Interleukin-6 healthy men respectively. Significant differences were observed between

Interleukin-6 (IL-6) is
involved in the proliferation and metastasis of many tumours. In the IL-6 gene
promoter, -174G>C (rs1800795) single
nucleotide polymorphisms (SNPs) are associated with transcriptional
pattern of this gene. The aim of this study is to assess the effect of IL-6 (rs1800795)
SNPs on susceptibility and risk of benign prostate hyperplasia (BPH) and the
prostatic adenocarcinoma (PCa). This study was performed on 112 men with PCa,
118 men with BPH and 250 healthful men as control group. After DNA extraction, Genotyping
of IL-6 (rs1800795) was performed using ABI MGB TaqMan Allelic
Discrimination kit based on PCR technique. As results, the G allele frequency for rs1800795 in IL-6 gene was 74.1%, 68.6%
and 67% in PCa patients, BPH patients and healthy men respectively. Significant
differences were observed between PCa and healthy groups (P =0.030, OR =
1.73, 95% CI: 1.05-2.21). The GG genotype of this position was found to be more
common in PCa group, whereas The GC genotype was seen mostly in BPH group in comparison
to other groups. Therefore this study
identified that IL-6 -174G>C (rs1800795) is a statistically
disease-susceptible SNP in prostate cancer and its bone metastasis in a
northwest Iranian population.

Keywords: Interleukin-6,
IL-6, prostate, adenocarcinoma, hyperplasia, BPH,
PCa.

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1.     Introduction

During
the past few decades, prostate disorders have changed into the most commonly
diagnosed male malignancies aged over 60 that still show an upward tendency in
their incidence 1.   According to the most updated cancer
statistic study, prostate cancer remains among 4 major lethal cancers (lung,
breast, prostate, and colorectum) and accounts for almost 1 in 5 new diagnoses 2.

 Prostate carcinoma progression is stimulated by many important risk factors. Inflammation has a very strong link with various types of cancer.
Malignant cells are highly proliferative in nature, which is facilitated by the
inflammatory molecules that are continuously being secreted by other cells
and/or tumour cells themselves in a microenvironment. One of important
inflammatory molecules produced and released by most of cancerous cells is Interleukin
6 (IL 6). This cytokine is involved in the proliferation, differentiation
and metastasis of many tumours of malignant cells and found to be high in serum
and tumour tissues of a majority of cancers 3.  It has been shown that expression of IL-6 is
elevated in conditions such as human benign prostate hyperplasia and prostate adenocarcinoma
4, 5.  Adrel et al. also showed that IL-6 elevation could
be considered as one of signs for metastatic prostate carcinoma  6.  

IL-6
gene is located in chromosomal locus 7p21-14. Three common single nucleotide
polymorphisms (SNPs) in the IL-6 gene promoter are -597G>A, -572G>C
and -174G>C. The -174G>C (rs1800795) has been
indicated to affect the transcription of the gene, and thus alter the cytokine
production 7. Several studies have shown an association between IL-6 gene
polymorphisms and the risk of various cancers including prostate cancer8-10. However,
according to some meta-analysis, the results are inconclusive and more studies
on various ethnical groups are needed to draw a reliable conclusions 11-13. 174G>C (rs1800795) gene polymorphisms are involved in IL-6
transcription, and different populations show various single nucleotide
polymorphism. We hypothesized that this variant might affect the susceptibility
and risk of benign prostate hyperplasia and the prostatic adenocarcinoma in an
Iranian population.

 

2.     Materials and
methods

2.1   Participants

A strict exclusion criteria was set for both
case and control groups. Firstly, a total of 150 men with prostate
adenocarcinoma and 170 men with benign prostate hyperplasia attending public hospitals
of northwestern region of the country were introduced as case group. However, according
to the exclusion criteria, 112 patients for PCa (Mean age: 67.8±10.3) and 118
patients for BPH (Mean age:  age 68±9.3)
were selected for the present study. For the control group, 250 unrelated ethnicity
and age matched (Mean age: 63±7.8) healthy men attending hospitals for routine
checkup or health awareness were selected. Determination of the sample size was based on
previous studies and the statistical availability of the disorder in the
population.

Inclusion criteria for the PCa was based on precise
pathological and histopathological records, Gleason score and PSA levels.
Moreover, participants had no other cancers, previous surgery, radiotherapy, or
chemotherapy, or any serious immunological disorder and taking any kind of
special drug.  For the BPH group, the statement
of an urologist, PSA levels, no history of any cancer, no treatments such as
surgery, radiotherapy, and chemotherapy. Lack of any serious immunological
disorder and taking any kind of special drug. Normal PSA level (C
(rs1800795) nucleotide variants and the occurrence PCa or BPH.  We found no significant
differences comparing some important indexes such as age, BMI, PSA, smoking
status and Gleason grade between cases and healthy controls (all P
>0.05) (Table 1).

 

3.    
Results

3.1 Allele and genotype frequencies

polymorphisms and clinicopathological variables of IL-6 in PCa patients, BPH
pateints and healthy controls are shown in table 2 and 3. The frequency
of the G allele in PCa, BPH and control group was calculated 74.1%, 68.6% and
67 % respectively. Therefore, significant differences was observed only between
PCa and healthy group (P =0.030, OR = 1.73, 95% CI: 1.05-2.21). Albeit
being less frequent allele, the The frequency of GG genotype was more in PCa
group in comparison to BPH and healthy individuals (51.6% vs. 51%,
respectively) and significantly different (P = 0.035, OR = 1.85, 95% CI:
1.12-2.63). However, The GC genotype frequency was seen mostly in BPH group (33.8%) compared with PCa (32.1%) and healthy group (32%), without
significant difference. Nonetheless, frequency of the CC genotype was
identified to be less common in PCa patients (9.8%) in comparison to BPH and
healthy groups (14.6% and 16%, respectively), leading to insignificant distribution
between two study subjects.

The
GG genotype in the PCa patients with bone metastasis was less than
non-metastasis group (58.4% vs 41.5%, P=0.04, OR = 2.02, 95% CI: 1.16-3.15)
(Table 2). Frequency of the GG genotype in PCa patients with high Gleason grade
and high serum PSA levels found to be more (53.1% and 52.2%, respectively) and
insignificant (P =0.83, OR = 1.01 95% CI: 0.49-2.01, and (P =0.10,
OR = 0.7, 95% CI: 0.41-1.23) (Table 2)

4.    
Discussion

 many factors including age, diet, life style,
genetic, family history and environmental factors play specific role in
etiology of the prostate carcinoma14. Studying gene polymorphisms in the
context of genetic susceptibility to the prostate cancer has been of particular
and growing interest. Indeed, the polymorphisms which are an inherent
mechanisms of human diseases, have sown to play a role in tumor incidence,
manifestations, and response to treatment, including prostate cancer 15.  

Multiple
investigations have demonstrated that IL-6 is increased in the serum of
patients with metastatic prostate cancer and IL-6 levels correlate with tumor
burden as well as with serum prostate specific antigen (PSA) or clinical
evident metastases 16. Previous
studies have shown that polymorphisms of inflammatory mediator genes can alter plasma
level and biological activity of the produced mediator 17. The rs1800795 polymorphism located in the promoter region of the
coding gene IL-6, has been reported to affect its gene transcription and thus
change serum IL-6 levels and the disease status from hormone-dependent to hormone-independent
18. Therefore,
it is hypothesized that the polymorphisms occurring in cytokine genes may
influence the susceptibility to prostate cancer and disease severity 19, 20. In this study, we report that the GG genotype and G allele of IL-6
-174G>C (rs1800795) is associated with an increased risk of prostate
cancer and its bone metastasis in an Iranian population.

According
to the several studies, Il-6 (rs1800795) gene polymorphisms might have an
association with prostate cancer risk 21, 22. Amirzargar
et al, investigated the frequency of Il-6 (rs1800795) in individuals from
central and east regions of Iran (Tehran, Yazd, Sistan and Balochistan). They
showed that -174 G allele is the most frequent allele in the general population
in almost all studied ethnic groups which is in parallel with our findings23. Mandal
et al, Mandi? et al. and Bao et al. found significant associations between IL-6
174G>C gene polymorphisms and susceptibility to prostate cancer 19, 24, 25.
However, Magalhães et al. and Chen et al. found no association26. Additionally,
the most updated meta-analysis conducted by Tong-Zu Liua et al. reported an
association only with African-American group which indicates that IL-6
-174G>C polymorphism might play totally opposite effects in different races 27.

Tan
et al. in a study on Chinese population found a strong association between IL-6
(-174 C) allele and aggressiveness and recurrence of PCa 28, and Kesarwani et al. showed that IL-6 (-174) polymorphism could
be associated with progression of PCa toward bone metastasis in Indian
population 22. In current study, our results indicate that the frequency of IL-6
(-174 C) allele is more and statistically significant in PCa bone metastasis.

Even
though some studies have shown associations among BMI, smoking and prostate disorders
29, 30, our data did not show such statistical associations neither in
PCa nor BPH groups. The main limitations of our study should be taken into
consideration. The sample size was relatively small and selected from the
northwestern region of the country which may not represent the general
population. Lack of complete information regarding the causal polymorphism and
its exact functional roles, and the influence of many other genetic factors in
development of prostate cancer. Due to some cultural issues, data regarding
alcohol consumption seemed to be unreliable and excluded from the study.

 

5.    
Conclusion

In summary, our results identified IL-6 -174G>C (rs1800795)
as a statistically disease-susceptible SNP in prostate cancer and its bone
metastasis in a new population. Owing to the limitations of our research, further
cellular and molecular-level studies with larger sample size in more ethnical
groups and races are required in order to investigate the probable role(s) of
this SNP in regulation of IL-6 production and its subsequent effect in the
initiation and/or development of prostate cancer and metastasis.