2Department of Molecular Biology and Genetics, Biruni University, İstanbul-Turkey DOI : 10.5505/tjo.2019.2202
Summary
Prostate cancer has been found to be the most life-threatening disease among men all over the world, given its wide occurrence and partially-successful therapies associated with a high rate of mortality. Thus, meticulous analysis of this cancer and its characteristics, including molecular biology, epigenetic mechanisms and markers during tumor development, may provide the scientists with valuable insights to design the therapeutic protocol with improved efficiency and low rate of failure and limited further side effects, such as infertility. Moreover, the risk associated with the current invasive procedures on prostate cancer patients has prompted researchers to invest effort in the discovery of being less-invasive and more advantageous procedures based on the patient"s own physiological and anatomical characteristics. This paper reviews past and present studies on epigenetics and molecular markers of prostate cancer, as well as the designed therapies. Additionally, we present a future vision and prospect of the current treatments.Introduction
Prostate cancer (PC), unlike many other cancers, such as lung cancer, has been posing a huge threat to men due to lack of its connection with carcinogenic chemicals and heterogeneity of prostate glands which has made it rather difficult to analyze the sole cause of cancer and eventually efficient precaution that arises from constraint causative factors.[1] PC has been in existence since ancient times; hence, the development of prostatectomy, a surgical means for PC treatment, has been achieved for more than a century.[2] PC is described as a heterogeneous type of cancer that exhibits various forms, from the slow-growing tumors to fast-growing tumors, which gradually turns out to be fatal. Years of studies and analysis have provided a rather more convenient way for the diagnosis of PC. Prostate-specific antigen (PSA) blood test is performed to determine the presence of kallikrein-related serine protease, the enzyme which is normally found in prostate secretion, but found in the bloodstream due to functional and histological anomaly of the prostate, and helps to diagnose PC in early stages for further treatment.[3]Human serine proteases are members of human tissue kallikrein (KLK) family, which contain 15 homologues serine proteases (KLK1-KLK15). This family is encoded by the largest clustered human genome located on chromosome 19 [4], out of which KLK2 and KLK3 are found only in prostate and KLK3 with 33-kDa weight are considered as the biomarker (PSA) in PC screening.[4,5] Discovery of PSA dates back to 1979 when it was found in prostatic tissues.[6] Apart from contributing to cancer diagnosis, KLK3 is the main modulator of sperm status in terms of semen liquefaction and coagulation.[7] Genetic polymorphism of KLK3 has also been shown to contribute to the high risk of male infertility as a degrading factor to semenogelin.[8] However, KLK3 activation and defragmentation are controlled by the KLK14 function, which was detected by analysis of KLK3 fragments invitro using recombinant KLK14.[9]
The cancer is initiated and developed in the prostate gland, part of the male reproductive system responsible for semen production in the male body and located inferior to the bladder.[10] Approximately 98% of the PCs are reported to be of glandular origin.[11] This organ is made of epithelial cell clusters arranged in the form of the basal layer and contains stem cells, transit-amplifying cells (TACs), and committed basal (CB) cells as the most dominant cell population in this structure.[12] Based on histological analysis of prostate organ, stem cells undergo division to form TA cells, which further divide by mitosis and differentiate into CB cells, the only cell type in prostate capable of DNA synthesis and proliferation, which are finally transformed into differentiating luminal cells in human.[13] PC was observed with a lack of or disruptive basal layer along with the disruption of the above-mentioned cell number present in the prostate gland.[9] Such an irregular growth of stem cells was first noticed in 1989.[13]
Stem cells characterization, collected by biopsy of patients, were carried out using CD44+ α2β1hi CD133+ markers as the phenotype, which unfortunately was not specific for only cancer stem cells (CSCs).[14] Additionally, PAP (prostatic acid phosphate) was found to not be fully special PC diagnosis since PAP was found to be elevated in benign prostatic hyperplasia (BPH) and other organ"s malfunctions, such as the liver.[15]
This paper reviews past and present studies on epigenetics and molecular markers of PC, as well as the designed therapies. Additionally, we present a future vision and prospect of the current treatments.
miRNA and DNA Methylation in PC
Studies on cancer show that epigenetic mechanisms are
effective above cancer prognosis. miRNAs have been
demonstrated that play a role in epigenetic mechanisms,
such as DNA methylation and histone deacetylation
(HDAC).[16,17]
There are regions called CpG islands, which are located there high rate repetition cytosine and guanine base pairs in the human genome. CpG islands mostly take part in promotor regions of a gene. In these regions, methylation occurs when attaching methyl (-CH3) to cytosine's fifth carbon. Abnormal situations, such as hypomethylation and hypermethylation, cause fall into decay cell functions, such as cell differentiation, cell division, and cell proliferation.[18,19]
Recent studies related to miRNA show that miRNA genes are situated near to CpG islands. In conclusion, methylation of the CpG islands will affect the expression of miRNAs.[20-22]
We can denote miRNA-152 as a sample to relationship miRNA and DNA methylation. In normal conditions, miRNA-152 prevent the expression of DNA (cytosine-5)-methyltransferase 1 (DNTM1) by targeting 3" UTR region of the DNMT1 gene. When DNMT1 expression and DNA methylation are lower, the gene is an expression. Studies with cell lines of PC show that methylation depending on increase DNMT1 expression down-regulate miRNA-152. Thus, the gene expression that serves a function in cell differentiation, cell division, and cell proliferation is prevented.[23,24]
miRNA and Histone Deacetylation in PC
miRNA and HDAC relationship is affecting the regulatory
roles of epigenetic mechanism.[25] Change of
electrostatic force in histone tails affects their binding
to DNA. To illustrate the positive charge of lysine,
amino acid in the amino tail is neutralized with acetylation
of histone protein. Consequently, region binding
to DNA of the histone protein is free, and the region is
clarified to transcription factors, which causes expression
in the region.[26] Two enzyme family function
in here. One of them is acetyltransferase (HAT). The
other is a histone deacetylase (HDAC). While HAT
enzymes are acetylating the region, HDAC enzymes
deacetylate the same region. This reversible situation
identifies whether it will be an expression of the region.
The breakdown of equilibrium between two enzymes
brings about the malignity of the cell.[27] Table 1
shows HDAC classification.[28]
;){kind=link}
Table 1: HDAC classification [28]
We can denote miRNA-449a as a sample to relationship miRNA and HDAC. In normal conditions, when expression miRNA-449, its down-regulate HDAC1, which brings on activation of p27/kip1 transcription, which causes cell proliferation. Studies with cell lines of PC show that down-regulation of miRNA-449a cause to up-regulation of HDAC1. Because of the HDCA1, up-regulation activation of p27/kip1 transcription causes cell proliferation out of control.[29]
Genetic Propensity and Markers of PC
Various genome-wide association studies (GWASs)
implicate single-nucleotide polymorphism (SNP) to be responsible for PC initiation.[30,31] (Table 2).
Although previous studies showed specific mutations
on chromosome 15 and 19 to be responsible for aggressive
PC [32,33], another genome analysis study
has reported some genes with a mutation in PC (Table
3). Unlike most of the cancer types, various analyses
indicate no specific oncogene connected to PC [68]
although some oncogene exhibit overexpression in
some cancers observed during anti-androgen therapy.
C-ERB-B2 oncogene, located on chromosome 17, appears
to be elevated in hormone-refractory PC in response
to anti-androgen therapy.[69] Moreover, EZH2 mRNA has shown a significant peak due to EZH2
protein encoded by EZH2 oncogene, which acts as a
repressor of transcription and causes cell proliferation
in PC.[70] Additionally, retinoblastoma (RB) proteins
seem to be reduced in malignant PC, which caused tumor
cell proliferation.[71]
;){kind=link}
;){kind=link}
Table 2: Single nucleotide polymorphism region with PC [31]
Table 3: Common genetic aberrations in PC
P53, also known as TP53, which protects against tumorgenesis, is observed to be increased in malignant and untreated PC, rather than primary or treated ones. [72] Some studies have tested wild type (WT) P53 with mutated P53 using DU145 cells (human prostate cancer cell lines) in response to chemotherapeutic drugs and observed that P53 increased tumor cells" susceptibility to drugs which could indicate high survival rate of prostatic cancer cells during chemotherapies when P53 is silenced or non-functional.[73] On the account of tumour suppressor genes being silenced resulting in PC cell's resistance, the other factor, over activation of androgen receptor (AR), plays significant role in development of castrate-resistant prostate cancer [74] due to hypermethylation of CpG islands (sequence of 5"-CG- 3") [75] on AR genes and proven to be not related to androgen level which was observed during anti-androgen therapy in PC patients.[76,77]
miRNAs as Biomarkers in PC
microRNAs, also known as miRNAs, are small, noncoding
endogenous RNA molecules that are found in
eukaryotes, as well as some viruses. They have been
found to play a key role in RNA regulations and diagnosis
of various diseases on account of their circulation
in body fluids.[78] Recent studies on miRNA
transcripts have demonstrated their significance as PC biomarkers. MicroRNA-21, also known as miR-
21, mammalian miRNA encoded by the MIR21 gene
located on chromosome 17, has been observed to
suppress PTEN (tumor suppressor gene) in various
cancers, such as colorectal and breast cancer, [79,80]
but no indication of its direct effects on PC. Yang et
al. conducted an experiment on the effects of miR-
21 on PC cells using PC-3 cell lines, transfecting the
cells with miR-21. They observed that in the presence
of matured miR-21, which is generally conserved in
mammalian cells, PC cells evade immune defence
due to suppression of PTEN by miR-21, which results
in cell growth and proliferation and eventually
metastasis.[81] Based on the above-mentioned analysis, miR-21 has been introduced as a PC biomarker,
which needs further studies and possible epigenetic
influence on cancer cells.
Up-regulation of miR-21 has been found to be correlated with down-regulation of miR-15 and mirR-16 as well as overexpression of TGF-β signalling due to suppression of SMAD7 (Mothers against decapentaplegic homolog 7 leads to degradation of TGF-β and inhibits hedgehog signalling), which leads to AR hyper- activation result in the bone lesion in PC.[82] Moreover, several studies showed the functional influence of miR-221 and miR-222 on tumorigenesis and cancer progression in various cancers, including PC.[83-86] In-vivo and in-vitro studies of PC3 cells have shown that reduction of cancer cell proliferation occurs when PC cells are induced with miR-221 and miR-222 inhibitors, which implicates miR-221/222 increasing expression in PC and its metastasis.[87]
Other miRNAs expressed rather significant volume changes in response to tumurgenesis. To demonstrate, miR-152-3p in LNCaP and PC3 were analyzed in vitro. The result indicated a low miR-152-3p level of tumour cells compared to healthy control cells. However, the same analysis experimented with the effects of highlevelmiR- 152-3p mimic on tumour cells, which resulted in a great deal of proliferation and metastasis presenting external effects of the above-mentioned miRNA on tumurogenesis.[88] In addition to miRNA"s direct effect on tumour progression, their function harbours inactivation or reduction of tumursupressors, such as tetraspanin, particularly tetraspanin CD4, which is found to suppress tumor progression and metastasis. In-vitro studies of miR-518f-5p on PC3 cells proved their down-regulating effects on CD4 leading to cancer progression and metastasis.[89] Table 4 shows that the role of miRNAs in PC.
;){kind=link}
Table 4: The role of miRNAs in PC
In PC cancer patients, cfDNA (cell-free DNA) is released from apoptotic cells as nucleosomes from both healthy and diseased tissue that includes tumor cells, as well as microbial nucleic acids from systemic infections.[107] The regional chromosomal ploidy heterogeneity detected in cfDNA is an early indicator of progressive genomic instability. The following result indicated that cfDNA in serum could be used as a remarkable biomarker to distinguish PC from benign prostatic hypertrophy and prostatitis.[108]
Prostate Cancer Therapy
Over the past few decades, PC has attracted the attention
of researchers working in this area considering its
mortality rate in men, specifically in developed countries.
Therefore, efforts have increased towards an efficient
means of therapy.[109,110]
Apoptosis as a Cancer Therapy (Apoptosis as Therapeutic
means in PC?)
One of the major observations on cancer cells is their
evasion from apoptosis. Studies demonstrate the presence
of Fas and FasL (Fas ligand) mediating apoptosis
in PC cells. However, resistance to such apoptosis
was observed.[109,110] Various in-vitro studies on PC
cells show an increase in FADD (Fas-associated protein
with death domain) and eventual apoptosis using
5-Azacitine combined with BCLT (bicalutamide) to
guide the cancer cells to death path and block further
progress and metastasis.[76]
Genetic Material into a Target Cell as Cancer Therapy
Gene therapy, defined as the introduction of genetic
material into a target cell for therapeutic benefit, is a
very promising treatment for many diseases, including
cancer. To date, more than 2000 clinical trials employing
gene transfer have taken place, and in general,
many vehicles or vectors have been established as safe.
[111,112] Various techniques and approaches are employed
to target the altered genes in PC, such as using
siRNA (small interfering RNA), antisense oligonucleotides
and plasmid DNA, along with chemotherapy
to achieve PC apoptosis and overcome multidrug resistance
conditions that arise from various drug-therapies.[113,114]
Re-activation of Tumor Growth as a Cancer Therapy
In prostate tumours, re-activation of tumor growth
has been observed in receptor-dependent androgen
state, which may induce apoptosis of these cells by
pro-apoptotic over-expressing tumor necrosis factor
(TNF).[115] At the same time silence anti-apoptotic
c-FLIP, allowing the development of a pro-apoptotic
therapy which acts downstream and independently of
androgen receptor (AR) signalling.[115] Analysis of
PC cells has shown that the cells that express resistance
towards castration-therapy also express a lower degree
of polyphosphate-4-phosphatase type II (INPP4B),
whose function includes potential tumor suppressor
and a cascade activation which results in the negative
control of phosphatidylinositol 3-kinase (PI3K) pathway
leading to inhibition of cell malignant transformation.
To prove the following findings, the PC cell line
was transfected with the INPP4B gene, which evidently
demonstrated a significant reduction in cancer cell viability
and in a decrease in pAKT levels that down-regulates
the PI3K pathway.[116] In addition to previous
findings, some research experimented effects of an
RNA-aptamer by transferring it into LNCaP and PC-3
and observed expression of genes that are observed
phenotypically in normal prostate cells leading PC
cells towards the apoptosis path and anti-proliferation
mechanism and an eventually positive prognosis.[117]
Gene Editing and Activation Tumor suppressor
Genes with Silencing RNA
Short interfering or silencing RNA (siRNA) was found
to enhance the gene editing and activation of tumor
suppressor genes and suppression of anti-apoptotic
proteins in PC therapy. In a study, they transfected PC
cell lines with siRNA molecules, treated with atecollagen, which facilitates the absorption of siRNA into
tumor cells. The aim of this experiment was to reduce
expression anti-apoptotic protein Bcl-xL, which is over
expressed in PC both in vitro and in vivo.[118] Moreover,
viruses have been found to express a rather efficient
tool as vectors in PC therapy for the purpose of
gene editing. For instance, baculoviruses are tested to
deliver genes in a variety of tissues and cells, including
benign prostate and PC cells line. Moreover, they can
introduce therapeutic genes into dividing or quiescent
cells, indicating that it might also act in tumor stem
cells of PC.[119]
Adenoviral Vector- mediated Gene Therapy
Some other studies observed the effects of adenoviral
vector- mediated gene therapy followed by radiotherapy,
which was applied to 178-2 BMA and TSUPr1
cells in vitro to observe the colony formation of cells
and their apoptosis process which led to tumor control
with higher efficiency.[120]
Arafat et al. experimented the same combined (adenovirus and radiotherapy) or sole effect of using other types of adenoviruses as a vector (TRA-8 or Ad TRAIL (adenoviral encoding TRAIL)) in Human PC cell lines (LNCaP, PC-3 and DU-145) in vitro and colony-forming assay and RT-PCR were employed to determine cells" growth and genetic changes. In addition to in vitro studies, in vivo study using murine injected subcutaneously with PC cells was carried out which presented higher efficiency and lower cancer cell survival in combination therapy (vector combined with radiotherapy) rather than single treatment only Evaluated by elevation of BAX protein (responsible for apoptosis) and eventually apoptosis of cancer cells.[121]
miRNAs as Therapeutic Means in PC
As previously discussed, miRNAs play a vital role in
PC recognition and diagnosis. However, their function
is far more than just a biomarker. Various studies
analyzed different miRNAs" effects in the treatment of
PC in-vitro, in vivo and in silico.[122] The function of
mature miRNA is achieved by seed sequence (short
sequence located upstream of 5` end of miRNA) in
miRNA, which binds to the complementary motif in
UTR (untranslated region) of targeted mRNA. For
miRNA to be a target of therapy, they must present
adequate stability inside and outside the cells, as well
as show pharmacokinetic factors which would be appropriate
to cell and environmental condition in vitro
and in vivo. Different approaches have been designed
and considered to use miRNA in PC therapy by either using complementary oligonucleotides targeting and
preventing the function of specific miRNA [123,124]
or transfecting PC cells with multiple miRNA-specific
complementary sequences harboured in vector.[125]
ASOs (antisense oligonucleotides) via liposomal complexes and SMIR (small molecule inhibitors of miRNAs), which are designed based on the function of other molecules used for other disease therapies. They are used to target miRNAs. miRNAs have the ability to inhibit function other miRNAs that express the same see sequence, which is not seen with ASOs and is considered as an advantage of using miRNAs over antisense oligonucleotides. The SMIR approach aims to find compounds that bind and subsequently decrease the levels of mature miRNAs; however, such compounds can principally function to prevent transcription.[126]
Scientists designed other types of miRNA, known as miRNA sponge, which consists of numbers of binding sites (4-10) containing antisense or mismatched nucleotides, which will result in cleavage by argonaute RNA-induced silencing complex (RISC) when completely base-paired. The efficacy of miRNA sponge lies in two factors as follows: the binding site affinity and the ratio of miRNA sponge concentration to the ratio of mRNA targets.[126] PC cells were transfected with sponge miRNAs using plasmid in vitro and viral vector in vivo and a reporter gene for monitoring the functional changes and their actions on target miRNAs.[127] Some groups tested various sponge miRNAs and found that most of them, specifically pseudogenes, function as ceRNAs. They compete with target mRNAs for miRNA binding, making them endogenous sponges. The Phosphatase and tensin homolog (PTEN) pseudogene was the first demonstrated example, but since then, other pseudogenes and long non-coding RNAs have been shown to be valid ceRNAs.[128,129] However, various pseudogenes demonstrated particularly different functions in cancer cells. For instance, NANOGP8 pseudogene is responsible for malignancy and metastasis and PC, and research studies indicate that the knock-out or deactivation of this pseudogene can benefit from the positive prognosis of PC therapy greatly.[130]
Studies have reported miR-185 as a tumor suppressor factor, was observed to be down-regulated in PC. Therefore, studies have been carried out to present miR-185 as a therapeutic mean for PA. miR-185, used along with bromodomain 8 isoform 2 (BRD8 ISO2) on PC3 and LNCaP, inhibited expression of androgen receptors (AR) directly by binding to the 3"- UTR region of AR mRNA.[131] Among several known miRNAs, the let-7 family is proved to play a significant rule in PC progress by regulating CSCs. BR-DIM upregulates the expression of the let-7 family, consequently downregulating the expression of EZH2 both in PC cell lines and human PC cells in the tissue. These results suggest that BR-DIM could serve as a novel agent for the inhibition of PC progression and recurrence.[132]
In addition to miRNA therapy, immunotherapy has expressed quite impressive results in cancer therapy that include vaccine therapy, which was administered in 2012 using the DNA fusion vaccine in PC cases. The designed vaccine consisted of the domain (DOM) from fragment C of tetanus toxin linked to an HLAA2- binding epitope from prostate-specific membrane antigen (PSMA) and induced DOM-specific CD4 and PSMA-specific CD8 T cells, generating anti-PSMA responses in most of the individuals suffering from PC.[133] 3D cell culture, as an in vitro condition, was proposed to be beneficiary in PA. In 2015, scientists designed a 3D cell culture model of PC bone metastasis in which collagen-based scaffolds were employed for a more efficient physiological microenvironment and helped to deliver siRNA to PC cells (PC3), which result in the alternative for PC bone metastases treatment. [134] Other researchers used aptamers along with 3D cultures as an efficient therapeutic way for PC. In 2016, scientists used eight aptamers with 3D cell culture for PC therapy.[117,135]
Studies about preventing activation of HDAC enzymes with HDAC inhibitors are carried out. HDAC inhibitors precluding activation of the HDAC enzyme may change gen expression. Recent cancer studies showed that inhibition of HDAC enzymes activate inactive G2 checkpoint starts apoptosis. Cell stimulated for apoptosis is stopped in G1 and G2 phases. Thus, cell proliferation is blocked.[136-140]
miRNA expression has an important role in HDAC enzyme functions. Studies showed that with HDAC inhibitors affected the miRNA expression levels.( Table 5).[141]
;){kind=link}
Table 5: miRNA expression affecting from HDACi and their mechanisms
Current Studies in PC: CRISPR-Cas System
(CRISPR-Cas as Therapeutic Means in PC)
CRISPR-Cas is a system that prokaryotes (84% archaea
and 45% bacteria) ensure gaining adaptive immunity
against viruses.[145] This system is composed of clustered
regularly interspaced short palindromic repeats
(CRISPR) and cas gene that is consist of similar sequence
to gene families many nuclease and helicase.[146]
The system works via RNA. Therefore, this system is called an immune system via RNA.[147] When bacteriophage infects bacteria, bacteria recognize the PAM (protospacer adjacent motif) sequence that belongs to bacteriophage via RNA. When bacteriophage infects bacteria, bacteria recognize the PAM sequence that belongs to bacteriophage via RNA. Consequently, the PAM region is cut by a cas enzyme showing endonuclease property. Information of the cutted region is attached above-mentioned among palindromic repeats. Thus, bacterium gains immunity memory against that virus. Pathogen property of the virus disappears with cutting the PAM region.[145,148]
The double-strand break occurs in target DNA. Because there is no compensation for this situation, the virus loses its function. Scientists have developed applications, such as gene silencing [with double- strand break] (knock out) and gene splice [with a donor constituting homology to target DNA sequence] (knock-in) using this property of the system. Thus, the CRISPR-Cas system is an inspiration for diagnosis and treatment in hereditary diseases, such as cancer. Consequently, change of arrays, such as insertion and deletion, in the gene region which they want to work is possible.[149,150] In Table 6, studies of PC benefited from the system of CRISPR-Cas are shown.
;){kind=link}
Table 6: Studies regarding PC benefited from the system of the CRISPR-Cas
Conclusion
Current statistics show that approximately one in nine men is diagnosed with PC during their lifetime. Although PC can be a severe disease, luckily, most men diagnosed with PC do not die of PC. More than 2.9 million men in the United States who have been diagnosed with PC at some point are still alive today.Genetic mutations are known to give rise to cancer. The epigenetic mechanisms which increase importance day by day and affect the structure of DNA play an important role in the pathogenesis of cancer.
As we understand the epigenetic mechanisms of PC better, we better modelling, which becomes a success in treatment will be.
miRNAs play a role in the epigenetic mechanism of cancer. When considering studies, we are clearly seen an important role in the therapeutic applications for PC.
Studies on the pathogenesis of the disease can be summarized in two steps as follows:
a. Modelling to better understand the pathogenesis of
the disease.
b. Design of the therapeutic studies with different options
for the treatment of the disease in consideration
of the modelling.
The information which we have on the effects of epigenetic mechanisms involved in the progress of cancer
is not yet at the desired level.
In particular, the use of miRNAs as a biomarker for
therapies that are developed based on affecting epigenetic
mechanisms is far away from the desired level.
Thus, cohort studies that include genomic and epigenetic
analyses are needed.
Peer-review: Externally peer-reviewed.
Conflict of Interest: Authors declare no conflict of interest.
Financial Support: No financial support has been used for this study.
References
1) Maitland NJ. Stem Cells in the Normal and Malignant
Prostate. In: Tindall DJ, editor. Prostate Cancer-Biochemistry,
Molecular Biology and Genetics. New
York: Springer; 2013. p. 3-41.
2) Capasso LL. Antiquity of cancer. Int J Cancer
2005;113(1):2?13.
3) Lilja H, Ulmert D, Vickers AJ. Prostate-specific antigen
and prostate cancer: prediction, detection and
monitoring. Nat Rev Cancer 2008;8(4):268-78.
4) Borgoño CA, Diamandis EP. The emerging roles of
human tissue kallikreins in cancer. Nat Rev Cancer
2004;4(11):876-90.
5) Shaw JL, Diamandis EP. Distribution of 15 human
kallikreins in tissues and biological fluids. Clin Chem
2007;53(8):1423-32.
6) Wang MC, Valenzuela LA, Murphy GP, Chu TM. Purification
of a human prostate specific antigen. Invest
Urol 1979;17(2):159-63.
7) Lilja H, Oldbring J, Rannevik G, Laurell CB. Seminal
vesicle-secreted proteins and their reactions during
gelation and liquefaction of human semen. J Clin Invest
1987;80(2):281-5.
8) Gupta N, Sudhakar DVS, Gangwar PK, Sankhwar
SN, Gupta NJ, Chakraborty B, et al. Mutations in the
prostate specific antigen (PSA/KLK3) correlate with
male infertility. Sci Rep 2017;7(1):11225.
9) Emami N, Deperthes D, Malm J, Diamandis EP. Major
role of human KLK14 in seminal clot liquefaction. J
Biol Chem 2008;283(28):19561-9.
10) Frame FM, Maitland NJ Cancer stem cells, models of
study and implications of therapy resistance mechanisms.
Adv Exp Med Biol 2011;720:105-18.
11) Greenberg R. Does prostate cancer represent more
than one cancer? In: Prostate Cancer: Science and
Clinical Practice. Mydlo JH, Godec CJ, editors. 1st
edition. San Diego: Academic Press; 2003. p. 29-34.
12) Robinson EJ, Neal DE, Collins AT. Basal cells are
progenitors of luminal cells in primary cultures of
differentiating human prostatic epithelium. Prostate
1998;37(3):149-60.
13) Isaacs JT, Coffey DS. Etiology and disease process of benign
prostatic hyperplasia. Prostate Suppl 1989;2:33-50.
14) Richardson GD, Robson CN, Lang SH, Neal DE, Maitland
NJ, Collins AT. CD133, a novel marker for human
prostatic epithelial stem cells. J Cell Sci 2004;117(Pt
16):3539-45.
15) Demichelis F, Stanford JL. Genetic predisposition to
prostate cancer: Update and future perspectives. Urol
Oncol 2015;33(2):75-84.
16) Swierczynski S, Klieser E, Illig R, Alinger-Scharinger B,
Kiesslich T, Neureiter D. Histone deacetylation meets
miRNA: epigenetics and post-transcriptional regulation
in cancer and chronic diseases. Expert Opin Biol
Ther 2015;15(5):651-64.
17) Bacalini MG, Friso S, Olivieri F, Pirazzini C, Giuliani
C, Capri M, et al. Present and future of anti-ageing epigenetic
diets. Mech Ageing Dev 2014;136-137:101-15.
18) Denis H, Ndlovu MN, Fuks F. Regulation of mammalian
DNA methyltransferases: a route to new mechanisms.
EMBO Rep 2011;12(7):647-56.
19) Eckhardt F, Lewin J, Cortese R, Rakyan VK, Attwood
J, Burger M, et al. DNA methylation profiling of
human chromosomes 6, 20 and 22. Nat Genet
2006;38(12):1378-85.
20) Singh PK, Campbell MJ. The Interactions of microRNA
and Epigenetic Modifications in Prostate
Cancer. Cancers (Basel) 2013;5(3):998-1019.
21) Bishop KS, Ferguson LR. The interaction between
epigenetics, nutrition and the development of cancer.
Nutrients 2015;7(2):922-47.
22) Holliday R. Epigenetics: a historical overview. Epigenetics
2006;1(2):76-80.
23) Theodore SC, Davis M, Zhao F, Wang H, Chen D, Rhim
J, et al. MicroRNA profiling of novel African American
and Caucasian Prostate Cancer cell lines reveals a reciprocal
regulatory relationship of miR-152 and DNA
methyltranferase 1. Oncotarget 2014;5(11):3512-25.
24) Wang YL, Wu S, Jiang B, Yin FF, Zheng SS, Hou SC.
Role of MicroRNAs in prostate cancer pathogenesis.
Clin Genitourin Cancer 2015;13(4):260-70.
25) Peterson CL, Laniel MA. Histones and histone modifications.
Curr Biol 2004;14(14):R546-51.
26) Narlikar GJ, Fan HY, Kingston RE. Cooperation between
complexes that regulate chromatin structure
and transcription. Cell 2002;108(4):475-87.
27) Fenrick R, Hiebert SW. Role of histone deacetylases
in acute leukemia. J Cell Biochem Suppl 1998;30-
31:194-202.
28) Lakshmaiah KC, Jacob LA, Aparna S, Lokanatha
D, Saldanha SC. Epigenetic therapy of cancer with
histone deacetylase inhibitors. J Cancer Res Ther
2014;10(3):469-78.
29) Noonan EJ, Place RF, Pookot D, Basak S, Whitson
JM, Hirata H, et al. miR-449a targets HDAC-1 and
induces growth arrest in prostate cancer. Oncogene
2009;28(14):1714-24.
30) Eeles RA, Al Olama AA, Benlloch S, Saunders EJ,
Leongamornlert DA, Tymrakiewicz M, et al. Identification
of 23 new prostate cancer susceptibility loci
using the iCOGS custom genotyping array. Nat Genet
2013;45(4):385?91, 391e1-2.
31) Amin Al Olama A, Kote-Jarai Z, Schumacher FR,
Wiklund F, Berndt SI, Benlloch S, et al. A meta-analysis
of genome-wide association studies to identify
prostate cancer susceptibility loci associated with aggressive
and non-aggressive disease. Hum Mol Genet
2013;22(2):408-15.
32) Fitzgerald LM, Kwon EM, Conomos MP, Kolb S, Holt
S, Levine D, et al. Genome-wide association study
identifies a genetic variant associated with risk for
more aggressive prostate cancer. Cancer Epidemiol
Biomarkers Prev 2011;20(6):1196-203.
33) Grasso CS, Wu YM, Robinson DR, Cao X,
Dhanasekaran SM, Khan AP, et al. The mutational
landscape of lethal castration-resistant prostate cancer.
Nature 2012;1487(7406):239-43.
34) Taplin SH, Barlow W, Urban N, Mandelson MT, Timlin
DJ, Ichikawa L, et al. Stage, age, comorbidity, and
direct costs of colon, prostate, and breast cancer care. J
Natl Cancer Inst 1995;87(6):417-26.
35) Visakorpi T, Hyytinen E, Koivisto P, Tanner M, Keinänen
R, Palmberg C, et al. In vivo amplification of the
androgen receptor gene and progression of human
prostate cancer. Nat Genet 1995;9(4):401-6.
36) Pritchard CC, Mateo J, Walsh MF, De Sarkar N, Abida
W, Beltran H, et al. Inherited DNA-Repair Gene Mutations
in Men with Metastatic Prostate Cancer. N Engl J
Med 2016;375(5):443-53.
37) Fraser M, Sabelnykova VY, Yamaguchi TN, Heisler
LE, Livingstone J, Huang V, et al. Genomic hallmarks
of localized, non-indolent prostate cancer. Nature
2017;541(7637):359-64.
38) Mateo J, Carreira S, Sandhu S, Miranda S, Mossop H,
Perez-Lopez R, et al. DNA-Repair Defects and Olaparib
in Metastatic Prostate Cancer. N Engl J Med
2015;373(18):1697-708.
39) Robinson D, Van Allen EM, Wu YM, Schultz N,
Lonigro RJ, Mosquera JM, et al. Integrative clinical
genomics of advanced prostate cancer. Cell
2015;161(5):1215-28.
40) Barbieri CE, Baca SC, Lawrence MS, Demichelis F,
Blattner M, Theurillat JP, et al. Exome sequencing
identifies recurrent SPOP, FOXA1 and MED12 mutations
in prostate cancer. Nat Genet 2012;44(6):685-9.
41) Burkhardt L, Fuchs S, Krohn A, Masser S, Mader M,
Kluth M, et al. CHD1 is a 5q21 tumor suppressor required
for ERG rearrangement in prostate cancer.
Cancer Res 2013;73(9):2795-805.
42) Zhao D, Lu X, Wang G, Lan Z, Liao W, Li J, et al.
Synthetic essentiality of chromatin re-modelling
factor CHD1 in PTEN-deficient cancer. Nature
2017;542(7642):484-8.
43) Bose R, Karthaus WR, Armenia J, Abida W, Iaquinta
PJ, Zhang Z, et al. ERF mutations reveal a balance of
ETS factors controlling prostate oncogenesis. Nature
2017;546(7660):671-5.
44) Huang FW, Mosquera JM, Garofalo A, Oh C, Baco M,
Amin-Mansour A, et al. Exome sequencing of African-
American prostate cancer reveals loss-of-function
ERF mutations. Cancer Discov 2017;7(9):973-83.
45) Tomlins SA, Rhodes DR, Perner S, Dhanasekaran SM,
Mehra R, Sun XW, et al. Recurrent fusion of TMPRSS2
and ETS transcription factor genes in prostate cancer.
Science 2005;310(5748):644-8.
46) Sizemore GM, Pitarresi JR, Balakrishnan S, Ostrowski
MC. The ETS family of oncogenic transcription factors
in solid tumours. Nat Rev Cancer 2017;17(6):337-51.
47) Xu K, Wu ZJ, Groner AC, He HH, Cai C, Lis RT,
et al. EZH2 oncogenic activity in castration-resistant
prostate cancer cells is Polycomb-independent.
Science 2012;338(6113):1465-9.
48) Zhang C, Wang L, Wu D, Chen H, Chen Z, Thomas-
Ahner JM, et al. Definition of a FoxA1 Cistrome
that is crucial for G1 to S-phase cell-cycle transit
in castration-resistant prostate cancer. Cancer Res
2011;71(21):6738-48.
49) Cancer Genome Atlas Research Network. The Molecular
Taxonomy of Primary Prostate Cancer. Cell
2015;163(4):1011-25.
50) Malik R, Khan AP, Asangani IA, Cie?lik M, Prensner
JR, Wang X, et al. Targeting the MLL complex
in castration-resistant prostate cancer. Nat Med
2015;21(4):344-52.
51) Beltran H, Prandi D, Mosquera JM, Benelli M, Puca L,
Cyrta J, et al. Divergent clonal evolution of castrationresistant
neuroendocrine prostate cancer. Nat Med
2016;22(3):298-305.
52) Sehrawat A, Gao L, Wang Y, Bankhead A 3rd,
McWeeney SK, King CJ, et al. LSD1 activates a lethal
prostate cancer gene network independently of its
demethylase function. Proc Natl Acad Sci U S A
2018;115(18):E4179-88.
53) Fan L, Zhang F, Xu S, Cui X, Hussain A, Fazli L, et
al. Histone demethylase JMJD1A promotes alternative
splicing of AR variant 7 (AR-V7) in prostate cancer
cells. Proc Natl Acad Sci U S A 2018;115(20):E4584-93.
54) Beltran H, Rickman DS, Park K, Chae SS, Sboner A,
MacDonald TY, et al. Molecular characterization of
neuroendocrine prostate cancer and identification of
new drug targets. Cancer Discov 2011;1(6):487-95.
55) Dardenne E, Beltran H, Benelli M, Gayvert K, Berger
A, Puca L, et al. N-Myc Induces an EZH2-Mediated
Transcriptional Program Driving Neuroendocrine
Prostate Cancer. Cancer Cell 2016;30(4):563-77.
56) Lee JK, Phillips JW, Smith BA, Park JW, Stoyanova T,
McCaffrey EF, et al. N-Myc Drives Neuroendocrine
Prostate Cancer Initiated from Human Protate Epithelial
Cells. Cancer Cell 2016;29(4):536-47.
57) Hodgson MC, Astapova I, Cheng S, Lee LJ, Verhoeven
MC, Choi E, et al. The androgen receptor recruits nuclear
receptor CoRepressor (N-CoR) in the presence
of mifepristone via its N and C termini revealing a
novel molecular mechanism for androgen receptor
antagonists. J Biol Chem 2005;280(8):6511-9.
58) Taylor BS, Schultz N, Hieronymus H, Gopalan A, Xiao
Y, Carver BS, et al. Integrative genomic profiling of human
prostate cancer. Cancer Cell 2010;18(1):11-22.
59) He WW, Sciavolino PJ, Wing J, Augustus M, Hudson
P, Meissner PS, et al. A novel human prostate-specific,
androgen-regulated homeobox gene (NKX3.1) that
maps to 8p21, a region frequently deleted in prostate
cancer. Genomics 1997;43(1):69-77.
60) Bhatia-Gaur R, Donjacour AA, Sciavolino PJ,
Kim M, Desai N, Young P, et al. Roles for Nkx3.1
in prostate development and cancer. Genes Dev
1999;13(8):966-77.
61) Wang S, Gao J, Lei Q, Rozengurt N, Pritchard C, Jiao
J, et al. Prostate-specific deletion of the murine Pten
tumor suppressor gene leads to metastatic prostate
cancer. Cancer Cell 2003;4(3):209-21.
62) Ku SY, Rosario S, Wang Y, Mu P, Seshadri M, Goodrich
ZW, et al. Rb1 and Trp53 cooperate to suppress prostate
cancer lineage plasticity, metastasis, and antiandrogen
resistance. Science 2017;355(6320):78-83.
63) Ding Z, Wu CJ, Chu GC, Xiao Y, Ho D, Zhang J, et
al. SMAD4-dependent barrier constrains prostate
cancer growth and metastatic progression. Nature
2011;470(7333):269-73.
64) Wang G, Lu X, Dey P, Deng P, Wu CC, Jiang S, et al.
Targeting YAP-Dependent MDSC Infiltration Impairs
Tumor Progression. Cancer Discov 2016;6(1):80-95.
65) Theurillat JP, Udeshi ND, Errington WJ, Svinkina
T, Baca SC, Pop M, et al. Prostate cancer. Ubiquitylome
analysis identifies dysregulation of effector substrates in SPOP-mutant prostate cancer. Science
2014;346(6205):85-89.
66) Blattner M, Liu D, Robinson BD, Huang D, Poliakov
A, Gao D, et al. SPOP Mutation Drives Prostate Tumorigenesis
In Vivo through Coordinate Regulation
of PI3K/mTOR and AR Signaling. Cancer Cell
2017;31(3):436-51.
67) Mu P, Zhang Z, Benelli M, Karthaus WR, Hoover E,
Chen CC, et al. SOX2 promotes lineage plasticity and
antiandrogen resistance in TP53- and RB1-deficient
prostate cancer. Science 2017;355(6320):84-8.
68) Hellawell GO, Brewster SF. Growth factors and their receptors
in prostate cancer. BJU Int 2002;89(3):230?40.
69) Jorda M, Morales A, Ghorab Z, Fernandez G, Nadji M,
Block N. Her2 expression in prostatic cancer: a comparison
with mammary carcinoma. J Urol 2002;168(4
Pt 1):1412-4.
70) Varambally S, Dhanasekaran SM, Zhou M, Barrette
TR, Kumar-Sinha C, Sanda MG, et al. The polycomb
group protein EZH2 is involved in progression of
prostate cancer. Nature 2002;419(6907):624-9.
71) Taneja SS, Ha S, Garabedian MJ. Androgen stimulated
cellular proliferation in the human prostate cancer cell
line LNCaP is associated with reduced retinoblastoma
protein expression. J Cell Biochem 2001;84(1):188-99.
72) Bálint E E, Vousden KH. Activation and activities
of the p53 tumour suppressor protein. Br J Cancer
2001;85(12):1813-23.
73) Chappell WH, Lehmann BD, Terrian DM, Abrams
SL, Steelman LS, McCubrey JA. p53 expression
controls prostate cancer sensitivity to chemotherapy
and the MDM2 inhibitor Nutlin-3. Cell Cycle
2012;11(24):4579-88.
74) Taplin ME. Androgen receptor: role and novel therapeutic
prospects in prostate cancer. Expert Rev Anticancer
Ther 2008;8(9):1495-508.
75) Takai D, Jones PA. Comprehensive analysis of CpG
islands in human chromosomes 21 and 22. Proc Natl
Acad Sci U S A 2002;99(6):3740-5.
76) Gravina GL, Marampon F, Di Staso M, Bonfili P, Vitturini
A, Jannini EA, et al. 5-Azacitidine restores and
amplifies the bicalutamide response on preclinical
models of androgen receptor expressing or deficient
prostate tumors. Prostate 2010;70(11):1166-78.
77) Urbanucci A, Sahu B, Seppälä J, Larjo A, Latonen
LM, Waltering KK, et al. Overexpression of androgen
receptor enhances the binding of the receptor
to the chromatin in prostate cancer. Oncogene
2012;31(17):2153-63.
78) Wahid F, Shehzad A, Khan T, Kim YY. MicroRNAs:
synthesis, mechanism, function, and recent clinical
trials. Biochim Biophys Acta 2010;1803(11):1231-43.
79) Yang Y, Guo JX, Shao ZQ. miR-21 targets and inhibits
tumor suppressor gene PTEN to promote prostate
cancer cell proliferation and invasion: An experimental
study. Asian Pac J Trop Med 2017;10(1):87-91.
80) Sheng WZ, Chen YS, Tu CT, He J, Zhang B, Gao
WD. MicroRNA-21 promotes phosphatase gene and
protein kinase B/phosphatidylinositol 3-kinase expression
in colorectal cancer. World J Gastroenterol
2016;22(24):5532-9.
81) Fragni M, Bonini SA, Bettinsoli P, Bodei S, Generali
D, Bottini A, et al. The miR-21/PTEN/Akt
signaling pathway is involved in the anti-tumoral
effects of zoledronic acid in human breast cancer
cell lines. Naunyn Schmiedebergs Arch Pharmacol
2016;389(5):529-38.
82) Bonci D, Coppola V, Patrizii M, Addario A, Cannistraci
A, Francescangeli F, et al. A microRNA
code for prostate cancer metastasis. Oncogene
2016;35(9):1180-92.
83) Chen WX, Hu Q, Qiu MT, Zhong SL, Xu JJ, Tang JH,
et al. miR-221/222: promising biomarkers for breast
cancer. Tumour Biol 2013;34(3):1361-70.
84) Hao J, Zhang C, Zhang A, Wang K, Jia Z, Wang
G, et al. miR-221/222 is the regulator of Cx43 expression
in human glioblastoma cells. Oncol Rep
2012;27(5):1504-10.
85) Jikuzono T, Kawamoto M, Yoshitake H, Kikuchi K,
Akasu H, Ishikawa H, et al. The miR-221/222 cluster,
miR-10b and miR-92a are highly upregulated in
metastatic minimally invasive follicular thyroid carcinoma.
Int J Oncol 2013;42(6):1858-68.
86) Sun T, Wang Q, Balk S, Brown M, Lee GS, Kantoff P.
The role of microRNA-221 and microRNA-222 in androgen-
independent prostate cancer cell lines. Cancer
Res 2009;69(8):3356-63.
87) Yang X, Yang Y, Gan R, Zhao L, Li W, Zhou H, et al.
Down-regulation of mir-221 and mir-222 restrain
prostate cancer cell proliferation and migration that
is partly mediated by activation of SIRT1. PLoS One
2014;9(6):e98833.
88) Matin F, Jeet V, Moya L, Selth LA, Chambers S; Australian
Prostate Cancer BioResource, et al. A Plasma
Biomarker Panel of Four MicroRNAs for the Diagnosis
of Prostate Cancer. Sci Rep 2018;8(1):6653.
89) Bond DR, Naudin C, Carroll AP, Goldie BJ, Brzozowski
JS, Jankowski HM, et al. miR-518f-5p decreases
tetraspanin CD9 protein levels and differentially
affects non-tumourigenic prostate and prostate
cancer cell migration and adhesion. Oncotarget
2017;9(2):1980-91.
90) Penson RT, Oliva E, Skates SJ, Glyptis T, Fuller AF
Jr, Goodman A, et al. Expression of multidrug resistance-1 protein inversely correlates with paclitaxel
response and survival in ovarian cancer patients:
a study in serial samples. Gynecol Oncol
2004;93(1):98-106.
91) He L, He X, Lim LP, de Stanchina E, Xuan Z, Liang
Y, et al. A microRNA component of the p53 tumour
suppressor network. Nature 2007;447(7148):1130-4.
92) Casanova-Salas I, Rubio-Briones J, Fernández-Serra A,
López-Guerrero JA. miRNAs as biomarkers in prostate
cancer. Clin Transl Oncol 2012;14(11):803-11.
93) Enomoto Y, Kitaura J, Hatakeyama K, Watanuki J,
Akasaka T, Kato N, et al. E?/miR-125b transgenic
mice develop lethal B-cell malignancies. Leukemia
2011;25(12):1849-56.
94) Feng B, Wang R, Chen LB. Review of miR-200b and
cancer chemosensitivity. Biomed Pharmacother
2012;66(6):397-402.
95) Lu Z, Liu M, Stribinskis V, Klinge CM, Ramos KS, Colburn
NH, et al. MicroRNA-21 promotes cell transformation
by targeting the programmed cell death 4 gene.
Oncogene 2008;27(31):4373-9.
96) Porkka KP, Pfeiffer MJ, Waltering KK, Vessella
RL, Tammela TL, Visakorpi T. MicroRNA expression
profiling in prostate cancer. Cancer Res
2007;67(13):6130-5.
97) Dahiya R, McCarville J, Lee C, Hu W, Kaur G, Carroll
P, et al. Deletion of chromosome 11p15, p12, q22,
q23-24 loci in human prostate cancer. Int J Cancer
1997;72(2):283-8.
98) Ellsworth RE, Vertrees A, Love B, Hooke JA, Ellsworth
DL, Shriver CD. Chromosomal alterations associated
with the transition from in situ to invasive breast cancer.
Ann Surg Oncol 2008;15(9):2519-25.
99) Rasio D, Negrini M, Manenti G, Dragani TA, Croce
CM. Loss of heterozygosity at chromosome 11q in
lung adenocarcinoma: identification of three independent
regions. Cancer Res 1995;55(18):3988-91.
100) Majid S, Dar AA, Saini S, Yamamura S, Hirata
H, Tanaka Y, et al. MicroRNA-205-directed transcriptional
activation of tumor suppressor genes in
prostate cancer. Cancer 2010;116(24):5637-49.
101) Fabbri M, Garzon R, Cimmino A, Liu Z, Zanesi N,
Callegari E, et al. MicroRNA-29 family reverts aberrant
methylation in lung cancer by targeting DNA
methyltransferases 3A and 3B. Proc Natl Acad Sci U
S A 2007;104(40):15805-10.
102) Chen Y, Zaman MS, Deng G, Majid S, Saini S, Liu J, et
al. MicroRNAs 221/222 and genistein-mediated regulation
of ARHI tumor suppressor gene in prostate
cancer. Cancer Prev Res (Phila) 2011;4(1):76-86.
103) Saini S, Majid S, Shahryari V, Arora S, Yamamura
S, Chang I, et al. miRNA-708 control of
CD44(+) prostate cancer-initiating cells. Cancer Res
2012;72(14):3618-30.
104) Brase JC, Johannes M, Schlomm T, Fälth M, Haese
A, Steuber T, et al. Circulating miRNAs are correlated
with tumor progression in prostate cancer. Int J
Cancer 2011;128(3):608-16.
105) Mahn R, Heukamp LC, Rogenhofer S, von Ruecker
A, Müller SC, Ellinger J. Circulating microRNAs
(miRNA) in serum of patients with prostate cancer.
Urology 2011;77(5):1265.e9-16.
106) Nadiminty N, Tummala R, Lou W, Zhu Y, Shi XB,
Xou JX, et al. MicroRNA let-7c is downregulated
in prostate cancer and suppresses prostate cancer
growth. PLoS ONE 2012;7(3):e32832.
107) Beck J, Urnovitz HB, Riggert J, Clerici M, Schütz E.
Profile of the circulating DNA in apparently healthy
individuals. Clin Chem 2009;55(4):730-8.
108) Schütz E, Akbari MR, Beck J, Urnovitz H, Zhang
WW, Bornemann-Kolatzki K, et al. Chromosomal
instability in cell-free DNA is a serum biomarker for
prostate cancer. Clin Chem 2015;61(1):239-48.
109) Liu QY, Rubin MA, Omene C, Lederman S, Stein CA.
Fas ligand is constitutively secreted by prostate cancer
cells in vitro. Clin Cancer Res 1998;4(7):1803-11.
110) Hyer ML, Voelkel-Johnson C, Rubinchik S, Dong J,
Norris JS. Intracellular Fas ligand expression causes
Fas-mediated apoptosis in human prostate cancer
cells resistant to monoclonal antibody-induced apoptosis.
Mol Ther 2000;2(4):348-58.
111) Nathwani AC, Tuddenham EG, Rangarajan S, Rosales
C, McIntosh J, Linch DC, et al. Adenovirus-associated
virus vector-mediated gene transfer in hemophilia
B. N Engl J Med 2011;365(25):2357-65.
112) Simonelli F, Maguire AM, Testa F, Pierce EA, Mingozzi
F, Bennicelli JL, et al. Gene therapy for Leber"s congenital
amaurosis is safe and effective through 1.5 years after
vector administration. Mol Ther 2010;18(3):643-50.
113) Izquierdo M. Short interfering RNAs as a tool
for cancer gene therapy. Cancer Gene Ther
2005;12(3):217-27.
114) Li J, Wang Y, Zhu Y, Oupick? D. Recent advances in
delivery of drug-nucleic acid combinations for cancer
treatment. J Control Release 2013;172(2):589-600.
115) Nastiuk KL, Krolewski JJ. Opportunities and challenges
in combination gene cancer therapy. Adv Drug
Deliv Rev 2016;98:35-40.
116) Ding H, Sun Y, Hou Y, Li L. Effects of INPP4B gene
transfection combined with PARP inhibitor on castration
therapy-resistant prostate cancer cell line,
PC3. Urol Oncol 2014;32(5):720-6.
117) Marangoni K, Neves AF, Rocha RM, Faria PR, Alves
PT, Souza AG, et al. Prostate-specific RNA aptamer: promising nucleic acid antibody-like cancer detection.
Sci Rep 2015;5:12090.
118) Mu P, Nagahara S, Makita N, Tarumi Y, Kadomatsu
K, Takei Y. Systemic delivery of siRNA specific to
tumor mediated by atelocollagen: combined therapy
using siRNA targeting Bcl-xL and cisplatin against
prostate cancer. Int J Cancer 2009;125(12):2978-90.
119) Kaikkonen MU, Ylä-Herttuala S, Airenne KJ. How
to avoid complement attack in baculovirus-mediated
gene delivery. J Invertebr Pathol 2011;107 Suppl:S71-9.
120) Fujita T, Satoh T, Timme TL, Hirayama T, Zhu JX,
Kusaka N, et al. Combined therapeutic effects of adenoviral
vector-mediated GLIPR1 gene therapy and
radiotherapy in prostate and bladder cancer models.
Urol Oncol 2014;32(2):92-100.