MMP-7 (− 181A > G) promoter polymorphisms and risk for cervical cancer

https://doi.org/10.1016/j.ygyno.2008.03.007Get rights and content

Abstract

Objectives

Matrix metalloproteinase (MMP-7) is a secreted matrilysin, which contributes to tumor progression through breakdown of basement membranes and angiogenesis. Therefore, we aimed to investigate the association of MMP-7 181A > G gene polymorphism with risk of cervical cancer.

Methods

In the present case control study, we enrolled a total of 150 cervical cancer patients confirmed by histopathology and 162 unrelated healthy individuals. Polymorphism for MMP-7 gene (− 181A > G) was genotyped by polymerase chain reaction and restriction enzyme length polymorphism.

Results

Frequency of MMP-7 181GG genotype and − 181G allele differed significantly between patients with cervical cancer (29.3%) and healthy individuals (19.4%) (P = 0.041; ORGG = 1.94 and P = 0.048; ORG = 1.94). Individuals with MMP-7 181GG genotype were at higher risk of stage II of cervical cancer with borderline significance (P = 0.05, OR = 2.78; 95%CI: 0.89–8.69). However, interaction of MMP-7 181AG and GG genotypes with tobacco usage did not modulate the cervical cancer risk significantly (OR 2.21, 95%CI = 0.59–8.1 and OR 3.17, 95%CI = 0.64–15.7).

Conclusion

Individuals with MMP-7 181GG genotype were at significantly higher risk of cervical cancer.

Introduction

Cervical cancer is the most common cancer among women in many developing countries including India [1]. Age-standardized incidence of 17.2 to 55 per 100,000 has been seen in women from different regions of India [2]. Though cervical cancer is multifactorial in origin, the genetic predisposition also plays an important role [3]. Identification of genetic variants that are associated with cervical cancer will contribute to understanding of underlying mechanisms behind its development and potentially provide therapeutic targets.

MMP-7 (also known as matrilysin or PUMP-1) is a protease with the lowest molecular weight and has broad substrate specificity. It degrades elastin, proteoglycans, fibronectin, and type IV collagen [4], [5], [6]. Over-expression of matrilysin (MMP-7) is predominantly associated with epithelial pre-malignant cells. MMPs are synthesized by stromal cells and produced exclusively by cancer cells, and participate directly in the process of invasion and metastasis, including squamous cell carcinomas of the head, neck and lung and adenocarcinoma of the breast and prostate cancer [7], [8], [9]. The gene encoding MMP-7 is localized on chromosome 11q21–q22. Two polymorphisms exist in the MMP-7 promoter region, − 181A > G and − 153 C > T which are known to modify the gene transcription activity [10], [11]. Numerous studies have shown association of MMP-7 181A > G polymorphisms with malignant diseases [12], [13], [14], [15], [16]. However, till date, association of the MMP-7 functional polymorphism − 181A > G with risk of cervical cancer has not been demonstrated. Wu et al. [17] reported that MMP-7 is highly expressed in metastatic cervical squamous cell carcinoma, and may serve as a marker in estimating the invasive and metastatic potential of cervical squamous cell carcinoma. Therefore, we evaluated the association of MMP-7 (181A > G) genetic variation and susceptibility to cervical cancer, its clinical stages and modulation of risk after interaction with tobacco habits.

Section snippets

Subjects

From January 2005 to April 2007, one hundred fifty invasive carcinoma of uterine cervix confirmed by cervical biopsy, were consecutively taken from different gynecology units of Lucknow hospitals. At the same time, one hundred sixty two unrelated cancer-free women, age, ethnicity matched, cervical cytology negative were recruited from routine colposcopy screening clinic belonging to the same institution. Clinical data were obtained by questionnaire, personal interviews and review of case

Results

The mean age (years ± SD) of patients and healthy controls were 47.2 years ± 8.8 and 48.3 years ± 8.3 respectively. Characteristics of cervical cancer patients are shown in Table 1.

Discussion

MMP-7 has tendency to localize in epithelial cells. It has been also shown that MMP-7 is immunolocalized predominantly to the cytoplasm of cervical carcinoma cells, monocytes and normal mucosa [21]. The present study showed that individuals with MMP-7 181GG genotypes and − 181G allele were at significant increased risk of cervical cancer (OR 1.94; OR 1.37). Previous studies have found that presence of − 181G variant allele results in higher level of MMP-7 expression [11]. Also, MMP-7 bears

Conflict of interest statement

The authors declare that they have no conflicts of interest to disclose.

Acknowledgments

We gratefully acknowledge the assistance of Dr. Rekha Sachan in sample collection. The study was supported by research grant from UP Council of Science and Technology (UPCST) India.

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      Among them, an A to G transition at the − 181 base pair position (− 181A/G) has been proved to be functional in vitro and may contribute to genetic susceptibility of cancers (Jormsjo et al., 2001). Recently, Many studies indicated that the common MMP-7 (− 181A>G) genetic polymorphism was correlated with cancer risk in many cancer types (Jaboin et al., 2011; Kim et al., 2011; Malik et al., 2011a; Ohtani, 2009; Peng et al., 2010; Qiu et al., 2008; Singh et al., 2008; Srivastava et al., 2010; Yi et al., 2010; Yuan-Yuan et al., 2012). However, this relationship remains controversial.

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