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miR-15b and miR-130b as biomarkers holds promise for screening methods, CCA is rarely diagnosed during early
patients with early-stage HCC, who may have low AFP stages of the disease when surgical procedures are most
levels despite the presence of disease. Similarly, serum effective. [114] Histopathological analyses suggest that
miR-16 was found to be a more sensitive biomarker than the presence of primary sclerosing cholangitis, chronic
serum AFP and Des-γ-carboxyprothrombin (DCP). [105] biliary irritation, or choledochal cysts may predispose
The combination of miR-16, AFP, AFP-L3%, and DCP individuals to CCA. [115] More recently, studies have
yielded the optimal combination of sensitivity (92.4%) identifi ed a role for miRNAs in the development of CCA
and specifi city (78.5%) for HCC overall and when the by altering different cholangiocyte features such as cell
analysis was restricted to patients with tumors smaller cycle, proliferation, migration and apoptosis. [116-118]
than 3 cm. [106] In addition, a recent meta-analysis of miRNAs as novel diagnostic and prognostic
8 studies showed the diagnostic value of miRNAs as biomarkers in CCA
follows: Pooled sensitivity 0.87 (0.72-0.98), pooled
specifi city 0.90 (0.76-1.00), pooled positive likelihood The study by Meng et al. [119] was the fi rst to hint at the
ratio 8.7 (3.52-97.45), pooled negative likelihood ratio potential of miRNAs as biomarkers. It was found that
0.13 (0.02-0.31), and pooled diagnostic odds ratio miR-21 and miR-200b expression levels were predictors
86.69 (19.06-2646.00). [107] of gemcitabine resistance.
Although sensitivity and stability of miRNAs as By sequencing and comparing the small RNA libraries of
biomarkers are suitable for a clinical setting, appropriate two CCA cell lines to one of a normal biliary epithelial
controls must be used in a research setting because HCC line, Kawahigashi et al. [120] identifi ed and confi rmed
is often accompanied by viral hepatitis, cirrhosis, or miR-22, miR-125a, miR-127, miR-199a/a0, miR-214,
other underlying liver conditions. [108] When assessing the miR-376a and miR-424 as specifi cally expressed in
specifi city of an miRNA for detecting HCC, it is critical normal biliary epithelial cells, but down-regulated in CCA
to ensure that patients and controls are matched, not only cell lines, suggesting their use as biomarkers for diagnosis.
by age and sex, but also by etiology and severity of the Chen et al. [121] took the approach of using miRNA sensor
underlying liver disease. constructs to compare spatiotemporal activity of six
miRNAs (miR-21, miR-200a, miR-200b, miR-146a,
Clinical application of miRNAs in HCC
miR-155 and miR-221) in primary tissue blocks of CCA
Recently, miravirsen, a locked nucleic acid-modifi ed and normal control tissue grown from three patients using
DNA phosphorothioate antisense oligonucleotide adeno-associated viral infections. They were unable to
against miR-122, became the fi rst miRNA-targeting identify a defi nitive pattern between activity of each
drug to receive permission for clinical use. [109] It miRNA and presence of CCA over the entire time frame
was developed to target HCV, as the stability and but when focusing on 24 h post-infection the miRNA
propagation of this virus are dependent on a functional profi les, displayed signifi cant differences between CCA
interaction between the HCV genome and miR-122. [110,111] and control as well as between patients, suggesting
Miravirsen resulted in a dose-dependent reduction in these miRNAs play an active role in CCA. Karakatsanis
HCV levels, without major adverse events and with no et al. [122] evaluated the expression levels of several miRNA
escape mutations in miR-122 binding sites of the HCV species in intrahepatic cholangiocellular carcinoma
genome. [109] The success of miravirsen is promising, not and their prognostic signifi cance. Although miR-21,
only as a novel anti-HCV drug, but also as the fi rst trial miR-31, and miR-223 were found to be up-regulated and
of miRNA-targeting therapy. In addition to miravirsen, a miR-122, miR-145, miR-200c, miR-221, and miR-222
clinical trial of MRX34 (miRNA Therapeutics, Austin, to be down-regulated, the group was unable to fi nd
TX, USA) as a mimic of miR-34 is underway. MRX34 any correlation with clinical or pathological features.
is a liposome-formulated mimic of the tumor suppressor, McNally et al. [123] tried to investigate the predictive role
miR-34. Further study of MRX34 is being conducted by of miRNAs on survival in resected CCAs and found 2 of
miRNA Therapeutics, which initiated a Phase I study in 43 miRNA species evaluated to have the best correlation
May 2013 to examine effects of MRX34 on unresectable with survival. Up-regulation of miR-151-3p (41.5 months
primary liver cancer or advanced or metastatic cancer vs. 12.3 months) correlated better than down-regulation
with liver involvement. If these oligonucleotide of miR-126 (21.9 months vs. 15.1 months). However,
therapies are successful, then therapeutic options concomitant dysregulation of both showed the
based on the numerous miRNAs deregulated during best overall correlation with survival (58.7 months vs.
hepatocarcinogenesis appear to be promising. [112] 15.1 months).
In a novel approach using bile, Li et al. [117] were able
Cholangiocarcinoma
to demonstrate the presence of miRNAs in extracellular
Cholangiocarcinoma (CCA) is one of the most common vesicles in bile and analyzed the miRNA expression of
malignancies derived from bile duct epithelial cells. [113] 74 different species that could be reliably amplifi ed. By
Due to slow growth, late metastasis, and lack of effective using a multivariate organization of the combinatorial

148 Journal of Cancer Metastasis and Treatment ¦ Volume 1 ¦ Issue 3 ¦ October 15, 2015 ¦