Department of Urology and Renal Transplantation, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareli Road, Lucknow-226014, Uttar Pradesh, India.
Gene. 2013 Nov 10;530(2):273-7. doi: 10.1016/j.gene.2013.06.087. Epub 2013 Jul 17.
Matrix metalloproteinases (MMPs) have been implicated in progression and metastases of different tumors. The balance between the MMPs and their natural inhibitors (tissue inhibitors of matrix metalloproteinases; TIMP) seem to be an important factor related to its role. The purpose of this study was to evaluate polymorphisms in the MMP-3 and TIMP-3 genes for their associations with prostate cancer (PCa) risk in North Indians.
Genotypes were determined by PCR-RFLP (Polymerase Chain Reaction Restriction Fragment Length Polymorphism) method in 150 PCa patients and 200 age matched controls of similar ethnicity.
We found significant association in the MMP-3(1171)5A/6A and TIMP-3 (1298) C/T polymorphism with PCa risk. Variant genotype (5A/5A) of MMP-3(1171)5A/6A polymorphism had a high PCa risk (p=0.037, OR=3.52, 95%CI=1.08-11.5). Individuals with TIMP-3 (1298) CT genotype as well as T allele showed reduced risk of PCa (p<0.001; OR=0.31; 95%CI=0.18-0.52, and p=0.001; OR=0.49; 95%CI=0.32-0.75). This effect was even more evident in case of T allele carrier (CT+TT) (p<0.001; OR=0.36; 95%CI=0.22-0.59). Overall no significant association was observed statistically in MMP-3 and TIMP-3 with any of the grading stages and smoking habits in PCa. Haplotype analysis of MMP-3 showed that A-5A-A was associated with three folds (OR=3.06; 95%CI=1.71-5.47; p<0.001) increased risk in PCa patients.
This is the first reported association between polymorphisms in the MMP-3 and TIMP-3 gene and PCa risk and supports the hypothesis that the protease/antiprotease balance has an important role. Due to the small sample size further investigations need to be done to prove a statistical significant correlation between the MMP/TIMP expression and clinicopathological parameters.
基质金属蛋白酶（MMPs）已被牵涉到不同肿瘤的进展和转移中。MMPs 与其天然抑制剂（基质金属蛋白酶组织抑制剂；TIMP）之间的平衡似乎是与其作用相关的一个重要因素。本研究的目的是评估 MMP-3 和 TIMP-3 基因的多态性与北印度人群中前列腺癌（PCa）风险的关系。
通过聚合酶链反应限制性片段长度多态性（PCR-RFLP）方法在 150 例 PCa 患者和 200 名年龄匹配的同种族对照中确定基因型。
我们发现 MMP-3(1171)5A/6A 和 TIMP-3(1298)C/T 多态性与 PCa 风险显著相关。MMP-3(1171)5A/6A 多态性的变异基因型（5A/5A）具有较高的 PCa 风险（p=0.037，OR=3.52，95%CI=1.08-11.5）。TIMP-3(1298)CT 基因型以及 T 等位基因的个体表现出降低的 PCa 风险（p<0.001；OR=0.31；95%CI=0.18-0.52，p=0.001；OR=0.49；95%CI=0.32-0.75）。在 T 等位基因携带者（CT+TT）中，这种效果更为明显（p<0.001；OR=0.36；95%CI=0.22-0.59）。总体而言，在 PCa 中，MMP-3 和 TIMP-3 与任何分级阶段和吸烟习惯均无统计学显著相关性。MMP-3 的单体型分析表明，A-5A-A 与三倍（OR=3.06；95%CI=1.71-5.47；p<0.001）的 PCa 患者风险增加相关。
这是首次报道 MMP-3 和 TIMP-3 基因多态性与 PCa 风险之间的关联，并支持蛋白酶/抗蛋白酶平衡具有重要作用的假说。由于样本量较小，需要进一步研究以证明 MMP/TIMP 表达与临床病理参数之间存在统计学显著相关性。
