Clinical implications of matrix metalloproteinase-1, -3, -7, -9, -12, and plasminogen activator inhibitor-1 gene polymorphisms in colorectal cancer.
OBJECTIVE
Overexpression of matrix metalloproteinase (MMP)-1, -3, -7, -9, and plasminogen activator inhibitor-1 (PAI-1) are implicated in the invasion and metastasis of colorectal cancer, while MMP-12 provides a protective role against colorectal cancer. The promoter and exon polymorphisms of their genes, which are known to affect the transcription of these genes, were assessed to correlate with colorectal cancer susceptibility.


METHODS
MMP1, 3, 7, 9, 12 and PAI1 were assayed in 185 colorectal cancer patients and 304 healthy controls using polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) analysis. Respective genotypes and haplotypes were compared between the population groups and also between clinicopathological characteristics in the colorectal cancer patients.


RESULTS
The homozygous MMP1-1,607 dupG genotype was significantly more frequent in colorectal cancer patients than in healthy controls. The frequency of MMP1-1,607 dupG homozygotes was also greater in patients of less than or equal to 50 years of age, and in patients with 10 or more metastatic lymph nodes, compared with those of older age or with fewer lymph nodes. The frequency of MMP9-1,562 C homozygotes was significantly greater in colorectal cancer patients than in healthy controls. However, the genotype and allele frequencies of MMP3-1,171dupA, MMP7-181A > G, MMP12-82A > G, MMP9-90(CA)(14-27), and R279Q did not differ between the population groups or clinicopathological parameters. The MMP7-181A-MMP1-1,607dupG-MMP3-1,171A-MMP12-82A and MMP9-1,562C-90(CA)(20)+ 279Q haplotypes were significantly more frequent in colorectal cancer patients than in healthy controls. The genotype and allele frequencies of PAI1-675 G were similar between patients and healthy controls, but the frequency of PAI1-675 G homozygotes was significantly greater in patents over 50 years of age.


CONCLUSIONS
MMP1-1,607 dupG and MMP9-1,562 C homozygotes demonstrated an increased risk of colorectal cancer regardless of ethnic differences, whereas other MMP and PAI1 polymorphisms did not. Nevertheless, specific MMP haplotypes on 11q22.1-23.3 and 20q12-13 seem to be implicated in susceptibility to colorectal cancer.
Woo
Mijung
M
Department of Biology, Graduate School SungShin Women's University, Seoul, Korea.
Park
Kyungsook
K
Nam
Junghyun
J
Kim
Jin C
JC
D015179:Colorectal Neoplasms / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000235:genetics*; D053508:Matrix Metalloproteinase 12 / Q000235:genetics*; D019278:Matrix Metalloproteinase 3 / Q000235:genetics*; D020783:Matrix Metalloproteinase 7 / Q000235:genetics*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics*; D008875:Middle Aged; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics*; D011110:Polymorphism, Genetic
D017395:Plasminogen Activator Inhibitor 1; D019278:Matrix Metalloproteinase 3; D020783:Matrix Metalloproteinase 7; D020780:Matrix Metalloproteinase 9; D053508:Matrix Metalloproteinase 12; D020781:Matrix Metalloproteinase 1