microRNA Biomarkers as Potential Diagnostic Markers for Cancer - Genomic Biomarkers for Pharmaceutical Development - page 111

healthy controls [199] . Interestingly, miR-221 levels were correlated with p53 as demonstrated
by immunohistochemical analysis. Kanaan et al. evaluated the expression of 380 miRNAs in
30 matched normal adjacent tissues and CRC tissues and identified 19 dysregulated miRNAs
[200] . Of those miRNAs, miR-21 was up-regulated in plasma of CRC patients and was able to
distinguish them from healthy controls with 90% sensitivity and specificity [200] .
Unlike miR-21, which has been shown to act as an oncomir, the level of miR-34 has been
shown to be reduced in several cancer types, including CRC and breast cancer, delineating its
function as a tumor suppressor [201] .
In another large study performed on a training set of 102 plasma samples and a valida-
tion set of 156 plasma samples, Cheng and coworkers showed that miR-141 was significantly
associated with stage IV colon cancer, and that the combination of miR-141 levels with CEA,
a commonly used CRC marker, resulted in increased accuracy of colon cancer detection [202] .
This study suggests that apart from being used as standalone markers, miRNAs may also be
used to complement existing cancer markers.
5.3.2.7 Liver Cancer
Liver cancer (hepatocellular carcinoma, HCC) is the most frequent cancer type worldwide,
accounting for over 750,000 new cases and 700,000 deaths every year [203] . The major etiologies
for HCC include hepatitis B virus infection, alcohol abuse, and toxic chemical exposure. HCC
is often diagnosed at a late stage when treatment options are limited and the prognosis is poor;
early diagnosis is thus instrumental to being able to control the disease. Because HCC has been
much more common in developing countries, cost-effective diagnosis and non-invasive sample
collection are needed. To address this persistent need, circulating miRNAs have been evaluated
for their ability to diagnose HCC.
miR-122 has been consistently identified as an important miRNA marker in liver, and
is the first miRNA to be targeted in clinical trials (see the section 'miRNAs as Potential
Therapeutics'). Jopling and colleagues were among the first to show that miR-122 inter-
acts with the 5' non-coding region of hepatitis C virus, and further that miR-122 could act to
facilitate replication of viral RNA [204] . Gui et al. examined the expression of miRNA using
TaqMan miRNA arrays and reported that the expression of miR-885-5p was significantly
higher in sera from HCC and liver cirrhosis as compared to healthy controls [205] . However,
this study did not reveal any correlation between miR-885-5p expression and liver function
protein. Zhang and coworkers examined miRNA expression in plasma from two mouse
models (D-galactosamine and alcohol-induced liver injury) and in human plasma sam-
ples collected from 83 patients with chronic Hepatitis B viral infections, 15 patients with
skeletal muscle disease, and 40 healthy volunteers. In plasma from both humans and mice,
increased levels of miR-122 were associated with aminotransferase activity in the blood [206] .
Interestingly, changes in miR-122 expression were specific to damage to the liver but not other
organs, and most importantly, correlated with liver histologic stage. Zhang's findings sug-
gested miR-122 as a potential diagnostic and predictive marker for viral, alcohol, and chemi-
cal-induced liver damage.
Another study examined expression of three miRNAs (miR-21, miR-122, and miR-223)
in sera from 101 HCC patients and 89 healthy controls [207] . These miRNAs are commonly
up-regulated in HCC tissues, and, as it turned out, they were also expressed at significantly
higher levels in serum samples collected from patients with HCC or chronic hepatitis than