microRNA Biomarkers as Potential Diagnostic Markers for Cancer - Genomic Biomarkers for Pharmaceutical Development - page 112

in the controls. This observation suggests that serum levels of miR-122, miR-21, and miR-223
could be useful markers for liver injury. Substantiating these findings for miR-122, Qi et al.
also found increased levels of miR-122 in HCC (N = 48) compared to controls (N = 24) [208] .
However, the miRNA did not distinguish HBV patients with and without HCC [207,208] . The
potential of using circulating miR-122 in HCC has been controversial, as other studies show
down-regulation in HCC instead of up-regulation [209] .
In an effort to identify circulating miRNAs that could distinguish HCC from chronic liver
disease, Qu et al. examined the expression levels of miR-16, miR-195, and miR-199a, alone or
in combination with conventional serum markers for HCC, in sera of 105 HCC patients, 107
chronic liver disease patients, and 71 healthy controls [210] . The authors found that miR-16
and miR-199a were significantly lower in HCC compared to chronic liver disease patients
or controls. Although miR-16 alone was able to distinguish HCC from controls, combining
miR-16 with conventional markers (such as α-fetoprotein) yielded improved sensitivity and
specificity for HCC compared to either miR-16 alone or conventional markers alone [210] .
Similarly to the other cancer types, circulating miR-21 has also been shown to be diagnostic
for HCC [211] , although this finding is controversial [212] .
5.3.2.8 Prostate Cancer
Prostate cancer is second only to lung cancer in worldwide incidence, and, in the US, it is
the second most common cause of cancer mortality in men aged 40 years or older. Prostate
cancer in general is categorized into two forms, castrate sensitive and castrate resistant.
The latter form often leads to bone metastasis and is incurable. Since prostate cancer is usu-
ally an indolent disease that predominantly occurs in an aging population, management at
times is limited to watchful waiting. However, the challenge of identifying the minority of
men with aggressive disease remains, as the treatment carries risks which can severely affect
quality of life. Currently, prostate specific antigen (PSA) is the only approved blood-based
marker for screening of prostate cancer. However, PSA is non-specific because it is also ele-
vated in benign prostate hyperplasia (BPH), and therefore cannot be accurately used to dis-
tinguish cancer from chronic inflammation of prostate tissue. In 2012, the FDA approved
the PROGENSA ® PCA3 assay by Gen-Probe, Inc. The test is an RNA-based assay in which
the expression levels for PCA3 and PSA are measured in the first catch urine sample follow-
ing a digital-rectal examination in men aged 50 years old or older. The ratio of PCA3 to PSA
RNA molecules is reported as a score that is used to guide the urologist in deciding whether
a repeat biopsy is needed in men with prior negative prostate biopsies, thereby reducing
the number of unnecessary biopsies. Evidence so far has also indicated that the PCA3 test
is more accurate in discriminating prostate cancer than PSA alone [213,214] . These findings
support the utility of RNA detection in non-invasive sample types to improve disease man-
agement. Circulating miRNAs are a non-invasive alternative biomarker that may also aid in
the diagnosis of prostate cancer.
Several miRNAs including miR-34a have been shown to be dysregulated in prostate can-
cer tissue relative to normal [215] . In addition, miR-15a, miR-16, miR-21, miR-125b, miR-143,
miR-145, miR-200 family, miR-221, miR-222, and miR-448 have been shown to influence the
progression of prostate cancer (reviewed in [215] ) as well as regulate key cancer genes like
BCL2, WNT3A, VEGF, KRAS, TPM1, and PDCD4 (reviewed in [215] ). Although this is an
active field of research, this section focuses only on reviewing work on circulating miRNAs.