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 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 9  |  Page : 299-305

Association between polymorphisms of interleukin-17A G197A and interleukin-17F A7488G and risk of colorectal cancer


1 Department of Pathology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Selangor, Malaysia
2 Department of Preclinical Sciences, Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Kuala Lumpur, Malaysia
3 Department of Surgery, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Selangor, Malaysia
4 Department of Pathology, Hospital Kuala Lumpur, Kuala Lumpur, Malaysia
5 Department of Pathology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia; Institute of Bioscience, Universiti Putra Malaysia, Selangor, Malaysia

Date of Web Publication29-Jun-2018

Correspondence Address:
Heng Fong Seow
Department of Pathology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor
Malaysia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.235345

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 > Abstract 

Background: Interleukin (IL)-17A and IL-17F are inflammatory cytokines mainly produced by T helper 17 cells. IL-17A is known to be protumorigenic while IL-17F has a protective role in cancer. A number of studies have been conducted to determine the association between polymorphisms of IL-17AG197A (rs2275913) and IL-17FA7488G (rs763780) and risk of cancers. No studies have yet to be conducted to genotype the IL-17AG197A polymorphism in colorectal cancer (CRC).
Objective: To assess the association of IL-17AG197A and IL-17FA7488G polymorphisms with CRC risk.
Materials and Methods: We performed the genotyping by polymerase chain reaction-restriction fragment length polymorphism method on blood samples from 80 healthy individuals and paraffin-embedded tumor tissues from 70 CRC patients.
Results: Our study showed that IL-17A197AA genotype was significantly associated with an increased CRC risk with odds ratios of 6.08 (95% confidence interval [CI]: 2.25–16.42, P < 0.001) and 2.80 (95% CI: 1.23–6.35, P = 0.014), in comparison with GG and AG genotypes, respectively. However, IL-17FA7488G polymorphism was not significantly associated with CRC risk (P = 0.102). No significant association of IL-17AG197A and IL-17FA7488G polymorphisms with patient and tumor variables was found.
Conclusion: This report from Malaysia shows the relationship of IL-17A197AA genotype with susceptibility to CRC.

Keywords: Colorectal cancer, interleukin-17A, interleukin-17F, polymorphism


How to cite this article:
Samiei G, Yip WK, Leong PP, Jabar MF, Dusa NM, Mohtarrudin N, Seow HF. Association between polymorphisms of interleukin-17A G197A and interleukin-17F A7488G and risk of colorectal cancer. J Can Res Ther 2018;14, Suppl S2:299-305

How to cite this URL:
Samiei G, Yip WK, Leong PP, Jabar MF, Dusa NM, Mohtarrudin N, Seow HF. Association between polymorphisms of interleukin-17A G197A and interleukin-17F A7488G and risk of colorectal cancer. J Can Res Ther [serial online] 2018 [cited 2019 Jul 20];14:299-305. Available from: http://www.cancerjournal.net/text.asp?2018/14/9/299/235345


 > Introduction Top


Colorectal cancer (CRC) is the third most common cancer in the world.[1] Approximately 1.4 million cases and 694,000 deaths have been reported for the year 2012.[2] In Malaysia, it is the second most common cancer and 63% of the patients are diagnosed at Stages II and IV.[3] The National Cancer Registry 2011 report states that there are 2246 new CRC cases in Malaysia in 2007.[3]

The relationship between inflammation and cancers, including CRC, has been long described and chronic inflammation has been reported to be associated with the promotion of tumor growth, angiogenesis, and metastasis.[4],[5] The molecular mechanisms by which chronic inflammation promotes cancer include increased expression of pro-inflammatory mediators such as cytokines, matrix metalloproteinases, and cyclooxygenase-2 and of transcription factors such as nuclear factor κB and signal transducer and activator of transcription-3. Host genetic factors such as cytokine gene polymorphisms can also influence the inflammatory and immune responses resulting in differences in susceptibility to diseases.[6]

Interleukin (IL)-17A is well known as a potent inflammatory cytokine mainly produced by T helper 17 (Th17) cells and innate immune cells and intestinal Paneth cells.[7] IL-17A is involved in host defense against microbial infections and is implicated in inflammatory conditions such as autoimmune diseases and cancers.[8] It plays a key role in recruitment of neutrophils and inducing expression of pro-inflammatory cytokines, such as IL-6, tumor necrosis factor, granulocyte colony-stimulating factor, and chemokines.[9],[10] The ability of IL-17A to promote tumor formation was first reported in year 1999.[11] Since then, overexpression of IL-17A in various human cancers such as ovarian, gastric, prostate, colorectal, lung, hepatocellular, and esophageal cancers has been reported.[12],[13],[14],[15],[16],[17],[18] In mice, overexpression of IL-17A promoted angiogenesis and tumor growth.[19] CD4 + T-cell-derived IL-17A has been shown to promote spontaneous intestinal tumorigenesis in ApcMin/+ mice.[20] Suppression of IL-17A at tumor sites suppressed tumor growth by inhibiting angiogenesis and activation of cytotoxic T lymphocytes as well as elimination of myeloid suppressor cells and regulatory T-cells.[21] Thus, many studies support the contribution of IL-17A in tumor development. Infiltration of Th17 and IL-17A secretion have been associated with poor prognosis in lung,[22] colorectal,[23] hepatocellular,[24],[25] and breast [26] carcinomas. These further support the protumorigenic role of IL-17A.

Among the six members of the IL-17 family, IL-17F shares the highest sequence homology (50%) with IL-17A. IL-17A and IL-17F bind to the IL-17 receptor A (IL-17RA) and IL-17RC complex, although IL-17F binds to IL-17RA with ~100–1000 times lower affinity than does IL-17A while the binding affinity for IL-17RC is comparable. In general, IL-17F is a weaker inducer of pro-inflammatory cytokine expression and is produced by a wider range of cells including epithelial and innate immune cells. In contrast to IL-17A, overexpression of IL-17F appears to inhibit tumor angiogenesis resulting in the suppression of tumorigenesis of colon and hepatocellular carcinomas.[27],[28] However, IL-17F can also promote intestinal tumorigenesis in ApcMin/+ mice in the presence of IL-17A.[29]

Since IL-17A and IL-17F play an important role in tumorigenesis, it is possible that the functional genetic variations of the IL-17A and IL-17F genes may contribute to the development of cancers. Single nucleotide polymorphism (SNP) in IL-17A G197A (rs2275913) has been associated with risk of gastric,[30] cervical,[31] breast,[32] bladder,[33] and lung [34] cancers. A recent study also showed that IL-17A rs4711998 A > G polymorphism might contribute to esophageal cancer susceptibility.[35] In addition, another study showed that IL-17F A7488G (rs763780), but not IL-17A G197A (rs2275913), polymorphism is associated with an increased risk of gastric cancer.[36] To date, the studies of the association between IL-17A G197A (rs2275913) and IL-17F A7488G (rs763780) polymorphisms and CRC risks have only been conducted in Tunisian and Iranian populations.[37],[38],[39]

The objective of this study was to determine whether the polymorphisms of IL-17A G197A (rs2275913) and IL-17F A7488G (rs763780) are associated with risk of CRC in Malaysia. It is also important to compare our findings with the previous studies and thereby provide additional data on these associations. Once the genotypes are determined, further studies can be conducted to investigate the relationship between the genotypes and protein expression of IL-17A and IL-17F as well as their roles in the modulation of intratumoral immune infiltrates, angiogenesis, and metastasis.


 > Materials and Methods Top


Tissue specimens, blood samples, and DNA isolation

Formalin-fixed, paraffin-embedded tumor tissues from 70 CRC patients were collected at a tertiary hospital in Kuala Lumpur, Malaysia, from 1999 to 2000. All diagnoses were confirmed by the qualified histopathologists. As a control, 80 individual blood samples were randomly selected from the apparently healthy donors at a hospital blood bank in Kuala Lumpur. None of them had a history of neoplastic disease. The study was approved by the National Medical Research Ethics Committee (NMRR-12-435-11565). Genomic DNA was extracted from the 5-μm-thick tissue sections and the whole-blood samples with the QIAamp DNA Mini Kit (QIAGEN, Valencia, CA, USA) and GeneAll Exgene Blood SV mini kit (GeneAll Biotechnology, Korea), respectively, according to the manufacturer's instructions.

Polymerase chain reaction and restriction fragment length polymorphism

Genotyping analysis of IL-17A G197A and IL-17F A7488G polymorphisms was conducted using polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) method. Primer sequences for IL-17F A7488G were adopted from a previous study [36] and as follows: (forward) 5'-ACCAAGGCTGCTCTGTTTCT-3' and (reverse) 5'-GGTAAGGAGTGGCATTTCTA-3'. The primer sequences for IL-17A G197A (forward: 5'-GGAACATGAATTTCTGCCCTTCCCA-3'; reverse: 5'-TAGGGCTTTTCTCCTTCTGTGGTCA-3') were designed using the NCBI Primer-BLAST (http://www.ncbi.nlm.nih.gov/tools/primer-blast/). Genomic PCR was performed in a 30-μl reaction volume containing 30 ng genomic DNA, 2.0 mM MgCl2, 0.2 mM of each deoxynucleotide triphosphate, 0.3 μM of each primer (forward and reverse), 1 U Taq DNA polymerase, and 1X Taq buffer with KCl (Fermentas; Thermo Fisher Scientific, Glen Burnie, MD, USA), using the Mastercycler gradient thermal cycler (Eppendorf, Hamburg, Germany). The thermal cycling conditions comprised an initial denaturing step at 94°C for 5 min and subsequent 30 cycles of denaturation at 94°C for 30 s, annealing at 54°C for IL-17A and 60°C for IL-17F for 30 s, and extension at 72°C for 30 s. A final extension at 72°C for 10 min was performed.

A volume of 10 μl of PCR products was digested for 1 h at 37°C with XagI (FastDigest, Fermentas) for IL-17A G197A and NlaIII (FastDigest, Fermentas) for IL-17F A7488G. The digested PCR products were electrophoresed on 5% (w/v) agarose gel prestained with ethidium bromide at 70 V for 50 min and visualized using the FluorChem 5500 imaging system (Alpha Innotech Corp., San Leandro, CA, USA).

DNA sequencing

To confirm the accuracy of PCR-RFLP results, randomly selected PCR products were subjected to DNA sequencing. PCR products were purified using the GeneAll Expin Combo GP kit (GeneAll Biotechnology), according to the manufacturer's instructions. Direct DNA sequencing was done on an automated capillary ABI PRISM 3100 Genetic Analyzer (Applied Biosystems; Life Technologies, Carlsbad, CA, USA). The DNA chromatograms were examined using the Sequence Scanner Software v1.0 (Applied Biosystems; Life Technologies, Carlsbad, CA, USA) to identify the genotypes of IL-17A G197A and IL-17F A7488G polymorphisms.

Statistical analysis

Hardy–Weinberg equilibrium in controls was tested using the Pearson's Chi-square test (1 degree of freedom). Crude odds ratios (ORs) and 95% confidence intervals (CIs) for CRC in association with genotypes were calculated and statistically tested by the Pearson's Chi-square test. The Freeman–Halton extension of Fisher's exact test and Pearson's Chi-square test were applied, where appropriate, to assess the difference in the distribution of genotypes between cases and controls and the association of genotypes with the patient and tumor variables. All statistical analyses were performed using VassarStats online software (Vassar College, Poughkeepsie, NY, USA; http://vassarstats.net/index.html). Two-sided P < 0.05 was considered statistically significant.


 > Results Top


A PCR-RFLP analysis was performed to determine the genotypes of IL-17A G197A and IL-17F A7488G polymorphisms in 80 apparently healthy individuals and 70 CRC patients. Genotypes of the SNP at a position of 197 bp upstream of the start codon of IL-17A gene and 7488 bp downstream of the start codon of IL-17F gene were determined by XagI and NlaIII restriction enzyme digestions of PCR products, respectively. The expected RFLP results for IL-17A G197A and IL-17F A7488G polymorphisms are shown in the representative gel electrophoreses in [Figure 1] and [Figure 2], respectively. PCR products not treated and treated with XagI or NlaIII restriction enzyme are labeled as 'U' and 'D', respectively, in [Figure 1] and [Figure 2].
Figure 1: Representative agarose gel electrophoreses showing RFLP analysis of the IL-17A G197A genotypes using XagI restriction digest of PCR products from DNA extracted from apparently healthy individuals' whole blood (a) and FFPE CRC tissues (b). “L” indicates the DNA ladder. PCR products not treated and treated with XagI restriction enzyme are shown with “U” and “D” labels, respectively. B 1, 3, 4, and 5 show a 150-bp band indicating that these samples harbored IL-17A 197AA genotype. B 2, 7 and CRC 3, 4, 6, and 8 show restriction fragment sizes of 150, 116, and 34 bp indicating that these samples had IL-17A 197AG genotype. B 6 and CRC 1, 2, 5, and 7 show the 116- and 34-bp restriction fragments indicating that these samples harbored IL-17A 197GG genotype. IL = Interleukin, CRC = Colorectal cancer, PCR = Polymerase chain reaction, RFLP = Restriction fragment length polymorphism, FFPE = Formalin-fixed, paraffin-embedded

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Figure 2: Representative agarose gel electrophoreses showing RFLP analysis of the IL-17F A7488G genotypes using NlaIII restriction digest of PCR products from DNA extracted from apparently healthy individuals' whole blood (a) and FFPE CRC tissues (b). “L” indicates the DNA ladder. PCR products not treated and treated with NlaIII restriction enzyme are shown with 'U' and 'D' labels, respectively. B 3 and CRC 4 show a 143-bp band indicating that these samples harbored IL-17F 7488GG genotype. B 1, 2, and 4 show restriction fragment sizes of 143, 80, and 63 bp indicating that these samples had IL-17F 7488AG genotype. B 5, 6, 7, and 8 and CRC 1, 2, 3, and 5 show the 80- and 63-bp restriction fragments indicating that these samples harbored IL-17F 7488AA genotype. IL = Interleukin, CRC = Colorectal cancer, PCR = Polymerase chain reaction, RFLP = Restriction fragment length polymorphism, FFPE = Formalin-fixed, paraffin-embedded

Click here to view


Results of the genotyping of IL-17A G197A polymorphism are as follows: The AA genotype was not digested and a single 150-bp band was seen [Figure 1], lanes B 1, 3, and 5]; the GG genotype yielded fragment sizes of 116 and 34 bp [Figure 1], lanes B 6 and CRC 1, 2, 5, and 7]; and the AG genotype showed fragments of 150, 116, and 34 bp in size [Figure 1], lanes B 2, 7 and CRC 3, 4, 6, and 8].

In RFLP analysis of IL-17F A7488G polymorphism, the GG genotype showed a single undigested 143-bp band [Figure 2], lanes B 3 and CRC 4], the AA genotype demonstrated fragments of 80 and 63 bp in size [Figure 2], lanes B 5, 6, 7, and 8 and CRC 1, 2, 3, and 5], and the AG genotype exhibited all three fragments (143, 80, and 63 bp) as shown in [Figure 2], lanes B 1, 2, and 4.

Eighteen PCR products were randomly selected and subjected to DNA sequencing to validate the RFLP analysis. Both techniques demonstrated similar genotyping results (data not shown). The representative electropherograms of DNA sequencing results for the IL-17A G197A are shown in [Figure 3]a and [Figure 3]b. IL-17F A7488G genotyping results are shown in [Figure 3]c and [Figure 3]d. The arrows indicate the SNP location. [Figure 3]a represents the result for heterozygous IL-17A 197AG, [Figure 3]b shows homozygous IL-17A 197GG, [Figure 3]c shows heterozygous IL-17F 7488AG, and [Figure 3]d shows homozygous IL-17F 7488AA genotypes.
Figure 3: Representative electropherograms showing DNA sequencing results for the IL-17A G197A (a and b) and IL-17F A7488G (c and d) genotyping. The arrows indicate the SNP location. (a) Heterozygous IL-17A 197AG, (b) homozygous IL-17A 197GG, (c) heterozygous IL-17F 7488AG, and (d) homozygous IL-17F 7488AA genotypes. IL = Interleukin, SNP = Single nucleotide polymorphism

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Distributions of IL-17F A7488G and IL-17A G197A genotype frequencies in healthy controls were in Hardy–Weinberg equilibrium (χ2 = 0.65; P = 0.419 and χ2 = 0.31; P = 0.577, respectively). The frequencies of the polymorphisms in CRC patients and controls are shown in [Table 1]. The distribution of IL-17A G197A genotype frequencies in CRC (AA, 38.6%; AG, 47.1%; GG, 14.3%) was significantly different from that in controls (AA, 15.0%; AG, 51.3%; GG, 33.8%) (χ2 = 13.84, P = 0.001). AA genotype was significantly associated with an increased CRC risk with ORs of 6.08 (95% CI: 2.25–16.42, P < 0.001) and 2.80 (95% CI: 1.23–6.35, P = 0.014), in comparison with GG and AG genotypes, respectively.
Table 1: Crude odds ratios for colorectal cancer in relation to IL-17A G197A and IL-17F A7488G genotypes

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Due to the low frequency of GG genotype in the distribution of IL-17F A7488G genotypes in CRC or controls, a dominant model was performed by combining the GG with the AG into a G carrier (AG/GG) group. This increases the statistical power for evaluation of CRC risk [Table 1]. We observed no significant difference in the distribution of AA and AG/GG genotypes between CRC (AA, 57.1%; AG/GG, 42.9%) and controls (AA, 70.0%; AG/GG, 30.0%) (χ2 = 2.68, P = 0.102).

The association of IL-17A G197A and IL-17F A7488G genotypes with patient and tumor variables including gender, age at diagnosis, race, histological grade, tumor site, and tumor stage was analyzed [Table 2]. Twenty-eight percent (17/60) of the tumor tissues were well-differentiated, 55% (33/60) were moderately differentiated, and 17% (10/60) were poorly differentiated. Thirty-nine percent (24/62) of the tumors were from the left colon, 37% (23/62) were from the right colon, and 24% (15/62) were from the rectum. 8.5% percent (5/59) were tumors of Duke Stage A, 40.5% (24/59) were of Duke Stage B1–B2, and 51% (30/59) were of Duke Stage C1–C2. No significant association of the genotypes with patient and tumor characteristics was found.
Table 2: Association of the IL-17A G197A and IL-17F A7488G genotypes with patient and tumor variables

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 > Discussion Top


The IL-17A 197AA genotype has been shown to be associated with inflammatory diseases such as ulcerative colitis, rheumatoid arthritis, and asthma-related traits.[40],[41],[42] Moreover, the overall A carriers (AA or AG) of IL-17A G197A polymorphism have been linked with an increased risk of gastroduodenal ulcer in Japanese patients.[43] Previous studies have associated IL-17A 197AA genotype with a higher risk of various cancers such as gastric,[30] cervical,[31] breast,[32] bladder,[33] and lung [34] cancers. A similar association has also been reported in CRC in Tunisian population.[38] Our current finding in Malaysian CRC patients is in agreement with this report. In contrast to a study in Iranian patients, the AG genotype of IL-17A G197A polymorphism was associated with increased risk of CRC as compared to AA genotype.[39] This contradiction might be due to the difference in ethnicity.

Our study revealed that there is no association between IL-17F A7488G polymorphism and CRC risk, and this is consistent with a previous study on CRC in Tunisian population.[37] However, the IL-17F 7488AG/GG genotype has been reported to be associated with an increase in gastric cancer risk.[36] Interestingly, the IL-17F A7488G polymorphism has been associated with various infections and immune-related diseases such as inflammatory bowel disease, ulcerative colitis, chronic fatigue syndrome, tuberculosis, asthma, Behcet's disease, and vogt–Koyanagi–Harada syndrome.[40],[44],[45],[46],[47],[48],[49]

We found no association of IL-17F A7488G and IL-17A G197A polymorphisms with patient and tumor variables including gender, age at diagnosis, race, histologic grade, tumor site, and tumor stage. However, the previous study on Tunisian CRC showed that the IL-17F 7488AG/GG genotype is associated with rectal cancer and TNM Stage III/IV.[37] Another study by the same research group has also shown an association of IL-17A 197AA genotype with tumor site at colon compared to rectum, with well differentiated tumor, and TNM Stage III/IV CRC.[38] This inconsistency might be attributed to the relatively small sample size in our study and remains to be verified and delineated by further studies.

The significance of IL-17A and IL-17F in the pathogenesis of CRC remains unknown. It is possible that the IL-17A G197A polymorphism, located at a position of (-) 197 nucleotides from the start codon (promoter region) of the IL-17A gene, may regulate the expression of mRNA. This is supported by an in vitro study, whereby stimulated T-cells from healthy individuals harboring the IL-17A 197A allele (AA or AG genotype) secreted significantly increased levels of IL-17 than those without the 197A allele (GG genotype).[50] The study also showed a higher affinity of 197A allele for the nuclear factor-activated T-cells, which is a critical regulator of the IL-17 gene transcription.[51] Therefore, it is conceivable that the IL-17A G197A (rs2275913) polymorphism located at the promoter region influences the transcriptional regulation of IL-17A, thus leading to a differential IL-17A production. We hypothesize that the IL-17A 197AA genotype may promote the development of CRC by increasing the inflammation through increased secretion of IL-17A.

With IL-17F A7488G (rs763780) polymorphism, the A-to-G nucleotide substitution at a position of 7488 nucleotides from the start codon of the IL-17F gene causes a histidine (His)-to-arginine (Arg) substitution at amino acid 161 (H161R) variant.In vitro functional analysis revealed that the IL-17F H161R variant is unable to induce expression of certain cytokines and chemokines and antagonizes the function of wild-type IL-17F.[52] The inhibitory role of IL-17F has been demonstrated in a mouse model of colon tumorigenesis, whereby IL-17F possibly suppresses tumor angiogenesis.[27] However, there is no evidence that the loss of normal protective functions of H161R variant of IL-17F may increase susceptibility to CRC.


 > Conclusion Top


Our data suggest that IL-17A 197AA genotype increases CRC risks. Although our study was conducted with a relatively small sample size, the results are consistent with previous studies in Tunisia. No studies have been conducted in the Western population or other parts of the world. Thus, this report is a another study on the relationship between IL-17A and IL-17F polymorphisms and risk of CRC. The relationship between the expression of IL-17A and IL-17F proteins and their respective genotypes in CRC tissue specimens will be worthwhile investigating in the future. This future study will provide further knowledge on the contribution of IL-17A G197A and IL-17F A7488G polymorphisms in the CRC pathogenesis. In addition, further investigations on other SNPs in IL-17A and IL-17F, such as IL-17A rs4711998, in relation to CRC risks are worthy to be performed.

Financial support and sponsorship

Research funding under the Malaysian Ministry of Science, Technology and Innovation (Project Number: 02-01-04-SF1312).

Conflicts of interest

There are no conflicts of interest.

 
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