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alterations, they were able to establish a miRNA-based measured 735 circulating miRNAs in PDAC cases, and
panel of fi ve different miRNA species that were able to controls sera and miR-1290 were found to show the best
distinguish CCA from primary sclerosing cholangitis or diagnostic performance. Kawaguchi et al. [135] found that
other biliary obstructions. This may offer an original way plasma miR-221 concentrations were signifi cantly higher
to make an early diagnosis of CCA. in PDAC patients than those with benign pancreatic
tumors and controls. In recent studies, miRNAs were also
Clinical application of miRNAs in CCA
found to be useful as diagnostic markers for precursor
Meng et al. [119] provided the fi rst evidence for the lesions of PDAC. Caponi et al. [136] found that miR-21
involvement of miRNAs, as well as its fi rst therapeutic and miR-155 were up-regulated in invasive intraductal
use in CCA. When they compared the miRNA expression papillary mucinous neoplasms (IPMNs) compared with
patterns between malignant and non-malignant human non-invasive IPMNs. Further multivariate analyses showed
cholangiocytes, miR-21, miR-141 and miR-200b were that high miR-21 expression emerged as an independent
highly overexpressed in malignant cells and inhibition prognostic biomarker in invasive IPMNs with a poor
of miR-21 and miR-200b sensitized cells to gemcitabine. survival. Lubezky et al. [137] also found miRNAs were
Treatment of xenografts with gemcitabine changed useful in identifying IPMN with high risk for malignant
several miRNA expression levels and modulated transformation. The expression levels of 15 miRNAs,
phosphatase and tensin homolog-dependent PI3 kinase including miR-217, miR-216a, miR-21 and miR-155, were
signaling. Okamoto et al. [124] sought to investigate the signifi cantly different between two IPMN subgroups (low/
role of miRNAs in chemoresistance and compared moderate-grade dysplastic IPMNs vs. high-grade dysplastic
miRNA profi les of two CCA cell lines distinguished IPMN) and invasive cancer with IPMN. Pancreatic cysts
by gemcitabine resistance. They identifi ed miR-29B, are a group of lesions with heterogeneous malignant
miR-205 and miR-221 whose ectopic overexpression potential. Farrell et al. [138] showed miR-21 and miR-221 in
could restore gemcitabine sensitivity in the resistant cell pancreatic cyst fl uid was associated with invasive cancer.
line. They showed that knockdown of two predicted With regard to survival, strong miR-21 expression was
targets, PIK3R1 (miR-29b and miR-221 target) and predictive of poorer outcomes compared with absent
MMP-2 (miR-29b target only), via small interfering or faint/focal miR-21 expression in patients with
RNA conferred the same level of gemcitabine to the node-negative PDAC. [139] Jamieson et al. [140] found that
resistant cell line. They showed that miR-125a-5p was high expression of miR-21 and reduced expression of
up-regulated in the resistant cell line and that inhibition miR-34a were signifi cantly associated with a poor OS in
of miR-125a-5p inhibited cell proliferation in that cell global miRNA microarray expression profi ling. Frampton
line independent of chemoresistance. et al. [141] found that a high level of a combination of
Pancreatic Cancer miR-21, miR-23a and miR-27a was associated with
shorter survival times after surgical resection. While
Pancreatic ductal adenocarcinoma (PDAC) is a lethal strong expression of miR-21 predicted limited survival in
malignancy with a poor prognosis due to advanced PDAC patients, high expression of miR-200c, a member
stage disease at initial diagnosis, frequent recurrence, of the miR-200 family, is a good prognostic sign. [142,143]
and the absence of treatment strategies that specifically Elevated levels of miR-155, miR-203, miR-210 and
and effectively target these tumors. [125] Only 15% of miR-222 expression in PDCA were signifi cantly
PDAC patients are candidates for surgical resection at associated with an increased risk of death compared to
the time of diagnosis. [126] Chemotherapy is considered patients with reduced expression of these miRNAs. [144] A
to be the main treatment option for unresectable subgroup of six miRNAs (miR-452, miR-105, miR-127,
cases, while chemoradiotherapy may improve the miR-518a-2, miR-187 and miR-30a-3p) was found to
survival and quality of life. [127,128] However, PDAC identify long-term survivors with node-positive disease
is still extremely resistant to the currently available from those dying within 24 months. [145] In addition,
regimens. Exploring miRNAs as therapeutic targets increased expression levels of miR-155, miR-203,
and biomarkers for the diagnosis and prognosis of miR-210 and miR-222 were found to be signifi cantly
PDAC is of interest. [129-131] associated with poorer survival. [144,146] In some recent
miRNAs as novel diagnostic and prognostic studies, reduced expressions of miR-218 [147] and
in PDAC tissues were found to correlate
[148]
miR-130b
biomarkers in pancreatic cancer
with a poor prognosis.
Kong et al. [132] found that three serum miRNAs, including Clinical application of miRNAs in pancreatic
miR-196a, were differentially expressed in PDAC compared
with control groups. Another investigation by Wang et al. cancer
showed that the expression levels of four miRNAs in Some prognostic miRNAs also play a role in the effi cacy
plasma (miR-21, miR-210, miR-155 and miR-196a) were of anticancer therapy, thus presenting themselves as
signifi cantly higher in patients with PDAC. [133] Li et al. [134] new therapeutic possibilities. For instance, PDAC cells

Journal of Cancer Metastasis and Treatment ¦ Volume 1 ¦ Issue 3 ¦ October 15, 2015 ¦ 149