Page 168 - Read Online

455 were significantly down-regulated in HCC, but to tumorigenesis itself. However, most etiologic
significantly upregulated in 5 other solid tumors. The relevant miRNAs were also consistently observed
down-regulated expression pattern of miR-142 and in overall HCC, indicating similar fundamental
miR-455 were confirmed in the CUMC HCC validation mechanisms involved in hepatocarcinogenesis
set [Supplementary Table 5]. These results suggest that regardless of different etiologies. These candidate
miR-142 and miR-455 may be potential HCC “tumor miRNAs may be applied to improve clinical early
specific” markers, but they should be considered as diagnosis of HCC and more precise prevention and
“tumor common” markers for 5 other tumor types. therapy. A similar research strategy can be adopted
to discover and verify other “tumor type specific”
Searching for target genes and biologically enriched miRNAs and promote early detection and precise
pathways treatment of different types of cancer.
Mirsystem was used to search for target genes of
the 5 HCC “tumor specific” miRNAs (miR-24-1, miR- Accumulating evidence based on genome-wide
130a, miR-505, miR-142 and miR-455). A total of and candidate miRNA approaches have uncovered
2,270 genes (1,937 unique genes) were obtained as miRNAs dysregulation in HCC acting as either
the targets of at least one miRNA [Supplementary oncogenes or tumor suppressors. [22,23] A few but
Table 6]. Among them, 619 genes were identified not all studies of the 5 “HCC tumor specific”
by 5 out of 7 predictive tools or are experimentally miRNAs are consistent. The expression of miR-
validated miRNA-targets including 577 unique genes 24 was significantly reduced in HCC with cirrhosis
because some might be targeted by 2 or 3 miRNAs compared to adjacent cirrhotic tissue, suggesting an
[Supplementary Figure 10]. Among target genes, influence on hepatocyte carcinogenic transformation
[24]
130 genes have been associated with HCC in at least of cirrhotic tissues. Significant down-regulation
one previous report by comparing with Liverome of miR-130a was observed in over 75% (78/102) of
database (http://liverome.kobic.re.kr/). [21] Upon HCC tumor tissues. The same repression pattern
[25]
further evaluation for enriched biological function, of miR-130a was also found in HCV-infected human
we identified several important biologic pathways, HCC cells and rat liver tissue after treatment
[26]
including transforming growth factor beta (TGFβ) with AFB , a strong hepatocarcinogen. A recent
[27]
1
receptor signaling pathway, endocytosis, signaling by study found that miR-142-3p and miR-142-5p were
[28]
epidermal growth factor receptor, signaling by nerve significantly downregulated in HCC. The ectopic
growth factor (NGF), NGF signaling via tropomyosin expression of miR-142 significantly reduced HCC cell
receptor kinase A from the plasma membrane, migration and invasion, and overexpression both
BMAL1: CLOCK/NPAS2 activates circadian expression miR-142-3p and miR-142-5p synergistically inhibited
and adherens junction [Supplementary Table 7], HCC cell migration, indicating their cooperative
which confirmed the potential biological role of HCC regulatory role. This result is supported by a
[28]
specific miRNAs involved in tumorigenesis. mechanistic study demonstrating that miR-142-3p
can directly repress the expression of RAC1 (Ras-
DISCUSSION Related C3 Botulinum Toxin Substrate 1), which
regulates a diverse array of cellular events including
The most interesting finding in the current study increased colony formation, migration and invasion
was significant down-regulation of miRNAs (miR-24- in HCC cell lines. Only one study observed miR-455
[29]
1, miR-130a, miR-505, miR-142 and miR-455) in HCC significantly down-regulated in HCC tissue and serum
tumor tissue that showed “tumor type specificity” in HCC related to type I glycogen storage disease.
[30]
[Figure 2, Supplementary Table 5]. Additionally, a The different up-regulation patterns of miR-130a and
panel of miRNAs (miR-21, miR-182, miR-183, miR- miR-505 in other solid tumors (bladder, breast,
[31]
[32]
139, miR-144, miR-101-2, miR-451 and miR-486) was gastric, ovarian, colorectal and non-small cell
[34]
[35]
[33]
first identified as “tumor common” markers that lung cancers ) provide further evidence for their
[36]
are significantly altered in most solid tumors by potential as HCC specific biomarkers.
comparing RNA-seq data from 9 different cancer types
[Figure 3, Supplementary Table 5]. A few miRNAs However, inconsistent results were also observed in
were also significantly dysregulated in etiology-specific previous studies that suggest significant up-regulation
(alcohol drinking, HBV- or HCV- infection) HCC [Table 3, for some of “HCC specific” miRNAs. For example,
Supplementary Figures 5 and 6], suggesting the miR-24 was found significantly up-regulated in HCC
potential impact of different etiologies in addition tumor tissue, cell lines, [37,38] and serum compared

Hepatoma Research | Volume 2 | June 1, 2016 159