Haplotype Effects on Matrix Metalloproteinase-1 Gene Promoter Activity in Cancer Cells

• Published in: Molecular cancer research Vol. 5; no. 3; pp. 221 - 227
• Main Authors: Pearce, Eve G, Laxton, Ross C, Pereira, Andresa C, Ye, Shu
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research 01-03-2007
• Subjects: Alleles; Base Sequence; Female; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Gene Frequency; gene polymorphism; haplotype; Humans; Male; Matrix Metalloproteinase 1 - genetics; matrix metalloproteinase-1; Molecular Sequence Data; Neoplasms - enzymology; Neoplasms - genetics; Polymorphism, Genetic; Promoter Regions, Genetic
• ISSN: 1541-7786; 1557-3125
• DOI: 10.1158/1541-7786.MCR-06-0139

Increased expression of matrix metalloproteinase-1 (MMP1) is associated with poor prognosis in cancers. Several single nucleotide
polymorphisms (−1607GG>G, −839G>A, −755G>T, −519A>G, −422T>A, −340C>T, and 320C>T) in the MMP1 gene promoter have recently
been identified. In this study, we assessed the functional effects of these polymorphisms on MMP1 gene promoter activity in
cell lines of melanoma (A2058 and A375), breast cancer (MCF7 and MDA-MB-231), lung cancer (A549 and H69), and colorectal cancer
(HT-29, SW-620) by comparing the promoter strengths of 10 most common haplotypes deriving from these polymorphisms. In A2058
cells, the GG-G-G-A-T-T-T and GG-G-G-A-C-T haplotypes had 2-fold higher promoter activity than the GG-G-T-A-T-T-C, GG-G-G-A-A-T-T,
GG-G-G-A-T-T-C, and GG-G-G-A-A-C-T haplotypes, which in turn, had 3-fold higher promoter activity than the G-G-T-A-A-C-T,
G-A-T-G-T-T-T, G-A-T-G-A-C-T, and G-A-T-G-A-T-G haplotypes. In A375 and MDA-MB-231 cells, high expression haplotypes include
not only the −1607GG-bearing haplotypes but also the G-A-T-G-A-T-T haplotype containing the −1607G allele. A similar trend
was detected in A549 cells. In addition, in A549 cells, the GG-G-G-A-T-T-T haplotype had >2-fold higher promoter activity
than several other −1607GG-bearing haplotypes. In MCF7 cells, the GG-G-G-A-T-T-T and G-G-T-A-A-C-T haplotypes had 1.5- to
4-fold higher promoter activity than the other haplotypes. These results suggest that the polymorphisms exert haplotype effects
on the transcriptional regulation of the MMP1 gene in cancer cells, and indicate a need to examine haplotypes rather than
any single polymorphism in genetic epidemiologic studies of the MMP1 gene in cancers. (Mol Cancer Res 2007;5(3):221–7)