|Year : 2014 | Volume
| Issue : 3 | Page : 594-601
Interleukin 1β and metalloproteinase 3 gene polymorphisms in hepatocellular carcinoma patients in Egypt
Ahmad Abass Rauf1, Hatem Mahmoud El-Sebaa2, Maathir Kamel El-Shafie2, Ashraf Yousif El-Fert1, Samar Ebrahim Mohmmed Ghanem MSc 1
1 Department of Medical Biochemistry, National Liver Institute, Menoufia University, Menoufia, Egypt
2 Department of Medical Biochemistry, Faculty of Medicine, Menoufia University, Menoufia, Egypt
|Date of Submission||12-Sep-2013|
|Date of Acceptance||04-Nov-2013|
|Date of Web Publication||26-Nov-2014|
Samar Ebrahim Mohmmed Ghanem
Department of Medical Biochemistry, National Liver Institute, Menoufia University, Menoufia
Source of Support: None, Conflict of Interest: None
The aim of this study was to evaluate the association between interleukin (IL)-1β −31T/C and matrix metalloproteinase 3 (MMP3) −1171 single-nucleotide polymorphisms and the susceptibility of hepatocellular carcinoma (HCC) patients.
IL-1β is an important cytokine. IL-1β −31T/C polymorphism located in the promoter region of IL-1β has been linked to an elevated risk of HCC. MMP3 is a MMP that has proteolytic activity. MMP3 polymorphism at 1171 has been linked to an elevated risk and a highly invasive type of HCC.
Patients and methods
This study included 30 HCC patients, 30 hepatitis C virus (HCV) patients, and 20 healthy controls. IL-1β and MMP3 polymorphisms were genotyped using the restriction fragment length polymorphism discrimination assay technique.
Data revealed that the frequency of IL-1β C/T and MMP3 5A/6A polymorphisms were higher in patient groups (HCC and HCV) compared with healthy controls. Our results indicated a significant association between IL-1β C/T polymorphism and HCC susceptibility; also, a significant association was detected between MMP3 5A/6A polymorphism and HCC susceptibility.
These results suggested that IL-1β C/T and MMP3 5A/6A polymorphisms are associated with an increased risk of developing HCC in Egyptian patients.
Keywords: hepatocellular carcinoma, interleukin 1β polymorphism, metalloproteinase 3 polymorphism
|How to cite this article:|
Rauf AA, El-Sebaa HM, El-Shafie MK, El-Fert AY, Ghanem SE. Interleukin 1β and metalloproteinase 3 gene polymorphisms in hepatocellular carcinoma patients in Egypt. Menoufia Med J 2014;27:594-601
|How to cite this URL:|
Rauf AA, El-Sebaa HM, El-Shafie MK, El-Fert AY, Ghanem SE. Interleukin 1β and metalloproteinase 3 gene polymorphisms in hepatocellular carcinoma patients in Egypt. Menoufia Med J [serial online] 2014 [cited 2020 Feb 24];27:594-601. Available from: http://www.mmj.eg.net/text.asp?2014/27/3/594/145523
| Introduction|| |
Hepatocellular carcinoma (HCC) ranks fifth in the frequency of cancers worldwide and is the third cause of cancer death . It is usually asymptomatic in the early stages and tends to be invasive in late stages. Therefore, most patients present with an incurable disease at the time of detection, which makes early diagnosis of HCC critical for a good prognosis. Surgical resection remains the treatment of choice for these tumors, but unfortunately only 10-20% of primary HCCs are resectable at the time of diagnosis. Continuous researches are ongoing worldwide to find out and evaluate sensitive and specific new markers for HCC diagnosis  . The most common cause of HCC is liver cirrhosis complicating chronic hepatitis caused by hepatitis C virus (HCV) and/or hepatitis B virus (HBV) infection. Therefore, early detection of patients at risk, such as chronic carriers of HBV and HCV, would improve the outcome of treatment of hepatocellular malignancy , .
In Egypt, the incidence of HCC has increased sharply in the last decade  . This could be due to HBV and HCV epidemic infections. Furthermore, improvements in diagnostic tools and healthcare have led to an increased survival rate among cirrhotic patients, allowing time for some of them to develop HCC  . However, not all the individuals infected with HBV/HCV develop HCC, indicating an implication of other environmental and genetic risk factors in the multistage process of this complex disease  .
The interleukin (IL) 1β gene is located on the long (q) arm of chromosome 2 at position 1  . IL-1β is a proinflammatory cytokine that is involved in a variety of immune and acute-phase inflammatory response activities, as well as bone resorption  . Moreover, IL-1β has been considered as an important factor in tumor growth, invasion, and metastasis depending on several independent studies that hinted at the implication of IL-1β polymorphisms in HCV infection [8-10].
The gene encoding IL-1β is highly polymorphic, and several allelic polymorphisms have been reported. Two of these are in the promoter region at positions 511 and 31  . IL-1β gene −31T/C substitution located in the TATA box motif in the promoter region of the gene IL-1β has been found to affect the binding of several transcription factors markedly and thereby affect the transcription activity of IL-1β  .
Matrix metalloproteinases (MMPs) have been suggested to play a key role in the growth, invasion, and remote metastasis of various human carcinomas, including HCC. Also, they were found to be involved in hepatic fibrosis, which is an important predisposing factor for HCC development  .
The MMP3 gene is located on the long (q) arm of chromosome 11 at position 22.2-22.3  .
The promoter region of MMP3 is characterized by a polymorphism due to variation in the number of adenosines located at position −1171 relative to the transcription start site, resulting in one allele having five adenosines (5A) and the other allele having six adenosines (6A). In-vitro promoter functional analysis studies showed that the 5A allele had greater promoter activities and that 6A allele is associated with reduced gene expression  .
MMP3 mRNA production is at a low level under normal physiological conditions, but can be markedly induced by IL-1β, TNFα, interferon γ, and some epidermal growth factors under pathological conditions. IL-1β upregulates MMP3 transcription by activating the extracellular-signal-regulated kinase (ERK) and the mitogen-activated protein kinase (MAPK) pathways. Functional polymorphisms of IL-1β and MMP3 genes may collectively accelerate HCC tumor progression and metastasis  .
The aim of this work was to study the association between IL-1β −31T/C and MMP3 −1171 single-nucleotide polymorphisms and the susceptibility of HCC patients in Egypt.
| Patients and methods|| |
This study was conducted on 80 participants including 30 diagnosed HCC patients also having HCV infection with exclusion of HBV-positive or combined HBV-positive and HCV-positive cases and 30 patients with chronic HCV infection. They were presented to the Hepatology Department, National Liver Institute, Menoufia University, in the period from October 2011 to October 2012. Diagnosis was based on clinical examination, laboratory tests, ultrasonography, and computed tomography. In addition, a control group of 20 individuals of matched age and sex was included. Informed consent was obtained from each individual.
About 10 ml of venous blood were withdrawn from all participants; 5 ml were collected into a plain tube, and then left to stand for 10 min and centrifuged at 3000 rpm for 5 min; the clear supernated sera was analyzed for liver function tests, using the fully automated autoanalyzer Synchron CX9ALX (Beckman Coulter Inc., California, USA). Serum viral markers HBS Ag and HCV Ab were determined by eletrochemiluminescence immunoassay using the Cobase immunoassay analyzer (Roche Diagnostic, Germany).
DNA extraction and genotyping
The remaining 5 ml were collected in an EDTA-containing tube. Genomic DNA was extracted from whole blood using the Gene JET Whole Blood Genomic DNA Purification Mini Kit (Thermo Scientific, Lithuania)  .
IL-1β −31T/C and MMP3 −1171 5A/6A genotyping were performed using PCR-restriction fragment length polymorphism with modification  .
A 210-bp amplification product was obtained using the standard PCR assay with the following primers (IL-1β forward: 5΄-AGAAG CTTCCACCA ATACTC-3΄; IL-1β reverse: 5΄-ACTAA CCTTTAGG GTGTCAG-3΄; MMP3 forward: 5΄-GGTTCT CCATTCCTTTGA TGGGGGGAAAGA-3΄; MMP3 reverse: 5΄-CTTCCTGG AATTCAC ATCACTG CCACCACT-3΄) (primers were purchased from Metabion, Martinsried, Germany)  .
The amplification mix was prepared of the following:
- 0.5 μl of each of the primers: IL-1β forward (5΄-AGAAGCTTCCACCAATACTC-3΄), IL-1β reverse (5΄-ACTAACC TTTAGGG TGTCAG-3΄), MMP3 forward (5΄-GGTT CTCCA TTCCTT TGATGGG GGGAAAGA-3΄), and MMP3 reverse (5΄-CTTCCTGGA ATTCACATCA CTGCC ACCACT-3΄).
- 12.5 μl of Dream Taq Green PCR Master Mix (Thermo Scientific) was used.
- 1.5 μl of sterile injection water (2X), and then 10 μl of extracted DNA were added to the corresponding reaction tubes  .
The cycling conditions consisted of an initial denaturation step at 94°C for 3 min, followed by 35 cycles of 94°C for 30 s, 55°C for 30 s, and 72°C for 30 s, with a final extension of 72°C for 5 min  .
Polymerase chain reaction/restriction fragment length polymorphism
After PCR, 10 μl of the amplification product was added to the digestion mixture of 3 μl 10X fast digest buffer, 1 μl (10 U) of PsyI (Tth11I) or AluI (Thermo Fisher Scientific Inc., Massachusetts, USA), for MMP3 −1171 and IL-1β −31T/C genotyping, respectively, and the volume was topped up with H 2 O to 30 μl and incubated at 37°C for 15 min. The reaction mixture was loaded directly and electrophoresed through 1% agarose gel for IL-1β and 3% agarose gel for MMP3 and stained with ethidium bromide. Fragments of DNA were photographed under ultraviolet transillumination. IL-1β −31C homozygous was identified by the presence of 344-, 79-, 20-, and 5-bp fragments. The IL-1β −31T homozygous was identified by the presence of 247-, 97-, 79-, 20-, and 5-bp fragments (the 20- and 5-bp fragments are usually not seen on the gel). However, MMP3 −1171 6A homozygous was identified by a 130-bp fragment, and MMP3 −1171 5A homozygous was identified by the presence of 97- and 33-bp fragments  .
Statistical analysis was performed with SPSS 16.0 software (SPSS Inc., Chicago, Illinois, USA). The χ2 -test was performed for qualitative variable analysis. The Student t-test was performed for normally distributed quantitative variables to measure mean and SD. The Mann-Whitney test was performed for quantitative variables that were not normally distributed. The analysis of variance test was performed to compare three variables: one qualitative variable and the other two were normally distributed quantitative variables. The Kruskal-Wallis test was performed to compare three or more variables: one qualitative variable and the other variables were non-normally distributed quantitative variables  .
| Results|| |
[Table 1] shows that there was a significant statistical difference among different groups regarding cirrhosis and the spleen size, whereas there was no statistically significant difference regarding the sex and age.
|Table 1: Demographic criteria and clinical findings of the studied groups |
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[Table 2] shows that there was a significant statistical difference among different groups concerning aspartate aminotransferase (AST), TP, albumin, alkaline phosphatase (ALP), γ-glutamyl transferase (GGT), direct bilirubin, α-feto-protein (AFP), and PT, whereas no significant difference could be detected regarding the total bilirubin and alanine transaminase.
|Table 2: Statistical comparison of liver function tests among the different studied groups |
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[Table 3] shows that there was a highly significant statistical difference among the studied groups regarding IL-1β polymorphism, with the highest percent of C/T in the HCC group and C/C in the HCV group, whereas TT represents the highest percent in the control group. Regarding MMP3, there was a significant statistical difference among the studied groups with regard to MMP3, with the highest percent of 6A/5A in the HCC group and the lowest percent of 6A/6A in the HCC group and 5A/5A in the HCV and the control groups.
|Table 3: Statistical comparison of interleukin 1β and metalloproteinase 3 genotyping among the studied groups |
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[Table 4] shows that there was a highly statistically significant difference among the HCC, the HCV, and the control groups regarding IL-1β alleles, with the highest frequency of C allele in HCV and HCC, whereas there was a statistically significant differences among the HCC, the HCV, and the control groups regarding the MMP3 allele distribution, with the highest frequency of 5A allele in HCC.
|Table 4: Statistical comparison of interleukin 1β and matrix metalloproteinase 3 allele distribution between the hepatocellular carcinoma and the hepatitis C virus groups |
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[Table 5] shows that there was no significant statistical difference between IL-1β C/T genotype in the HCC and the HCV groups regarding the spleen size and lymph nodes, ascitis, and cirrhosis.
|Table 5: Statistical comparison of interleukin 1β C/T genotype in the hepatocellular carcinoma and the hepatitis C virus groups with regard to the spleen size, cirrhosis, ascitis, and lymph nodes |
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[Table 6] shows that there was a highly significant statistical difference between MMP3 6A/5A genotype in the HCC and the HCV groups regarding cirrhosis and a significant statistical difference regarding lymph nodes, whereas there was no significant statistical difference regarding the sex and ascitis.
|Table 6: Statistical comparison of matrix metalloproteinase 3 6A/5A genotypes in hepatocellular carcinoma and hepatitis C virus groups regarding the spleen size, cirrhosis, ascitis, and lymph nodes |
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[Table 7] shows that there was a significant statistical difference between IL-1β and MMP3 genotypes regarding the TNM staging, with the worst staging for IL-1β C/T and MMP3 6A/5A.
|Table 7: Statistical comparison between interleukin 1β and matrix metalloproteinase 3 genotypes in the hepatocellular carcinoma group regarding the TNM staging |
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[Table 8] shows that the genotype combination of IL-1β C/T and MMP3 6A/5A and the genotype combination of IL-1β C/T and MMP3 5A/5A are more risky than each genotype alone ([Figure 1] and [Figure 2]).
|Table 8: Statistical comparison of interleukin 1β and matrix metalloproteinase 3 risky genotypes between the hepatocellular carcinoma and the hepatitis C virus groups |
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|Figure 1: Interleukin (IL) 1βgenotyping by PCR-restriction fragment length polymorphism (PCR-RFLP) analysis followed by separation on 2% agarose gel; samples were electrophoresed against a 100-bp ladder (100 bp gene ruler DNA ladder; Thermo Fisher Scientific Inc.). Lane 1 shows the IL-1βT/T genotype, which was identified by the presence of 247-, 97-, 79-, and 20-bp bands (the 20-bp band was not seen); lane 2 shows the IL-1βC/C genotype, which was identified by the presence of 344-, 79-, and 20-bp bands (the 20-bp band was not seen); lane 3 shows the IL-1βC/T genotype, which was identified by 344-, 247-, 97-, 79-, and 20-bp bands (the 20-bp band was not seen) (note that each of the RFLP genotype analyzed was compared with the IL-1βamplified undigested region of 443 bp in post-1, 2, 3 lanes. The landmark band of the ladder was 500 bp).|
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|Figure 2: Matrix metalloproteinase 3 (MMP3) genotyping by PCR-restriction fragment length polymorphism (PCR-RFLP) analysis followed by separation on 3% agarose gel; samples were electrophoresed against a low-range ladder (25-bp gene ruler DNA ladder; Thermo Fisher Scientific Inc.). Lane 1 shows the MMP3 5A/6A genotype, which was identified by the presence of 130-, 97-, and 33-bp bands (the 33-bp band was not seen); lane 2 shows the MMP3 5A/5A genotype, which was identified by the presence of 97- and 33-bp bands (the 33-bp band was not seen); lane 3 shows the MMP3 6A/6A genotype, which was identified by the presence of the 130-bp band (note than each of the RFLP genotype analyzed was compared with the MMP3 amplified undigested region of 130 bp in post-1, 2, 3 lanes. The landmark band of the ladder was 100 300 bp).|
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| Discussion|| |
HCC is one of the most frequent carcinomas worldwide and it accounts for 80-90% cancers of the liver  . HCC may arise both in liver cirrhosis (60-80% of HCCs) and in noncirrhotic liver, suggesting that different hepatocarcinogenetic pathways exist. As with other kinds of cancer, the etiology and carcinogenesis of HCC are multifactorial: infection by HBV and HCV viruses, cirrhosis of any etiology, primary hemochromatosis and prolonged exposure to mycotoxins such as aflatoxin B  .
Hepatocarcinogenesis is a multistep process involving different genetic alterations that ultimately lead to malignant transformation of hepatocytes  .
Functional gene polymorphisms of IL-1β −31C/T and MMP3 −1171 5A/6A may cooperate by a cascade acceleration of HCC tumor progression and metastasis  .
The current study found a highly significant statistical difference among the studied groups with regard to cirrhosis and the spleen size, These results are in agreement with Apte et al.  and Akkiz et al.  , who found a significant difference between the HCC group and the HCV group with regard to the spleen size and cirrhosis.
Our results found that AST, TP, albumin, ALP, GGT, direct bilirubin, AFP, and PT (P < 0.01) were higher in HCC and HCV patients compared with healthy controls.
Okamoto et al.  and Fanale et al.  agreed with the results of this study as they found a significant increase in the mean serum level of AST, ALP, GGT, and direct bilirubin and ALP in HCC patients.
Apte et al.  reported that IL-1β higher transcriptional −31T allele may affect microenvironmental IL-1β levels in HCC and result in a poorer prognosis.
The current study demonstrated that the IL-1β C/T heterozygous genotype has a higher frequency in HCC patients compared with HCV patients and healthy controls: 56.7 vs. 20% and 56.7 vs. 30%, respectively; this was consistent with Guo et al.  , Peng et al.  , Souslova et al.  , and Landvik et al.  , who reported that the frequency of the C/T genotype was higher in HCC patients compared with healthy controls and HCV patients.
The current study showed that the frequency of the 6A/5A genotype was higher in HCC patients compared with healthy controls (56.7 vs. 55%); this was consistent with Ghilardi et al.  , who reported that the frequency of the 6A/5A genotype was higher in HCC patients compared with healthy controls. Also, the frequency of 6A/5A was higher in HCC patients compared with HCV (56.7 vs. 50%); this was consistent with Okamoto et al.  .
Bodey et al.  reported that strong expression of MMP3 was found in the HCC tissue, especially in the extracellular matrix adjacent to blood vessels  .
The current study demonstrated that the frequency of the C allele was higher in HCV patients compared with HCC and also higher in HCC when compared with T allele; Wang et al.  agreed with these results.
Our study showed that the 5A allele is more prevalent in HCC patients (61.7%) than in HCV patients (38.3%) and controls (37.5%).
In agreement with this study, Okamoto et al.  reported that the 5A allele was more prevalent in HCC.
MMP3 −1171 5A allele enhances the growth of HCC and is related to a poorer prognosis in HCC patients. The 5A allele has a higher transcriptional activity than the 6A allele due to the preferential binding of a transcriptional repressor  .
Fang et al.  have shown that the presence of the 5A allele represents an unfavorable prognostic feature.
It is conceivable that the higher transcriptional activity associated with the 5A allele may enhance tumor invasiveness. It is suggested that the presence of the 5A allele in the MMP3 gene promoter sequence may be a facilitating factor for cancer growth and metastasis .
This study showed that there is a highly significant statistical difference among IL-1β and MMP3 genotypes regarding the TNM staging, with the worst staging and pathological grading in IL-1β C/T, MMP3 6A/5A, and 5A/5A genotypes ([Table 7]).
In agreement with our results, Okamoto et al.  suggested a positive relationship between the −31T homozygote and poorer HCC histological grades. It has been thoroughly demonstrated that higher cell proliferation and vascular invasion play important roles in lowering of the differentiation grade of HCC. The functional gene polymorphism at IL-1β −31 may influence tumor tissue differentiation through upregulating the microenvironmental IL-1β level; they also reported that MMP3 1171 5A heterozygote had significantly larger tumors than MMP3 6A homozygotes.
The present study showed that there is no statistically significant difference among IL-1β C/T genotype in HCC and HCV regarding cirrhosis, the spleen size, ascitis, and lymph nodes, despite the highest percent of cirrhosis (100%), moderate ascitis (64.7%), and positive lymph nodes (14.3%). These results are in agreement with Higai et al.  and Kohga et al.  .
In the this study, there was a highly statistically significant difference between MMP3 6A/5A genotype in the HCC and the HCV groups regarding cirrhosis and a statistically significant difference regarding lymph nodes, whereas there was no statistically significant difference regarding ascitis and liver function tests.
These results are in accordance with Zhao et al.  who found that most of the HCC patients had cirrhosis, a high serum level of AFP and lymphadenopathy in the MMP3 6A/5A genotype.
This study found that the genotype combinations of IL-1β C/T and MMP3 6A/5A are more risky than each genotype alone. Their presence in the same patient together indicates poor prognosis and more complication.
This can be explained by the fact that IL-1β upregulates MMP3 transcription by activating the ERK and the p38 MAPK pathways. Functional gene polymorphisms of IL-1β −31 and MMP3 may cooperate by a cascade acceleration of HCC tumor progression and metastasis  .
Holliday et al.  who reported that fibroblasts derived from breast cancer patients who are 5A homozygous demonstrate a significantly higher MMP3 release and have more aggressive invasion-promoting capacity than 6A carriers or those with normal fibroblasts with the same genotype. They also showed that the higher genotype combination, IL-1β −31T and MMP3 1171 5A, leads to a distinctly poorer prognosis in HCC patients compared with a single genotype analysis.
Okamoto et al  reported that IL-1β T homozygotes and MMP3 5A carriers had a significantly higher transcriptional activity and poorer prognosis than those of C carriers and 6A homozygotes among HCC patients. MMP3 is known to lyse basal membrane collagen and to induce the synthesis of other MMPs. The IL-1β −31T allele and MMP3 5A allele are cooperative risk factors for a poor prognosis in HCC patients, suggesting that these gene polymorphisms might be potential markers for predicting the prognosis of HCC patients.
| Conclusion|| |
IL-1β −31C/T and MMP3 −1171 6A/5A gene polymorphisms influence the prognosis of HCV-related HCC patients, the highest percent of MMP3 6A/5A genotype in HCC followed by HCV means that 6A/5A is a risk factor for HCC and a bad prognostic factor for both HCV and HCC and that a combination of these genotypes has a synergistic effect. Further investigation with a larger sample size is recommended to confirm these results. Thus, screening of these polymorphisms and functional studies would be useful in clinical practice to identify groups at high risk for HCC. In addition to epidemiologic analysis, functional studies are also needed to further explore the role of IL-1β and MMP3 gene polymorphisms in HCC carcinogenesis.
| Acknowledgements|| |
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8]