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Guerriero et al. Hepatoma Res 2019;5:6  I  http://dx.doi.org/10.20517/2394-5079.2018.108                                      Page 11 of 22


               Table 3. Circulating miRNAs as prognostic biomarkers of hepatocellular carcinoma
                                                     Experimental             Sample   Kaplan-Meier
                miRNA            Expression 1  Body fluid        Clinical setting                    Ref.
                                                       setting                 size  analysis (P value)
                miR-101          Down       Plasma   Single      Prognosis (DFS)  163    P < 0.001  [144]
                miR-122          Down       Serum    Single      Prognosis (OS)  122     P < 0.01   [145]
                miR-1247-3p      Up         Serum    Single      Prognosis (OS)  85      P < 0.05   [131]
                miR-1247-3p      Up         Serum    Single      Prognosis (DFS)  85     P < 0.01   [131]
                miR-125a-5p      Down       Serum    Single      Prognosis (OS)  120     P < 0.01   [76]
                miR-125b         Down       Exosomes  Single     Prognosis (OS)  128     P < 0.01   [77]
                miR-143          Down       Serum    Single      Prognosis (OS)  131     P < 0.05   [132]
                miR-148a         Down       Serum    Single      Prognosis (OS)  76      P < 0.001  [71]
                miR-152          Down       Serum    Single      Prognosis (OS)  76      P < 0.05   [71]
                miR-192-5p       Up         Serum    Single      Prognosis (OS)  74      P < 0.01   [125]
                miR-192-5p       Up         Serum    Single      Prognosis (PFS)  74     P < 0.01   [125]
                miR-29a-3p       Up         Serum    Single      Prognosis (OS)  74      P < 0.01   [125]
                miR-29a-3p       Up         Serum    Single      Prognosis (PFS)  74     P < 0.05   [125]
                miR-21, lncRNA-ATB   Up     Exosomes  Single + lncRNA  Prognosis (OS)  79  P < 0.05  [80]
                miR-21, lncRNA-ATB   Up     Exosomes  Single + lncRNA  Prognosis (PFS)  79  P < 0.05  [80]
                miR-218          Down       Serum    Single      Prognosis (OS)  156     P < 0.05   [73]
                miR-221          Up         Serum    Single      Prognosis (OS)  46      P < 0.05   [72]
                miR-224          Down       Serum    Single      Prognosis (OS)  182     P < 0.05   [146]
                miR-24-3p        Up         Serum    Single      Prognosis (OS)  84      P < 0.01   [67]
                miR-24-3p        Up         Serum    Single      Prognosis (DFS)  84     P < 0.01   [67]
                miR-638          Down       Exosomes  Single     Prognosis (OS)  126     P < 0.01   [75]
                miR-96           Up         Serum    Single      Prognosis (OS)  49      P < 0.05   [143]

               1 Expression in the group with the poorest prognosis. lncRNA: long noncoding RNA; OS: overall survival; PFS: progression free survival; DFS: disease-
               free survival

                                                                          [59]
               125b could differentiate HCC from cirrhotic patients, and Guo et al.  found that serum miR-21 analysis
               had also a good diagnostic efficacy in discriminating HCC patients both from non-HCC populations or
               from cirrhotic patients. Analyses of miRNA panels have been used for discriminating cirrhotic patients with
               or without HCC. For example, two different miRNA panels have been employed to efficiently distinguish
                                                                                                [60]
               HCC patients from cirrhotic patients, one in serum (miR-122, miR-885-5p, miR-221, miR-181b ) and one
                                                                                      [49]
               in plasma (miR-122, miR-192, miR-21, miR-223, miR-26a, miR-27a and miR-803 ). More recently, Tat
                         [61]
               Trung et al.  showed that a miRNA panel including miR-21, miR-122 and miR-192 had a good diagnostic
               performance in discriminating HCC patients from other groups, in particular from cirrhotic and chronic
               hepatitis patients.

               Another potential limitation of several published studies is the fact that they were based on the assumption
               that cell-free miRNA levels were altered as a consequence of their release by neoplastic cells, and tried to
               validate as circulating cancer biomarkers the same miRNAs deregulated in tumor tissues. This assumption
               may not be correct [62,63] . In fact, if we consider that ctDNA represents a small or very small fraction of
               cfDNA (approximately 0.1%-1% or less for non-metastatic tumors and 1%-10% for large metastatic tumors),
               it is difficult to conceive that cancer cells could instead release such a high amount of RNA to significantly
               change content and levels of specific circulating RNAs. While this consideration raises doubts about
                                                                                                 [64]
               the source of circulating RNAs, a number of studies (see review by McAllister and Weinberg ) offer a
               possible explanation by indicating that cancer should be considered a systemic disease. In this view, tumor-
               associated systemic processes may unbalance the release of miRNAs from non-tumor cells and therefore
               change circulating RNA profiles. Thus, finding altered circulating miRNA profiles would represent evidence
               of a systemic pathophysiological process closely linked to the presence of a tumor, and such RNAs would
               then represent actual circulating tumor biomarkers, although largely not directly released by tumor cells. In
               this viewpoint, the numerous evidences that the altered levels of miRNAs in circulation do not necessarily
               reflect the miRNA deregulation found in cancer tissues would become plausible and results should be re-
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