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Page 10 of 22                                       Guerriero et al. Hepatoma Res 2019;5:6  I  http://dx.doi.org/10.20517/2394-5079.2018.108


                miR-30e   Down    Serum  Single    Diagnosis HCC vs. HL + CLD 39 vs. 14 + 17  91.7  70.5  0.93  [139]
                miR-331-3p  Up    Serum  Single    Diagnosis HCC vs. HL + BLD 103 vs. 40 +   79.6  92.6  0.89  [135]
                                                                      95
                miR-331-3p   Up   Serum  Single + AFP  Diagnosis HCC vs. HL + BLD 103 vs. 40 +   91.2  92.6  N/A  [135]
                                                                      95
                miR-335   Down    Serum  Single    Diagnosis HCC vs. HL + CH 125 vs. 125 +   N/A  N/A  N/A  [86]
                                                                      125
                miR-519d  Up      Exosomes Single  Diagnosis HCC vs. LC  87 vs. 31  N/A   N/A    0.82  [57]
                miR-595   Up      Exosomes Single  Diagnosis HCC vs. LC  87 vs. 31  N/A   N/A    0.92  [57]
                miR-638   Down    Exosomes Single  Diagnosis HCC vs. HL  126 vs. 21  N/A  N/A    N/A  [75]
                miR-665   Up      Exosomes Single  Diagnosis HCC vs. HL  30 vs. 10  N/A   N/A    N/A  [74]
                miR-885-5p  Up    Serum  Single    Diagnosis HCC + CHB + LC  46 + 23 + 26   90.5  79.2  0.94  [142]
                                                          vs. HL      vs. 24
                miR-939   Up      Exosomes Single  Diagnosis HCC vs. LC  87 vs. 31  N/A   N/A    0.84  [57]
                miR-96    Up      Serum  Single    Diagnosis HCC vs. CHB     104 vs. 100  77.9  75.3  0.83  [143]
                miR-96    Up      Serum  Single + AFP  Diagnosis HCC vs. CHB   104 vs. 100  83.6  82.4  0.88  [143]
                miR-96    Up      Serum  Single    Diagnosis HCC vs. CHB   104 vs. 100  77.9  75.3  0.80  [143]
                miR-96    Up      Serum  Single    Diagnosis HCC vs. HL    104 vs. 120  N/A  N/A  N/A  [143]
                miR-96    Up      Serum  Single    Diagnosis HCC vs. LC   104 vs. 90  N/A  N/A   N/A  [143]
               AUC: area under the receiver-operating characteristic curve; AFP: alpha fetoprotein; BLD: benign liver disease; CH: chronic hepatitis;
               CHB: chronic hepatitis B; CHC: chronic hepatitis C; CLD: chronic liver disease; DN: dysplastic nodules; HBV: hepatitis B virus; HCC:
               hepatocellular carcinoma; HL: healthy liver; LC: liver cirrhosis; (T): training set; (V): validation set; N/A: not available data


               two reports [45,47] , but others reported miR-21 high in plasma of HCC patients [48,49] . Analysis of miR-125-b
               and miR-101 levels also displayed variances between serum and plasma: an upregulation of plasma miR-
                                                                                    [43]
               125-b levels was reported in HCC patients in comparison with healthy controls , while downregulation
                                                  [50]
               of the same miRNA was found in serum ; miR-101 levels were found high in plasma of HCC patients in
                                             [51]
               comparison with healthy controls , whereas this miRNA was found downregulated in serum of HCC
               patients in comparison with healthy controls at least by two reports [52,53] . These several examples support the
               concept that differences between plasma and serum are common and should be taken in consideration when
               comparing results from different studies.

               The use of plasma or serum is not the only source of variability of achieved results. An analysis of published
               studies strongly suggests that both pre-analytical and analytical procedures can affect results. Any change
               in tissue collection steps (like type of blood tubes, centrifugation strength and sample conservation) can
               generate differences in miRNA levels [54,55] . Considering the different hard-to-control sources of variability, it
               is not difficult to understand how uneven and sometimes even opposite results can easily derive.

               In addition to technical reasons, aspects linked to experimental design can also be added to factors
               responsible for heterogeneity of results. The existence of various types of control populations represents
               indeed a source of variability and, in some cases, a limitation to the practical value of such results. In fact,
               for identifying useful biomarkers for the early detection of HCC it is very important to compare HCC not
               only with healthy controls but vs. cirrhotic patients, considering that 80%-90% of HCCs arise in this group
               of high-risk patients. A paradigmatic example is miR-122, a liver-specific miRNA whose level was found
               increased in serum/plasma of HCC patients in comparison with healthy patients [45,51] , but studies found
               no significant differences when HCC patients were compared to cirrhotic or chronic hepatitis patients [51,56] .
               These findings indicate that increased circulating miR-122 levels likely reflect liver damage rather than the
               presence of an underlying HCC, indicating the importance of controls to draw conclusions. Among studies
                                                                                                        [57]
               that produced results on differential circulating miRNAs between HCC vs. cirrhotic patients, Fornari et al.
               found that serum miR-939, miR-595 and miR-494 could separate cirrhotic patients with and without HCC,
                                                   [51]
               performing better than AFP. Moshiri et al.  showed that the combination of three plasma miRNAs, miR-
               101-3p, miR-106b-3p and miR-1246, exhibited a high diagnostic accuracy in discriminating HCC from
               cirrhotic patients. Combination of two of the same miRNAs, miR-101-3p and miR-106b-3p, exhibited also an
                                                                                  [58]
               excellent diagnostic accuracy in serum of HCC vs. cirrhotic patients. Chen et al.  proved that plasma miR-
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