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with healthy controls and/or chronic liver disease and miR-183 was up-regulated in 9 others. Down-
[53]
patients. [39,40] Serum miR-505 level was also increased regulation of miR-139, miR-144, miR-101-2, miR-451
[41]
in HCC cases compared to controls. The expression and miR-486 was also reported in various cancer types
of miR-130a was significantly higher in HCV-infected besides HCC. These observations are biologically
hepatocytes and liver biopsy specimens. While plausible because the “tumor common” miRNAs and
[42]
in prostate cancer and glioblastoma, miR-130a their target genes participate in general carcinogenic
[43]
[44]
was significantly down-regulated showing the same processes and tumorigenic pathways, such as p53,
pattern as in HCC, indicating possible non-specificity phosphatase and tensin homolog, fibroblast growth
as HCC biomarker. It is known that certain miRNAs factor receptor 3, DNA damage/repair, apoptosis,
may act as both tumor suppressor and oncogene in angiogenesis, cell cycle, phosphoinositide 3-kinase,
a cell/tissue specific manner or vary by etiology and mitogen-activated protein kinase, TGFβ, NOTCH, and
cancer stage because they simultaneously regulate Wnt signaling pathways, etc. [54-56] Therefore, “tumor
multiple target genes involved in different biological common” miRNAs aberrantly expressed in various
pathways. The function of miR-24 as a tumor tumors may provide clues to further investigate
suppressor can inhibit cell proliferation, migration and their common similar underlying mechanisms in
invasion by regulating cMyc and E2F2 in HCC-derived tumorigenesis. If verified, the miRNA signatures may
HepG2 cell line, and Fascin homologue 1 (FSCN1) in be promising targets for precision cancer prevention
[45]
nasopharyngeal carcinoma cell lines. On the other and therapy. However, these miRNAs may have limited
[46]
hand, miR-24 acted as an oncogene directly repressing power as diagnostic tools to detect specific cancer
SOX7 (Sex Determining Region Y-Box 7), a putative type because of their “non-specificity”.
tumor suppressor, and overexpressed miR-24 led
[47]
to inhibition of hepatocyte nuclear factor 4α and The advantages of the current research include a two-
initiated hepatocellular transformation through an phase study design using a discovery and independent
epigenetic positive feedback circuit in the absence of validation sample sets, paired tumor/non-tumor
genetic alterations. Tumor suppressor gene (p16) tissues, and unpaired tissues to verify promising
[49]
[48]
and pro-apoptotic protein FAF1 can be negatively miRNAs; simultaneously analyzing miRNA sequencing
[50]
regulated by miR-24 in cervical carcinoma, prostate, data in multiple cancer types that allows us to identify
gastric and HeLa cells. These data strongly suggested “HCC specific” and “tumor common” miRNAs panels.
the complicated network of miRNA alterations in We used the most stringent criteria to select miRNAs
tumorigenesis that needs further clarification. for the final data analyses, i.e., RPMM ≥ 10 in at least
90% of samples and P-value < 0.0001 as the significant
Several “tumor common” miRNAs have been extensively level to adjust for multiple comparisons. Other studies,
studied in HCC, as well as in various other cancers, but such as Wojcicka et al. analyzed miRNAs (GSE63046)
[57]
have not been recognized for their generalizability passing the criteria of RPMM ≥ 5 in samples with over
as “tumor type non-specific” biomarkers. The over- 50% detectable rate; Zhang et al. excluded miRNAs
[58]
expression of miR-21 has been commonly observed in with missing data exceeding 10% of all subjects but
HCC tumor compared to adjacent non-tumor tissues, without precluding unreliable sequencing reads less
as well as in the circulation of patients with HCC. The than 10, which may lead to biased results or identify
overall pooled results from a diagnostic meta-analysis miRNAs with too much missing data, and are unable
of miR-21 revealed a sensitivity of 74% and a specificity to be applied in clinical samples.
of 78% for HCC classification that is far from ideal
[51]
for clinical application. Meanwhile, miR-21 was also In interpreting the results, some drawbacks need
significantly up-regulated in other cancer types (breast, to be recognized. First, for some miRNAs, the
colorectal, esophageal, gastric, lung, pancreatic and results are not in agreement with previous studies.
prostate), and the overall predictive sensitivity and For example, miR-122 was identified as the most
specificity were, respectively 76% and 79%, which abundant miRNAs in liver tissue previously, [59,60] but
[52]
were similar to HCC. The cluster of miR-182/miR-96/ is only the 7th in the TCGA data; miR-3591 has been
[60]
miR-183 located within 2-4 kb at chromosome 7q32 reported as abundant in liver tissue, but is not
functions as micro-oncogenes in carcinogenesis even detectable in TCGA data. So we may miss a
and the metastatic cascade. Two members (miR- few important candidates due to different detection
182, miR-183) of this cluster showed frequent up- techniques (RNA-seq, microarrays and RT-qPCR);
regulation in HCC. The expression of miR-182 was different approaches and criteria for data processing
[53]
also consistently increased in 14 other cancer types and analysis, and the heterogeneity of tumor tissue

160 Hepatoma Research | Volume 2 | June 1, 2016