Tan Mei Lee 260110142014

Jackie Kang Sing Lung 260110142017

REVIEW FROM JOURNAL TITLE: MicroRNA in prostate cancer: functional

importance and potential as circulating biomarker by Benjamin L Jackson,
Anna Grabowska and Hari L Ratan

NAME OF MARKER

microRNA

DESCRIPTIONS

Prostate cancer (PCa) is the development of cancer in the prostate associated with a
substantial morbidity and mortality. It has reported that 233,000 new cases and 29,480
deaths occurred in the year 2014. Early diagnosis and treatment before tumor
metastasizes is crucial for improving the patient survival. The 5 year survival ratio for
men diagnosed while the PCa is localized is nearly 100 %. And only 28 % of the men
who diagnosed with metastatic PCa survive beyond 5 years. There are still to be
challenges for the early diagnosis of PCa due to its variable presentation.

Diagnostic testing for PCa has been widely studied and searches from biomarkers, such
as the prostate-specific antigen (PSA) assay, to radiologic imaging, such as magnetic
resonance imaging (MRI), and Biopsy. Although widely used as a diagnosis tool,
serum PSA assays are sensitive but not specific enough to detecting PCa. Novel
biomarkers with enhanced detective accuracy would greatly assist the diagnosis of
PCa.

The miRNAs are important regulators of biologic processes in PCa progression. A

common expression profile characterizing each tumor subtype and stage has still not
been identified for PCa, probably due to molecular heterogeneity as well as
differences in study design and patient selection. Large-scale studies that should
provide additional important information are still missing. Further studies, based on
common clinical parameters and guidelines, are necessary to validate the translational
potential of miRNAs in PCa clinical management. Such common signatures are
promising in the field and emerge as potential biomarkers.

MiRNAs present an appealing target for biomarker discovery. Each miRNA possesses
the ability to interact with a number of cellular pathways, and consequently changes
in the expression of a small number of miRNAs may reflect dysregulation of a broad
range of cellular processes, in keeping with the complexity of neoplasia. Furthermore,
miRNAs are relatively resistant to RNase degradation due to their short sequence
length which improves their longevity in both serum and tissue samples. A number of
techniques for miRNA profiling have been developed, and the principle that increased
tissue expression of miRNAs may lead to elevated serum levels has been
demonstrated experimentally.

It may eventually be possible to identify a panel of miRNAs that can be measured in

serum or tissue and used to better establish which patients with localised prostate
cancer will ultimately progress and should therefore be treated aggressively, or indeed
to establish which patients with more advanced disease are most likely to benefit from
particular therapies, including novel agents acting on the androgen pathway. Serum
miRNA profiling is especially exciting given that it is accessible in a non-invasive
manner, and it may be possible to establish a diagnostic serum miRNA panel that
would reduce the need for prostate biopsies in patients with elevated PSA levels,
some of whom ultimately will not have prostate cancer.

None of these aims have yet been met, but this review aims to summarise the progress
made both with understanding the role of miRNA dysregulation in prostate cancer
tumourigenesis, and with establishing which miRNAs may be useful serum
biomarkers.

INDICATIONS/APPLICATIONS

microRNA specific markers for detection, profiling, diagnosis, prognosis and

therapeutic targets for prostate cancer progressing, esp early stage of prostate
cancer.

MicroRNAs (miRNAs) are made up of -22 endogenous nucleotides and are small,
noncoding RNAs that are important regulators of gene expression at the
posttranscriptional level by degrading or repressing target miRNAs. miRNA
expression profiles can be used for the detection of diagnostic and prognostic markers
for various cancers. Also, alterations of miRNAs in cancer tissues have been
associated with clinicopathological parameters. Along with circulating miRNAs,
tissue miRNAs have shown promise as markers that can predict cancer recurrence
and/or the potential for survival of cancer patients. Additionally, some miRNAs have
therapeutic potential. In this review, we discuss and assess the usefulness of
tissue-derived and circulating miRNAs for the diagnosis and prognosis of prostate
cancer.

miR-29b

play a tumour suppressive role by inhibiting EMT. Expression levels were

reduced in prostate cancer tissue compared to patient-matched non-tumour
tissue, and investigators found increased E-cadherin expression and reduced
N-Cadherin, Twist, and Snail expression in cells transfected with miR-29b,
suggesting that miR-29b inhibits EMT.
miR-145

been suggested to lead to enhanced cell proliferation, migration and invasion

in prostate cancer. Fuse and colleagues demonstrated that the capacity of PC3
and DU145 prostate cancer cells to proliferate, migrate, and invade was
impaired by transfection with miR-145.
identified as potential regulators of EMT.
had a reduced propensity to bony invasion in vivo in a murine intra-tibial
injection model, and that in a cohort of 22 patients, reduced expression levels
of miR-143 and miR-145 correlated with higher Gleason grade, PSA, and
bony metastasis .

MiR-143

also downregulated in prostate cancer, and has been shown in vitro to inhibit
proliferation and migration of prostate cancer cells by suppressing V-Ki-ras2
Kirsten rat sarcoma viral oncogene homolog (KRAS) expression, thereby
inhibiting the EGFR/RAS/mitogen-activated protein kinase (MAPK) pathway.
identified as potential regulators of EMT.
had a reduced propensity to bony invasion in vivo in a murine intra-tibial
injection model, and that in a cohort of 22 patients, reduced expression levels
of miR-143 and miR-145 correlated with higher Gleason grade, PSA, and
bony metastasis .

MiR-133 and miR-146a

have also been shown to target EGFR and to produce similar anti-proliferative,
anti-migratory effects in androgen-insensitive prostate cancer cell lines in
vitro.

MiR-205

is downregulated in prostate cancer cells, and this has been implicated in the
stimulation of EMT. Prostate cancer cells transfected with miR-205
demonstrated enhanced expression of epithelial adhesion molecules such as
E-cadherin, and displayed other features of a more epithelial phenotype,
suggesting that miR-205 downregulation may be partly responsible for
stimulating EMT.

MiR-125b

has an androgen-responsive element within the promoter region of its gene.

Mi-R125b upregulation has been demonstrated to result in
androgen-independent growth in prostate tumour xenografts in castrate mice
perhaps through its anti-apoptotic effects (see MiRNAs and avoidance of
apoptosis).
MiR-21
In vitro, transfection of LnCaP cells with a miR-21 expressing retrovirus has
been shown not only to stimulate androgen-dependent cell growth, but also to
rescue cells from androgen-deficient growth arrest. This indicates that miR-21
may also mediate castrate-resistant prostate cancer (CRPC) development. Li
and colleagues recently established that tissue miR-21 expression levels may
have clinical importance. They evaluated miR-21 expression levels in a cohort
of 169 radical prostatectomy tissue samples and found increased miR-21
expression was associated with pathological stage, lymph node status,
extracapsular extension and biochemical recurrence. They went on to
demonstrate in vivo tumour growth repression in a mouse model treated with a
miR-21 inhibitor.

MiR-32

is a further example of an androgen-regulated miRNA that is upregulated in

CRPC. MiR-32 upregulation is associated with downregulation of the protein
BTG2, and reduced BTG2 staining in radical prostatectomy specimens has been
shown to predict tumour progression.

MiR-27a
androgen-stimulated upregulation of miR-27a results in reduced prohibitin
expression. Prohibitin is a known tumour-suppressor gene and co-repressor of
the androgen receptor, and miR-27a mediated downregulation of its protein
product results in increased expression of androgen receptor target genes and
increased prostate cancer cell growth.

MiR-141
attempted to profile differential miRNA expression in androgen treated and
untreated LnCaP cells in vitro and in prostate cancer xenografts in intact and
castrated mice. MiR-141 demonstrated the greatest androgen-dependent
expression in that study. MiR-141 is overexpressed in various forms of human
epithelial malignancy including prostate cancer. Separate analysis of prostate
epithelial and stromal cells has demonstrated miR-141 expression to be
epithelium-restricted.

RESULTS

A number of miRNAs have been shown to influence key cellular processes involved
in prostate tumourigenesis, including apoptosis-avoidance, cell proliferation and
migration and the androgen signalling pathway. An overlapping group of miRNAs
have shown differential expression in the serum of patients with prostate cancer of
varying stages compared with unaffected individuals. The majority of studies thus far
however, involve small numbers of patients and have shown variable and occasionally
conflicting results.

Besides that, microRNA also can used for screening chronic diseases includes viral
infections, nervous system disorders, cardiovascular disorders, and diabetes.

REVIEWS

There is evidence from in vitro and in vivo studies that alteration in miRNA function
plays a role in prostatic carcinogenesis. miRNA dysregulation influences a number of
critical cellular processes involved in this process, including but not limited to:
stimulation of the cell cycle, avoidance of apoptosis, epithelial-mesenchymal transition
and modulation of AR-mediated signalling. Further understanding of the functional
importance of miRNA dysregulation may allow the development of novel therapeutic
strategies involving miRNA augmentation or inhibition in the future.

Circulating miRNA profiling in prostate cancer patients has been carried out by various
investigators, but studies thus far have involved small numbers of patients, and a
variety of methodologies, and have yielded heterogeneous results. However, the
potential to detect circulating miRNAs in serum and potentially, in urine, clearly exists.

Furthermore, despite the variability of results, there are a number of miRNA targets
that have both a demonstrable functional role in prostate cancer pathogenesis and
have demonstrated over- or under-expression in serum samples in at least one study.
The investigation of these miRNAs, either singularly or as part of a panel, in larger,
prospective patient cohorts will help to define their potential role as diagnostic and
prognostic biomarkers in the future.

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