNHG and UCA1 or low levels of JPX and X inactive-specific transcript (XIST)
significantly correlated with a poorer prognosis in HCC patients.
lncRNAs were also evaluated as biomarkers for monitoring tumor recurrence after surgery. In this clinical
setting, it was found that patients with higher DANCR levels after surgery were prone to develop HCC
[105]
recurrence . It was also reported that the circulating levels of PCDH9-13:1 were significantly reduced after
curative hepatectomy. However, it increased again in case of a relapse, suggesting that this lncRNA could be
[97]
used to monitor patients after surgery [107] . Similarly, based on the decreased levels of SNHG1 or PVT1 [100]
after surgery, it was speculated that a subsequent increase of their expression might serve as biomarkers to
monitor patients for HCC relapse.

CONCLUSION
Analysis of cell free DNA and RNA in body fluids, the so-called liquid biopsy, represents a very promising
strategy for the early detection of cancer at an early stage or during monitoring of patients for the early
detection of cancer relapse. The approach has the potential to significantly improve the clinical management
of HCC cancer patients. Studies on circulating DNA/RNA in HCC originate from the need to identify more
effective biomarkers than those currently in use, AFP and DCP. This review presents the results obtained so
far in HCC. Although the specific studies still require further validation, overall they demonstrate a good
sensitivity and specificity, higher than the current biomarkers and, once present limitations are over, can
successfully find a valuable clinical use.