Clinical significance of a single nucleotide polymorphism and allelic imbalance of matrix metalloproteinase-1 promoter region in prostate cancer

Abstract

Abstract. Matrix metalloproteinase-1 (MMP-1) is associated with cancer invasion and metastasis. The 2G allele of the polymorphic site in the MMP-1 promoter was demonstrated to have a higher transcription activity than the 1G allele. Allelic imbalance (AI) at 11q22 harboring the MMP-1 is frequently observed in various cancers and may be associated with an advanced disease. We conducted a case-control study to determine the association of the MMP-1 genotype with susceptibility to prostate cancer involving 283 prostate cancer patients and 251 controls. Furthermore, AI, retention allele of the MMP-1 promoter, and MMP-1 protein expression were analyzed in 77 prostate cancer specimens. The MMP-1 promoter polymorphism was associated with neither susceptibility nor progression of prostate cancer. Tumors with 1G/2G and 2G/2G genotypes had a significantly higher MMP-1 expression level compared to those with 1G/1G genotype (P=0.006 and 0.013, respectively). AI at 11q22 was observed in 13 (40.6%) of 32 informative cases. Retention of the 1G and 2G alleles were observed in 4 and 9 cases, respectively. AI was significantly associated with the Gleason score (P=0.003) and pathological stage (P=0.022). In addition, retention of the 2G allele showed a significant association with the pathological stage (P=0.026). AI at 11q22 region, retention of the 2G allele, specifically appeared to be involved in the progression of prostate cancer. However, the presence of the 2G allele of the MMP-1 promoter polymorphism itself seems to influence neither the susceptibility nor the progression of prostate cancer. IntroductionTumor invasion or metastasis is one of the most crucial events for determining the outcome of cancer patients. In the first step of these events, several proteinases such as serine proteinase urokinase plasminogen activator and matrix metalloproteinases (MMPs) degrade the extra-cellular matrix (ECM), so that the tumor cells can migrate to the stromal tissue through the basement membrane (1). MMP-1, a member of MMP family, is abundantly expressed in many types of cancer cells and adjacent stromal fibroblasts (2-5), and digests various elements of the ECM including collagen types I, II, II, VII, VIII, X, and XI (6). The overexpression of MMP-1 has been shown to be associated with tumor progression and poor outcomes for cancers of the digestive system and melanoma (3,5,7,8).The expression of MMP-1 is mainly regulated by activated protein-1 (AP-1) transcription factor that mediates signal transduction from cytokines and growth factors such as interferons, interleukins, epidermal growth factor, and fibroblast growth factor (9). In the promoter region of the MMP-1, three AP-1 binding sites are located at -72, -186, and -1062 bp from the transcription start site. Insertion of an extra guanine residue adjacent to the AP-1 binding site at -1062 bp creates a new binding site for ETS transcription factor at -1602 bp (5'-AAGGAT-3'; 2G), and both the AP-1 and ETS cooperatively enhance the expression of MMP-1 (10). AP-1 binding to the -1...

MMP1, 2, 3, 7, and 9 Gene Polymorphisms and Urinary Cancer Risk: A Meta-Analysis

“…We also found only one Chinese article in the WanFang database. As a result, 12 case-control articles were included in our meta-analysis: (Hirata et al, 2004;Zhong et al, 2005;Kader et al, 2006;Albayrak et al, 2007;Piccoli et al, 2007;Tasci et al, 2008;Tsuchiya et al, 2009;Srivastava et al, 2010aSrivastava et al, , 2010bWieczorek et al, 2013Wieczorek et al, , 2014Srivastava et al, 2013a) (Fig. 1).…”

“…studies, several polymorphisms in the promoters of a number of MMP genes have been well characterized. These polymorphisms may affect the production or gene expression of these MMPs in an allele-specific manner (Piccoli et al, 2007;Tsuchiya et al, 2009;Wieczorek et al, 2013;Yaykas xli et al, 2014). Furthermore, there is an increasing evidence indicating that these functional polymorphisms may contribute to interindividual differences in a wide spectrum of cancer susceptibility (Decock et al, 2008;Pereira et al, 2012;Wieczorek et al, 2012).…”

“…A quantitative synthesis to accumulate data from different studies is needed to provide better evidence on these associations. Here, in this report, we performed a meta-analysis of 12 publications to estimate the effect of eight polymorphisms: MMP1 -1607 1G/2G (Hirata et al, 2004;Kader et al, 2006;Albayrak et al, 2007;Piccoli et al, 2007;Tasci et al, 2008;Tsuchiya et al, 2009;Srivastava et al, 2010a;Wieczorek et al, 2013), MMP2 -1306 C/T (Zhong et al, 2005;Kader et al, 2006;Srivastava et al, 2013a;Wieczorek et al, 2013), MMP3 (45E/K) G/A (Kader et al, 2006;Srivastava et al, 2010b), MMP7 -181 A/G (Srivastava et al, 2010a;Wieczorek et al, 2014), MMP9 -1562 C/T (Zhong et al, 2005;Kader et al, 2006;Wieczorek et al, 2013), MMP9 (279R/Q) A/G (Kader et al, 2006;Tasci et al, 2008;Srivastava et al, 2010b), and MMP9 (574R/P) T/C (Kader et al, 2006;Srivastava et al, 2010b), MMP9 (668Q/R) A/G (Kader et al, 2006;Srivastava et al, 2010b) on urinary cancer risk.…”

Prostate cancer relevant antigens and enzymes for targeted drug delivery

“…151, 154-156 It is highly expressed on the surface of cancer cells and induces synthesis of various matrix metalloproteinases ( MMP-1, MMP-2, MMP-3 ) 157 by inducing neighboring fibroblasts and tumor cells. 158, 159 …”

Epigenetic regulation of matrix metalloproteinases and their collagen substrates in cancer

“…Nine MMPs (MMP-1, -3, -7, -8, -10, -12, -13, -20, and -27) are clustered in the 11q22.3 region of chromosome 11 (Figure 2A). Chromosomal abnormalities and multiple polymorphisms in the 11q22.3 region predispose to prostate and lung cancer (57, 58) and coronary artery aneurysm formation in patients with Kawasaki’s disease (59). The approximately 0.43 Mb 11q22.3 region is largely deficient of CpGIs.…”