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Table 4. Circulating miRNAs as predictive biomarkers of therapy response in hepatocellular carcinoma
Expression in Experimental Sampling
miRNA circulation 1 Body fluid Setting Clinical setting Treatment (pre/post Ref.
therapy)
miR-1246 Up Plasma Single Monitoring LT Pre/post [82]
miR-182 Up Serum Single Monitoring TACE Pre/post [135]
miR-331-3p Up Serum Single Monitoring TACE Pre/post [135]
miR-122 Up Plasma Single Response prediction TACE Pre [84]
miR-122 Up Plasma Single Response prediction RFA Pre [147]
miR-181a-5p Down Serum Single Response prediction Sorafenib Pre [89]
miR-200 Up Serum Single Response prediction TACE Pre [87]
miR-21 Up Serum Single Response prediction Resection Pre [79]
miR-21, miR-26a, Plasma Multiple Response prediction TACE Pre [148]
miR-29a-3p
miR-221 Up Serum Single Response prediction Sorafenib Pre [88]
miR-26a Down Plasma Single Response prediction Resection or RFA Pre [149]
miR-29a Down Plasma Single Response prediction Resection or RFA Pre [149]
miR-339-5p Down Serum Single Response prediction Sorafenib Pre [89]
miR-34a Down Serum Single Response prediction Resection Pre [150]
miR-665 Up Serum exosomes Single Response prediction Resection Pre [74]
miR-718 Down Serum exosomes Single Response prediction LT Pre [151]
miR-1246 Up Plasma Single Responsive vs. non responsive LT Post [82]
miR-148, miR-1246 Up Plasma Multiple Responsive vs. non responsive LT Post [82]
miR-148a Up Plasma Single Responsive vs. non responsive LT Post [82]
miR-148a, miR-148b, Down Serum Multiple Responsive vs. non responsive Resection Post [71]
miR-152
miR-182 Up Serum Single Responsive vs. non responsive TACE Post [135]
miR-221 Down Serum Single Responsive vs. non responsive Sorafenib Post [88]
miR-331-3p Up Serum Single Responsive vs. non responsive TACE Post [135]
miR-335 Down Serum Single Responsive vs. non responsive TACE Post [86]
miR-423-5p Down Serum Single Responsive vs. non responsive Sorafenib Post [152]
miR-122 Down Exosomal Single Responsive vs. non responsive TACE Pre/Post [85]

1 Circulating miRNA levels in non-responsive patients. LT: liver transplantion; RFA: radiofrequency ablation; TACE: transcatheter arterial
chemoembolisation

interpreted in accordance. In this context, an example is miR-101-3p, which was found downregulated in
[51]
[66]
[65]
HCC tissues but upregulated in plasma . Other examples include miR-21, upregulated in HCC tissues
but in some cases they are reported to be downregulated in patients serum [45,47] or the previously mentioned
miR-122, whose altered circulating level is predominantly a sign of hepatic injury [51,56] .
The combination of biomarkers can potentially overcome the individual limitations. For this reason,
miRNAs have been tested in association with AFP for improving test performance. Some studies indicated
that the combination of miR-21 and AFP improved the discrimination between HCC patients vs. chronic
[48]
[67]
hepatitis patients . Meng et al. showed that the combination of miR-24-3p and AFP allowed to better
separate HCC from chronic liver disease affected patients and also a combination of miRNA panels
with AFP provided a very good discriminating power between HCC vs. cirrhotic or chronic hepatitis
patients [52,60,61] .

Circulating miRNAs for HCC prognosis
Differences in median level of plasma/serum miRNAs as a cut-off value provided information about tumor
stage and prognosis in HCC patients [Table 3]. Some studies have shown correlations of miRNA levels with
pathological characteristics associated with prognosis. Members of the miR-148/152 family (miR-148a, miR-
[71]
148b and miR-152) are important modulators of cell growth and progression of HCC [68-70] . Wang et al.
showed that low levels of miR-148a and miR-148b were significantly associated with tumor size and TNM
stage, whereas low levels of miR-152 correlated with TNM stage. Additionally, the combination of circulating