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Guerriero et al. Hepatoma Res 2019;5:6 I http://dx.doi.org/10.20517/2394-5079.2018.108 Page 13 of 22

[71]
miR-148/152 family could discriminate HCC from non-malignant chronic liver diseases . Other studies
[72]
associated circulating miRNA levels with HCC patients’ prognoses. For example, Li et al. showed that
high serum levels of miR-221 correlated with tumor size, cirrhosis, tumor stage and with a lower OS in
comparison with patient with low miR-221 expression levels, suggesting serum miR-221 as an independent
[73]
risk factor for poor prognosis. A study by Yang et al. reported that low serum levels of miR-218 were
associated with clinic-pathological features such as tumor size, vascular invasion and TNM stage, as well
as OS of patients. All these reports supported the potential role of circulating miRNAs in the assessment
of prognosis in HCC. Studies described also the correlation between exosomal serum miRNA levels with
pathological features and survival in HCC patients. For example, HCC patients with low levels of miR-665
[74]
[75]
showed a strong association with large tumour size (> 5 cm), local tumour invasion and metastases ; Shi et al.
[76]
showed that decreased levels of exosomal miR-638 had poor OS. Zheng et al. reported that low levels of
serum miR-125a-5p were associated with a lower OS compared with those exhibiting higher expression
[77]
levels, and more recently Liu et al. confirmed by a Kaplan-Meier analysis that HCC patients with lower
serum miR-125b levels showed reduced time to recurrence and OS. Many studies involved the analysis
of circulating miR-21. In one study, high levels of serum miR-21 were found correlated with cirrhosis and
[78]
[80]
[79]
tumor stage , another revealed an association with metastasis ; Lee et al. reported that exosomal miR-
21 was an independent predictor of disease progression in HCC patients and high circulating levels of
exosomal miRNA-21 were associated with lower OS and progression-free survival. These data support the
role of miRNAs as potential prognostic biomarker in HCC.
Circulating miRNAs for prediction of HCC recurrence and treatment response
Many studies focused their attention on miRNAs ability to predict treatment response and monitor disease
relapse after surgery or drug therapy [Table 4].

[81]
Surgery is the treatment of choice for early HCC, however relapse is common . Levels of circulating
miRNAs were studied in patients who underwent surgical resection, revealing a correlation with the post-
operative survival. For example, subjects with low serum miR-21 levels had a 29% 5-year survival rate,
[71]
[79]
whereas those with high expression had a 14.3% 5-year survival rate . Wang et al. showed that levels of
[82]
serum miR-148/152 family decreased in case of relapse after surgery. Ng et al. showed that miR-1246 was
an independent predictor of OS and disease-free survival of HCC patients after liver transplant.
In patients at intermediate HCC stage, recommended first-line therapy is trans-arterial chemoembolization
[83]
(TACE) , while sorafenib is the standard first line-systemic therapy for patients with advanced tumors
[81]
(BCLC C) . The association between circulating levels of miR-122 and treatment outcome after TACE was
[84]
evaluated in two recent studies. Kim et al. found that high plasma miR-122 expression levels could be
[85]
predictive for early and overall TACE insufficient responses and refractoriness in HCC patients. Suehiro et al.
found that exosomal miR-122 expression levels were significantly decreased after TACE, especially in
patients with cirrhosis, and suggest that the reduction in exosomal miR-122 levels may reflect a decrease in
the liver function, rather than the anti-tumor effects of the procedure. Other miRNAs were studied in HCC
[86]
patients treated with TACE. For example, lower serum miR-335 levels were associated with a shorter OS ,
while lower expression of miR-200 in HCC patients predicted a better prognosis in HCC patients treated
[87]
with TACE . Considering the data reported, circulating miRNAs could be associated with clinical outcome
of HCC patients treated with TACE.

There are no biomarkers to predict response to sorafenib. A small number of studies evaluated whether
circulating miRNAs could predict or anticipate therapy responsiveness. From the analysis of miR-221 levels
.[88]
in sera from HCC patients who received sorafenib, Fornari et al found that the treatment determined
an increase of miR-221 only in responders. Moreover, analyzing miR-221 levels in sera from HCC patients
before sorafenib treatment, lower miR-221-circulating levels were associated with better response to the
[88]
[89]
drug . Analysing serum miRNA profiles during sorafenib therapy, Nishida et al. found that miR-181a-