Polymorphisms in the promoter regions of the matrix metalloproteinases-1, -3, -7, and -9 and the risk of epithelial ovarian cancer in China
Introduction
Ovarian cancer is the second most common cause of death of the gynecological malignancies in China [1], and epithelial ovarian cancer is the leading of the ovarian cancer. In the initial, symptom-free period of the disease, approximately two-thirds of the patients have developed peritoneum and lymph node metastasis. Currently, the overall 5-year survival rate is only 35 to 38% [2]. Early detection is clearly a priority to improve the patient prognosis and in order to do this it is important to clarify the molecular mechanism of ovarian cancer development.
The human ovarian surface epithelium is a single layer of flat to columnar epithelium separated from the underlying ovarian structures by a basement membrane. The major components of the basement membrane include collagen IV, laminin, entactin, and heparin sulfate proteoglycans [3], [4]. The basement membrane is often absent from preneoplastic ovarian surface epithelia located immediately adjacent to a morphologically neoplastic lesion, suggesting that the loss of the basement membrane is an early step toward the ovarian tumorigenicity [5]. Several studies have shown that the expression of various members of the MMPs family in ovarian tumours is associated with their invasive behavior and potential to metastasis [6], [7], [8], [9].
The matrix metalloproteinases (MMPs) are proteolytic enzymes, and various members of this family are expressed in nearly all tumors. They play important roles in tumor invasion and metastasis by degrading extracellular matrix components, and there is recent evidence to show that MMPs are involved in tumor initiation and development, including regulation of cell proliferation, apoptosis, angiogenesis, and immune surveillance [10]. Although overexpressions of MMPs are found in many tumor tissues, the somatic cell mutation and gene transposal of MMPs are rarely seen.
Polymorphisms have recently been demonstrated in the promoter region of some MMPs, and there is growing evidence to indicate that naturally occurring sequence variations in the promoters of MMP genes may result in differential expression of MMPs in different individuals [11]. These promoter polymorphisms have been associated with changes in susceptibility to some diseases including acute myocardial infarction, rheumatoid arthritis, multiple sclerosis, and cancers [12], [13], [14], [15], [16].
The promoters of the MMP-1, MMP-3, MMP-7, and MMP-9 genes contain polymorphism and have allele-specific effects on the regulation of MMP gene transcription and are associated with development of some cancers [17], [18], [19], [20], [21], [22], [23], [24], [25]. Polymorphisms in the MMP-1 and MMP-3 genes have previously been analyzed in relation to susceptibility of ovarian cancer, but the findings from different studies were inconsistent [26], [27].
To address the question as to whether MMP genotypes are genetic determinants of ovarian cancer, we analyzed several promoter polymorphisms in the MMP-1 −1607bp1G/2G, MMP-3 −1171bp5A/6A, MMP-7 A-181G, and MMP-9 C-1562T genes in a sample of epithelium ovarian cancer and control women, all from North China.
Section snippets
Subjects
Study subjects were patients with ovarian cancer admitted for tumor resection in the Fourth Affiliated Hospital, Hebei Medical University between January 2001 and December 2004. The epithelial ovarian cancer was identified in the resection specimens by the Department of Pathology of the same hospital. The control group consisted of women with benign disease who visited the same hospital for physical examination over the same period. None of these women had previous oophorectomy, and all
Results
The characteristics of woman with ovarian cancer and controls women are summarized in Table 2. The mean age of patients with ovarian cancer was 51.1 ± 11.7 years (range 20–75), and that of controls was 49.3 ± 7.9 years (range 24–66). There was no statistically significant difference in age distribution between the two groups (P = 0.11).
The results of the genetic analyses are presented in Table 3, Table 4. The distributions of the MMP-1, MMP-3, MMP-7, MMP-9 genotypes were compatible with those
Discussion
To the best of our knowledge, this is the first study to look for an association between MMP-7and MMP-9 polymorphism and epithelial ovarian cancer genetic susceptibility. The relationship between the MMP-7, MMP-9 SNPs, and risk of the development of epithelial ovarian cancer has not been documented to date, and there have been only 2 reported studies on MMP-1 gene polymorphisms in relation to ovarian cancer with conflicting results [26], [27]. Two reported studies found no association between
Acknowledgment
We would like to thank Dr. Charles Hocart, Australian National University, for critical reading of the manuscript.
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