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A similar study found that levels of miR-141 were elevated cells to 5FU leads to increased miR-21 expression, and
in metastatic CRC and its expression was associated with this may be a response to genotoxic stress to help cells
a poor prognosis, suggesting that this miRNA may be overcome the effects of 5FU. Additional in vitro data
[84]
used in conjunction with carcinoembryonic antigen to support the roles for altered expression of miR-140,
[85]
detect CRC with distant metastases. [67] miR-215, miR-224 and miR-20a in developing
[87]
[88]
[86]
chemoresistance. Further studies are warranted to
Measuring miRNAs in stool offers another non-invasive
approach to detect CRC. One small study of 29 CRC determine whether expression of these miRNAs can
cases and 8 healthy controls found that stool from CRC predict response to chemotherapy and if those miRNAs
cases expressed higher levels of miR-21 and miR-106a. can be used as therapeutic targets themselves. MiRNA
[68]
A larger study of 197 cases and 134 healthy controls replacement involves reintroducing synthetic miRNA
investigated miRNA expression patterns of colonocytes mimics or expression vectors that will produce the
isolated from feces and was able to demonstrate that miRNA of interest. This has shown promise in preclinical
miRNA expression patterns could distinguish cases from murine models where the reintroduction of miR-145 and
[69]
controls with 74% sensitivity and 79% specifi city. miR-33a had an antitumor effect in a model of colon
[89]
A similar strategy found that miRNA methylation patterns cancer.
from DNA isolated from stool may be promising as Hepatocellular Carcinoma
[70]
a screening tool for CRC. The hypermethylation
pattern of miR-34b/c in stool samples could distinguish Hepatocellular carcinoma (HCC), the most common
CRC cases from controls with 75% sensitivity and 84% primary liver cancer, is the 5th most frequent cancer
specifi city. Further tests are warranted to determine and the third cause of cancer-related mortality
[90]
whether miRNA expression or methylation patterns worldwide. The incidence of this disease
in stool can be utilized, either alone or in combination is > 600,000 cases annually. [91,92] HCC usually develops
with a fecal occult blood test, as an effective screening as a consequence of underlying liver disease and is often
[93]
strategy for CRC. associated with cirrhosis. Hepatitis B virus (HBV) and
hepatitis C virus (HCV) viral infections, the major risk
The elevated expression of miR-21 has a robust and factors for HCC development, lead to liver cirrhosis and
reproducible association with the CRC prognosis. account for 75% of HCC cases. [94,95] miRNAs have been
Schetter et al. fi rst reported that elevated miR-21 widely reported to be involved in HCC development and
[71]
expression in tumors was associated with a worse survival may be new targets for HCC therapy. [96-98]
prognosis and therapeutic outcome. The association of
elevated miR-21 expression and worse survival outcomes miRNAs as novel diagnostic and prognostic
in CRC has been validated in at least three additional biomarkers in HCC
studies. These include the studies of 156 Japanese CRC Many miRNAs are dysregulated in HCC; thus, it is to
[72]
[73]
patients, 46 CRC patients from the Czech Republic, be expected that circulating miRNA levels are also
and 130 tumor node metastasis stage II colon cancer affected by HCC progression. The high stability of
[74]
patients from Denmark. Additional studies have miRNAs in circulation makes them excellent biomarkers,
identifi ed miRNA expression patterns that are associated especially for early detection. It is interesting that
[99]
with either prognosis or therapeutic outcome. Expression circulating miR-21, [100,101] miR-222 [101] and miR-223, [102]
[75]
levels of miR-106b, miR-320, miR-498, were up-regulated in serum/plasma of HCC patients
[76]
[76]
[78]
[79]
[77]
miR-125b, miR-145, miR-185, miR-133b, associated with HBV or HCV. Circulating miR-21
[79]
[80]
[81]
miR-215 and miR-17 have each been reported to levels were signifi cantly higher in HCC patients than
be associated with prognosis or therapeutic outcome. An in those with chronic hepatitis and healthy controls.
elevated expression of Dicer, an important gene encoding A receiver-operating characteristic analysis of miR-21
an RNA nuclease involved in miRNA processing, is yielded an AUC of 0.773 when differentiating HCC
associated with poor prognosis in CRC. Further from chronic hepatitis, and an AUC of 0.953 when
[82]
validation of these associations is warranted and may differentiating HCC from healthy controls. Both sets of
reveal additional prognostic classifi ers.
values were superior to alpha-fetoprotein (AFP) as an
Clinical application of miRNAs in CRC HCC biomarker. [102] At the same time, the serum levels of
miR-1, miR-25, miR-92a, miR-206, miR-375 and let-7f
Schetter et al. have shown that miR-21 expression is [103]
[71]
associated with therapeutic outcome with 5FU-based were also signifi cantly elevated.
therapies. This association, in combination with the Serum miR-15b and miR-130b levels were also
known oncogenic role for miR-21, suggests that increased up-regulated in HCC. [104] MiR-130b had the largest
miR-21 expression is, in part, responsible for resistance AUC (0.913), with a sensitivity of 87.7% and specifi city
to 5FU. Elevated miR-21 induces resistance to 5FU in of 81.4%, and miR-15b had the highest sensitivity of
colon cancer cell lines by down-regulating DNA repair miRNAs examined (98.3%), although its specifi city was
protein MutS homolog 2. Exposure of colon cancer very low (15.3%). The high sensitivity of circulating
[83]
Journal of Cancer Metastasis and Treatment ¦ Volume 1 ¦ Issue 3 ¦ October 15, 2015 ¦ 147