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Analysis of serum miRNAs in 10 prostate cancer patients, patients with BPH, and healthy
controls revealed that miR-26a could distinguish prostate cancer form BPH subjects
[216]
.
Most importantly, Mahn's studies showed that miR-195 and let-7i were significantly cor-
related with Gleason score, and further that the levels of these circulating miRNAs were
decreased after prostatectomy
[216]
. Circulating murine miR-141, miR-375, and miR-298 were
demonstrated to be highly expressed in sera of TRAMP mice with advanced prostate can-
cer relative to healthy controls
[217]
. The human homologs of the same three miRNAs were
confirmed to be up-regulated in sera of 25 men with prostate cancer relative to sera from 25
healthy controls. This confirmation of animal model results in human specimens validates
the use of animal models in discovery of circulating miRNA biomarkers, and furthermore
strongly suggested that miR-141 and miR-375 could be used as potential biomarkers for detec-
tion of prostate cancer. The role of circulating miR-141 and miR-375 in prostate cancer was
also further confirmed by the findings of Bryant et al. using plasma derived micro-vesicles
from 78 prostate cancer patients and 28 controls
[218]
. In that study, Bryant showed that
plasma miR-141 and miR-375 were associated with metastatic prostate cancer, a finding that
was also confirmed in serum from an independent patient group. An interesting finding from
Bryant's studies was that urine levels of miR-107 and miR-574-3p were much higher in pros-
tate cancer compared to controls, supporting the use of urine as a potential biomarker spec-
imen
[218]
. Gonzales et al. examined the utility of plasma miR-141 as a treatment response
marker in 21 prostate cancer patients and correlated the data to PSA and CTCs as well as lac-
tate dehydrogenase
[219]
. Each patient had multiple serial collections of plasma during the
course of the study. miR-141 was found to be correlated with clinical outcome and was highly
correlated with PSA changes over time. The miR-141 and miR-375 findings were also sup-
ported by studies by Nguyen et al. who showed that serum miR-141, miR-375, and miR-378*
were expressed at significantly higher levels in patients with localized prostate cancer com-
pared to those with metastatic disease
[220]
. Both miR-141 and miR-375 have also been shown
to be overexpressed in prostate tumors compared to normal prostate tissue. Based on these
reports, both miR-141 and miR-375 are good candidates for diagnosis as well as predicting
disease course. Recently, Shen and coworkers examined the ability of plasma miRNA to iden-
tify prostate cancer patients with aggressive disease
[221]
. The study showed that miR-20a,
miR-21, miR-145, and miR-221 were able to distinguish low risk from high risk prostate cancer
as classified by the D'Amico system. Levels of miRs-20a and miR-21 were elevated and associ-
ated with high CAPRA scores
[221]
, a measure used to predict recurrence.
5.
4 THE CHALLENGE OF miRNAs AS BIOMARKER
S
The expression of miRNA is influenced by patient-specific factors such as the specific dis-
ease condition. However, not fully understood are other factors that affect miRNA expression
and detection. In general, these can be classified into pre-analytical and analytical variables.
While the patient-specific variables such as smoking and alcohol cannot be controlled, pre-
analytical variables such as the choice of sample type (e.g., whole blood, plasma, or serum),
sample numbers, study design, sample collection method, sample stabilization and storage,
and RNA extraction method can be controlled. Using the example of circulating miRNAs in
lung cancer, it is important to note that, although all of the studies supported the diagnostic
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