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Table of Contents
ORIGINAL ARTICLE
Year : 2019  |  Volume : 62  |  Issue : 5  |  Page : 210-216

The association of matrix metalloproteinas-2 promoter polymorphisms with lung cancer susceptibility in Taiwan


1 Graduate Institute of Biomedical Sciences, China Medical University; Taichung Armed Forces General Hospital, Taichung; National Defense Medical Center, Taipei, Taiwan
2 Taichung Armed Forces General Hospital, Taichung; National Defense Medical Center, Taipei, Taiwan
3 Terry Fox Cancer Research Laboratory, Translational Medicine Research Center, China Medical University Hospital, Taichung, Taiwan
4 Department of Medical Laboratory Science and Biotechnology, Central Taiwan University of Science and Technology, Taichung, Taiwan
5 Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan
6 Graduate Institute of Biomedical Sciences, China Medical University; Terry Fox Cancer Research Laboratory, Translational Medicine Research Center, China Medical University Hospital; Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan

Date of Submission17-May-2019
Date of Decision28-Aug-2019
Date of Acceptance29-Aug-2019
Date of Web Publication24-Oct-2019

Correspondence Address:
Dr. Da-Tian Bau
Translational Medicine Research Center, Terry Fox Cancer Research Laboratory, China Medical University Hospital, Taichung
Taiwan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/CJP.CJP_43_19

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  Abstract 

Matrix metalloproteinases-2 (MMP2) has been reported to be overexpressed in various types of cancer. However, the contribution of various genotypes of MMP2 to lung cancer is controversial and not yet been examined in Taiwan. Therefore, in the current study, we investigated the association of MMP2 genotypes with lung cancer risk among Taiwanese. In this hospital-based, case–control study, 358 lung cancer patients and 716 age- and gender-matched healthy controls were recruited, and the genotypic distributions of MMP2-1306 and MMP2- 735 were determined. Then, their association with lung cancer was evaluated, and their interaction with personal smoking status was also examined via stratification analysis. The results showed that the percentages of variant CT and TT at MMP2-1306 were 17.3% and 1.7% among the lung cancer patients, respectively, much lower than those of 28.7% and 2.4%, respectively, among the healthy controls (P for trend = 0.0001). The allelic frequency distribution analysis showed that the variant T allele at MMP2-1306 conferred a statistically significantly lower lung cancer risk than the wild-type C allele (adjusted odds ratio = 0.54, 95% confidence interval = 0.41–0.72, P = 0.0001). There was an obvious effect of MMP2-1306 genotype on lung cancer risk among the subpopulations of ever smokers but not nonsmokers. As for the genotypes of MMP2-735, there was no such differential distribution in the aspects of genotypic or allelic frequencies, or combinative effects with smoking status. The genotypes of MMP2-1306 may act as a biomarker in determining personal susceptibility to lung cancer in Taiwan. The contribution of MMP2 genotypes alone and its joint effects with personal cigarette smoking habit on lung cancer susceptibility should be taken into consideration of the clinical practices for early detection and prediction of lung cancer in Taiwan.

Keywords: Genotype, lung cancer, matrix metalloproteinase-2, polymorphism, smoking, Taiwan


How to cite this article:
Chen GL, Wang SC, Shen TC, Tsai CW, Chang WS, Li HT, Wu CN, Chao CY, Hsia TC, Bau DT. The association of matrix metalloproteinas-2 promoter polymorphisms with lung cancer susceptibility in Taiwan. Chin J Physiol 2019;62:210-6

How to cite this URL:
Chen GL, Wang SC, Shen TC, Tsai CW, Chang WS, Li HT, Wu CN, Chao CY, Hsia TC, Bau DT. The association of matrix metalloproteinas-2 promoter polymorphisms with lung cancer susceptibility in Taiwan. Chin J Physiol [serial online] 2019 [cited 2019 Nov 20];62:210-6. Available from: http://www.cjphysiology.org/text.asp?2019/62/5/210/269834

Guan-Liang Chen, Shou-Cheng Wang and Te-Chun Shen contributed equally to this study.



  Introduction Top


For many years, lung cancer has been the most common and leading cause of cancer mortality all over the world.[1] Although there is a rapid development of personalized therapies and medicine, the prognosis of patients with lung cancer remains unsatisfying, with a 5-year survival rate of <20%.[1] Thus, updated useful predictive and prognostic markers may strengthen the current genomic predictive systems for revealing the personalized lung etiology.

Matrix metalloproteinases (MMPs), also named as matrixins, are a family of proteins regulating the homeostasis of extracellular matrix (ECM) contents.[2],[3],[4] Mounting evidence supported the concept that MMPs involved in many tumorigenesis events, such as cell proliferation, differentiation, apoptosis, invasion, migration, metastasis, angiogenesis, and immune surveillance.[5] In recent years, several reports indicated that genotypes of MMPs, especially those in the promoter regions of MMPs, may be associated to determining interindividual variations of susceptibility to various types of cancer,[6],[7],[8],[9],[10],[11],[12],[13],[14] whereas some other reports brought us negative results.[15],[16],[17]

Human MMP2 gene located on chromosome 16q21 and its encoded protein belong to the endopeptidase family, which are found in a wide variety of tissues and cell types.[18],[19],[20] In literature, the alterations in the expression levels of mRNA and protein of MMP2 may be closely related to the metastatic behavior of several types of solid cancer, including breast, lung, esophageal, and colon cancers.[8],[21],[22],[23] For instance, it was reported that MMP2 was elevated in the tumor tissues of oral cancer patients, particularly those with lymph node metastasis.[24] As for the contribution of MMP2 to lung cancer, the genotypic articles are extremely few. In literature, it was reported that variant genotypes of CT and TT at MMP2-1306 were nondifferentially distributed among the lung cancer group and the control group and therefore cannot serve as a risk biomarker for lung cancer in a Turkey population.[25] This is the typical literature which investigated the association of MMP2 genotypes with lung cancer; however, the findings are negative, urgently waiting for validation in other populations. In addition, their population is composed of 200 lung cancer patients and 100 healthy controls and could be enlarged to become more representative. Thus, in the present study, the genotyping study was conducted first in Taiwan with a representative population containing 358 lung cancer patients and 716 noncancer healthy controls, to examine the contributions of MMP2 promoter-1306 (rs243865) and MMP2 promoter-735 (rs2285053) polymorphisms to the susceptibility of lung cancer in Taiwan.


  Materials and Methods Top


Patient collection

Three hundred and fifty-eight patients with lung cancer were histologically confirmed and recruited at the medical center in central Taiwan as previously described with the approval of the Institutional Review Board of China Medical University Hospital (DMR100-IRB-284).[17],[26],[27] Briefly, the exclusion criteria of the cases were any patients with a history of any other malignancy and pulmonary diseases, such as chronic obstructive pulmonary disease, pneumothorax, and asthma. During the same period, 716 healthy volunteers were selected from the databank of Health Examination Cohort of China Medical University Hospital with more than 15,000 individuals as controls, matched for their age (differences <5), gender, and smoking behavior. The exclusion criteria of the control group included previous malignancy, metastasized cancer from other known or unknown origin, and any genetic or familial diseases. The controls and cases are all Taiwanese, and their selected recorded characteristics are summarized in [Table 1].
Table 1: Distribution of selected demographics of the 358 patients with lung cancer and the 716 matched controls

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Concise matrix metalloproteinase 2 genotyping methodologies

The genomic DNA was extracted from the leukocytes of each participant's peripheral blood within 24 h after their availability, was quantitated, was diluted, and was stored at −80°C until processed as per our previous articles.[28],[29],[30] In the current study, the genotypes at MMP2-1306 and MMP2-735 were determined for all the investigated participants via the typical polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodologies with the BioRad Mycycler (BioRad, Hercules, CA, USA). All PCR reactions were uniformly performed as a 5-min initial cycle at 94°C for 5 min; 40 cycles of 94°C for 30 s, 55°C for 30 s, and 72°C for 30 s, and a final extension at 72°C for 10 min. After the PCR, the target single-nucleotide polymorphism (SNP)-containing DNA amplicons were digested by the corresponding restriction endonucleases of 4 h or overnight in the same incubator. Following the digestion procedure, each enzyme-digested DNA amplicon was analyzed by agarose gel electrophoresis, pictures were taken, and its individual genotypes were identified with at least two well-trained researchers. In addition, all the genotypic procedures were repeated by two researchers independently, blindly within the same week, and their results of all the samples were 100% concordant. In addition, approximately 5% of the samples were selected and examined by direct sequencing, and the results were found to be 100% concordant. The detailed information of forward and reverse primer residues and the corresponding restriction endonucleases for each DNA amplicon is summarized in [Table 2].
Table 2: Summary of the primer sequences, restriction enzymes and amplicons after enzyme digestion for childhood leukemia matrix metalloproteinase-2 genotyping polymerase chain reaction-restriction fragment length polymorphism methodology

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Statistical analyses

The Student's t-test was applied for the comparison of the ages between the lung cancer patient and control groups. Pearson's Chi-square or Fisher's exact test (as any number was <5) was applied to compare the distributions of the numbers among the subgroups. The Hardy–Weinberg equilibriums were checked by Chi-square goodness-of-fit test (P > 0.05) using gene frequencies of the healthy individuals in the control group. The associations between MMP2 genotypes and lung cancer risk were estimated by calculating the odds ratios (ORs) and their 95% confidence intervals (CIs) from logistic regression analysis. Statistically, any difference at P < 0.05 was considered significant between any two groups compared.


  Results Top


The frequency distributions of selected demographic indexes, such as age and gender for the 358 cases of lung cancer and 716 noncancer healthy controls, are compared and presented in [Table 1]. As for the lung cancer group, the histology of all the patients was also recorded. As we applied frequency matching in our methodology in recruiting the noncancer healthy individuals as the control group, the analyzed results showed that there was no difference with respect to the distributions of age and gender between the control and case groups (P = 0.5871 and 0.3642, respectively) [[Table 1], top part]. About three-fifth of the lung cancer patients (60.9%, 218 out of 358) were of adenocarcinoma type, whereas 29.6% (106 out of 358) were of squamous cell carcinoma type and 9.5% (34 out of 358) were of other types [[Table 1], bottom part].

The distributions and frequencies of the MMP promoter-1306 (rs243865) and MMP promoter-735 (rs2285053) genotypes among the 358 lung cancer patients (cases) and the 716 noncancer healthy controls (controls) are presented and compared in [Table 3]. First, the PCR-RFLP genotyping results showed that the genotype of MMP2-735 among Taiwan citizens was not different between the lung cancer patient and healthy control groups [Table 3], bottom panel]. Second, the genotypes of MMP2-1306 were differently distributed between the two groups (P for trend = 0.0001) [Table 3], top panel]. In detail, the MMP2-1306 homozygous variant TT and heterozygous variant CT were not associated with lowered lung cancer risk, compared with wild-type CC genotype (adjusted OR [aOR] =0.64 and 0.53, 95% CI = 0.26–1.73 and 0.41–0.71, P = 0.2829 and 0.0001, respectively [Table 3], top panel]). To confirm these findings, there was also no association between the CT + TT genotype of MMP2-735 and lung cancer risk, compared with CC wild-type genotype in the dominant analyzing model (aOR = 0.83, 95% CI = 0.63–1.09, P = 0.2363 [Table 3], bottom panel]). On the contrary, there was an obvious association between the CT + TT genotype of MMP2-1306 and lung cancer risk, compared with CC wild-type genotype in the dominant analyzing model (aOR = 0.54, 95% CI = 0.39–0.74, P = 0.0001 [[Table 3], top panel]).
Table 3: Distributions of matrix metalloproteinase-2 genotypes among lung cancer patients and healthy subjects

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To confirm the findings in [Table 3], the analyses of allelic frequency distribution as for the MMP2-1306 and MMP2-735 were also performed, and the results are shown in [Table 4]. The results showed that the variant T allele of MMP2- 1306 was associated with a relatively lower risk than wild-type C allele in determining lung cancer risk. On the other hand, the T allele of MMP2- 1306 was not a determiner of lung cancer risk in Taiwan. In detail, the variant allele T was found to be 10.3% in the lung cancer group, much lower than the level of 16.8% in the control group (aOR = 0.54, 95% CI = 0.41–0.72, P = 0.0001 [[Table 4], top panel]). On the contrary, there was no such significant difference as for MMP2- 735 between the two groups examined [[Table 4], bottom panel].
Table 4: Distribution of allelic frequencies for matrix metalloproteinase-2 among the lung cancer patients and healthy subjects

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Because cigarette smoking behavior is the major risk factor for lung cancer in Taiwan,[31] we are extremely interested in the interaction between the MMP2 genotypes and personal cigarette exposure status, and the analyzed results as for MMP2- 1306 are summarized in [Table 5]. Among the nonsmokers, there was no statistically significantly increased risk of lung cancer for those MMP2- 1306 variant CT or CC genotype carriers (OR = 0.47 and 0.50, 95% CI = 0.22–1.01 and 0.05–4.54, P = 0.0504 and 1.0000, respectively, P value of trend analysis = 0.1299) [[Table 5], left part]. As for those smokers, the MMP2- 1306 variant CT genotype carriers were of lower lung cancer risk than those CC genotype carriers (OR = 0.52, 95% CI = 0.36–0.74, P = 0.0002) [[Table 5], right part]. After adjusting for age and gender, the results were still positive (OR = 0.57, 95% CI = 0.43–0.81) [[Table 5], right part]. As for MMP2-735, there was no interaction between MMP2-735 genotypes and smoking status in the investigated population (data not shown).
Table 5: Odds ratios for matrix metalloproteinas-2-1306 genotype and lung cancer after stratification by smoking status

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  Discussion Top


In the present study, the contribution of genotypes of MMP2- 1306 and MMP2-735, which are located in the promoter region, to Taiwan lung cancer risk was first examined among a representative population comprising 358 lung cancer patients and 716 age- and gender-matched healthy controls in Taiwan. In literature, the variations at the two SNP loci of MMP2-1306 and MMP2-735 might destroy the binding site of Sp1 to MMP2 mRNA, resulting in the decrement of its transcription level, and eventually decrease the expression of MMP2.[32] The results in [Table 3] and [Table 4] indicate that none of the genotypic or the allelic frequencies at MMP2- 735 were differentially distributed among the investigated case and control groups. Interestingly and valuably, the genotypes of MMP2- 1306, especially the heterozygous variant CT genotype, could serve as a protective factor for determining personal lung cancer susceptibility (aOR = 0.64, 95% CI = 0.41–0.71, P = 0.0001) [Table 3].

Our finding is consistent with that of a previous article, reporting that the C allele frequency at MMP2-1306 was significantly higher among the lung cancer patients (91%) than that among the controls (83%).[33] In addition, people carrying the CC genotype had about 2.18-fold higher risk for developing lung cancer than those carrying the CT or TT genotypes.[33] Furthermore, the stratified analysis indicated that the ORs for lung cancer for people carrying the CC genotype, having smoking behavior, and with both factors combined were 2.38 (95% CI = 1.64–3.45), 4.26 (95% CI = 2.57–8.44), and 7.64 (95% CI = 4.74–12.33), respectively. As for the smoking status, the joint effect was more evident and stronger in heavy smokers (OR = 10.25, 95% CI = 5.80–18.09) than that in light smokers (OR = 5.55, 95% CI = 3.34–9.22).[33] To sum up, findings of both the present study and the study by Yu et al. demonstrated a significant association between the MMP2-1306C/T genotype and risk of lung cancer alone or in a manner of interaction with cigarette smoking status.

In literature, there have been four articles examining the contribution of MMP2-1306 genotypes,[33],[34],[35],[36],[37] whereas three articles examined that of MMP2-735 to lung cancer risk.[34],[35],[38] From the current meta-analysis, it seemed that several conclusions may be deduced from the limited results. First, among the various polymorphic sites of MMP2, the major contributor on MMP2 gene to serve as lung cancer risk determiners seemed to be the MMP2-1306 genotypes.[39],[40],[41] Second, those studies with MMP2-1306 CC genotype frequency in lung cancer patients from Asian countries contribute around 80%, and the CC MMP2-1306 genotype constitutes a genomic marker for lung cancer susceptibility.[33],[34],[36] On the other hand, those studies with MMP2-1306 CC genotype frequency in lung cancer patients from European countries contribute around 60%, and there was no significant difference in MMP2-1306 CC genotype frequency between the healthy control and lung cancer patient groups.[35],[37] Our data showed that the frequencies of CC, CT, and TT genotypes at MMP2-1306 were 81.0%, 17.3%, and 1.7%, respectively, in the case group, very similar to those of Asian countries.[33],[34],[36] In addition, we have found that the CC MMP2-1306 genotype was a genomic marker for lung cancer susceptibility in Taiwan [Table 3]. Because there were only two and three studies available for Caucasians and Asians before the current study, the results should be further validated in other countries and larger populations.

In the stratification analysis, a joint effect between the MMP2-1306 genotypes and personal smoking status was evident in the current study [Table 5]. We found that the risk was markedly elevated in smokers, whereas in articles by Zhou et al. and Yu et al., the authors have found that lung cancer risk was mostly elevated in smokers, especially in heavy smokers.[33],[34] Several articles have reported that MMP expression can be induced by smoking,[42],[43] while the detailed mechanisms are not well revealed. Further investigations examining the mechanism(s) by which these MMP2 promoter SNPs modify the development of lung cancer are warranted.

The MMP2 protein is responsible for the metabolism of several substrates including some other MMPs, MMP-9, MMP-13, fibrillar collagen, elastin, endothelin, fibroblast growth factor, plasminogen, and transforming growth factor-β.[44] It is believed that MMP2-mediated ECM degradation is critical for the processes of epithelial–mesenchymal transition which the metastatic tumor cells need to carry on their invasive and migration capacities.[45],[46] In 2005, it was summarized that overexpressed MMP2 is commonly found in the tumor sites and frequently correlated with the poor prognosis of lots of tumors including melanoma, colorectal, breast, ovarian, prostate, and lung cancers.[47] The 1306 polymorphic site of MMP2 may affect the protein expression by modulating the activity of its transcription, hence leading to the occurrence of human diseases, such as bladder cancer and sclerosing cholangitis.[48],[49] Mechanically, various transcription factors such as activator protein-1 (AP-1), specificity protein-1 (SP-1), and AP-2 have their specific binding sites at the MMP2 promoter region to directly regulate the transcriptional activity of the gene.[50],[51] The most strong evidence of the functional regulation at the MMP2 promoter region comes from the report that substituting the C nucleotide with T at MMP2-1306 will inactivate the SP-1 binding region and lead to downregulation of the transcriptional and translational expression levels of MMP2.[9] In 2016, Bchir et al. found that MMP2 was upregulated in people carrying MMP2-1306 CC genotype, compared to those with CT and TT genotypes. In addition, MMP2 activity was enhanced in people carrying the MMP2-1306 CC genotype, compared to those carrying the variant CT and TT genotypes.[52] Thus, the variant MMP2 genotypes, especially those at MMP2-1306 and MMP2-735, may directly alter the expression levels in many cells reported to express MMP2, leading to various types of human diseases, such as cancer.

The MMPs and their modulators are essential in the etiology of lung cancer and are potential targets for the therapy of lung cancer. Because MMP-2 plays a very important part in tumor development and angiogenesis, many strategies have been focused on the inhibition of MMP2 for lung cancer therapy, such as MMP2 RNA interference [53] and adenoviral-mediated MMP2 knockout RNA approaches.[54] The results are promising that the invasion and metastasis were indeed suppressed by the delivery of adenovirus-mediated MMP-2 siRNA to the malignant tissues,[54] suggesting that targeting MMP-2 is a rational approach for lung cancer treatment. In literature, the role of MMP2 in lung tumor initiation and progression and its contribution to prognosis are not well revealed or documented. In the current and previous articles, smoking and MMP2 genotype may have a joint effect on lung cancer risk determination. As for this point, Zhou et al. proposed that in addition to higher constitutive expression owing to the gain of two Sp1 promoter sites, the inducibility of the C-1306–C-732 haplotype of MMP2 by smoking may also be higher than that of the T-1306–T-732 haplotype, which lacks two Sp1 sites. Given these conditions, it would be expected that individuals who smoked and carried the MMP2-1306CC and MMP2-735CC genotypes or the C-1306–C-732 haplotype were more susceptible to developing lung cancer.[34]

In recent years, we have investigated the contribution of genomic variants of other MMPs to lung cancer susceptibility in Taiwan. For example, 1G/2G genotypic variations at MMP-1 promoter-1607 (rs1799750) were found to have no effect on lung cancer risk.[26] Similarly, the promoter region of MMP-8 (C-799T) and two nonsynonymous polymorphisms (Val436Ala and Lys460Thr) may not play an important role in determining personal susceptibility to lung cancer.[55] As for MMP-7, variant genotypes at polymorphic sites of the promoter region, A-181G and C-153T, were not associated with higher risk of lung cancer alone or combined with smoking behavior.[30] In 2016, it was found that the CC genotype of TIMP1 rs4898 compared to the TT wild-type genotype may increase lung cancer risk,[27] and this genotype may serve as a genomic biomarker for lung cancer in Taiwan, similar to MMP2-1306 in the current study. In future, our work on investigating the genotypes of other MMPs will also be helpful to reveal their role in ECM dysregulation in lung cancer etiology. In addition, the markers on those genes whose coded proteins closely interact with MMP2, such as CCL7,[56] TIMP2,[57],[58] TIMP4,[59],[60] THBS2,[61] and thrombospondin 1,[61] may also provide further evidence for revealing the genomic contribution of MMP2 and its signaling network to the development of lung cancer.


  Conclusion Top


The results provide evidence showing that the variant CT genotypes at MMP2 promoter-1306 may play a role in determining the susceptibility to lung cancer in Taiwan.

Acknowledgments

We appreciate the Tissue-bank of China Medical University Hospital for their excellent technical assistance and all the participants, doctors, nurses, and colleagues. The excellent genotyping work performed by Huai-Mei Hsu and Yun-Chi Wang in Terry Fox Cancer Research Lab was also appreciated by all the authors.

Financial support and sponsorship

This study was supported mainly by the Taiwan Ministry of Science and Technology (MOST 106-2314-B-039-022) to Dr. Hsia, and partially by research grant from Taichung Armed Forces General Hospital (108A08) to Dr. Chen.

Conflicts of interest

There are no conflicts of interest.



 
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