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[Cancer Research 62, 7200-7202, December 15, 2002]
© 2002 American Association for Cancer Research

Advances in Brief

Potential for the 2G Single Nucleotide Polymorphism in the Promoter of Matrix Metalloproteinase to Enhance Gene Expression in Normal Stromal Cells1

Colby A. Wyatt, Charles I. Coon, Jennifer J. Gibson and Constance E. Brinckerhoff2

Departments of Biochemistry [C. A. W., C. E. B.] and Medicine [C. I. C., C. E. B.], Dartmouth Medical School, Hanover, New Hampshire 03755, and the Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire 03766 [J. J. G.]


   ABSTRACT
Top
 ABSTRACT
Introduction
 Materials and Methods
 Results and Discussion
 REFERENCES
 
The 1G/2G polymorphism of matrix metalloproteinase 1 (MMP-1) affects activity of the promoter in transient transfections, and has been associated with the incidence orinvasiveness of five types of cancer. In light of these findings, and because stromal cells may contribute to tumor cell invasion, we used quantitative real-time reverse transcription-PCR to measure endogenous MMP-1 mRNA expression in 34 human foreskin fibroblasts homozygous or heterozygous for the 1G and 2G alleles. We measured basal, cytokine, and growth factor induced MMP-1 mRNA expression. The genotype of the MMP-1 promoter polymorphism was not predictive of mean MMP-1 mRNA expression. However, within the population of cell lines with at least one 2G polymorphism, there were more individuals with higher levels of MMP-1 mRNA after treatment with a cytokine or growth factors. Our data suggest that the presence of the 2G polymorphism does not significantly affect mean expression levels of a population but may increase the potential for an individual to have higher MMP-1 expression in response to growth factors and cytokines.


   Introduction
Top
 ABSTRACT
 Introduction
Materials and Methods
 Results and Discussion
 REFERENCES
 
The ECM3 gives structural and functional support to organs and organ systems. In addition to serving as scaffolding for normal biological function, the ECM and its remodeling play major roles in diseases ranging from emphysema to cancer metastasis (1) . A family of metalloenzymes, the MMPs, is largely responsible for degradation of the ECM. MMP-1 is one of only a few MMPs capable of degrading interstitial collagen types I, II, and III, and MMP-1 is widely expressed at low levels in normal physiology. However, expression increases markedly in disease pathologies, and increased expression of MMP-1 has been associated with a poor prognosis in several cancers (2) .

In 1998, Rutter et al. (3) used transient transfections to demonstrate that a SNP in the MMP-1 promoter affected its transcriptional activity. The polymorphism is commonly found in the population and consists of the deletion or insertion (1G or 2G) of a guanine nucleotide at position -1607bp of the MMP-1 promoter. The insertion of the guanine nucleotide produces the consensus sequence for an ETS transcription factor binding site (5'-GGA-3'), and using transient transfections in A2058 melanoma cells, Rutter et al. described a >20-fold increase in transcriptional activity when the 2G polymorphism was present, as well as a 5–10-fold increase in normal fibroblasts. These findings led to the hypothesis that the presence of a 2G polymorphism could increase transcriptional activity of endogenous MMP-1. Because MMP-1 protein levels mirror MMP-1 mRNA expression (4) , this increase in transcription may increase the invasive characteristics of cancer cells containing the 2G polymorphism, perhaps through the tumor cells and/or the neighboring stromal cells.

Since that initial study, four separate investigative groups have examined the association between the MMP-1 2G polymorphism and the incidence or invasiveness of five different types of cancer. The 2G polymorphism was positively correlated with an increased risk for developing smoking-associated lung cancer, ovarian cancer, and endometrial carcinoma (5, 6, 7) . Furthermore, the 2G polymorphism was associated with increased invasiveness of melanoma (8) and colon cancer (9) . These epidemiological data establish a potential role for the 2G polymorphism in cancer and metastasis. Theoretically, the 2G polymorphism leads to greater transcriptional activity of the endogenous MMP-1 promoter. Kanamori et al. (6) examined MMP-1 mRNA expression in the tumor tissue of ovarian cancer patients using semiquantitative, radioactive RT-PCR and found higher expression of MMP-1 mRNA in tumor tissues of patients that contained at least one 2G allele in their genome. Likewise, using immunohistochemistry, Nishioka et al. (7) found that more patients with the 2G allele had high levels of MMP-1 in their tumor than patients with the 1G allele. These studies begin to deal with the influence of the polymorphism on endogenous MMP-1 expression; however, in the context of metastasis, increased transcriptional activity of the MMP-1 promoter may occur in a variety of cell types including normal stromal cells, tumor-associated fibroblasts, and neoplastic cells.

It is increasingly recognized that stromal cells play a prominent role in facilitating tumor invasion (2 , 10, 11, 12) . Stromal cells respond to growth factors and cytokines in the tumor milieu, such as EGF, bFGF, and IL-1ß, by increasing the production of several MMPs, including MMP-1 (2 , 4) . In light of the documented associations of the 2G SNP and tumor incidence and invasiveness and because of the important contributions of stromal cells to tumor invasion/metastasis, the present study was designed to determine whether the presence of the 2G polymorphism influences MMP-1 mRNA expression in normal fibroblasts. We used quantitative real-time RT-PCR to measure basal and induced MMP-1 mRNA levels in 34 HFF primary isolates homozygous or heterozygous for the 1G and 2G alleles. We found that the genotype of the MMP-1 promoter polymorphism was not predictive of mean MMP-1 mRNA levels. However, within the population of cells with a 2G allele, there were more individuals with higher levels of MMP-1 mRNA after cytokine or growth factor treatment. Our data suggest that the presence of the 2G polymorphism does not significantly affect mean MMP-1 mRNA expression of a population but may increase the potential for an individual to have higher MMP-1 expression in response to growth factors and cytokines.


   Materials and Methods
Top
 ABSTRACT
 Introduction
 Materials and Methods
Results and Discussion
 REFERENCES
 
Culture of HFFs and Harvesting of RNA.
HFFs were isolated and cultured in 50-mm culture dishes in DMEM/20% FCS with penicillin/streptomycin, glutamine, and fungisone as described previously (3) . At confluence, cell lines were passed to a 100-mm culture dish, then to five 100-mm culture dishes. When the cell lines reached ~90% confluence, the growth media were removed, and the cells were washed twice with HBSS. The cells were then incubated for 20 h in 5 ml of serum-free media containing 0.2% LH (DMEM), serum-free media plus 10 ng/ml EGF (R&D systems), serum-free media plus 10 ng/ml FGF (Calbiochem), or serum-free media plus 5 ng/ml IL-1 (Promega). RNA was harvested with TRIzol (Promega), and DNA contamination was removed from the RNA samples with DNA-free (Ambion).

Real-Time RT-PCR.
RT and real-time PCR were performed using protocols and reagents from Applied Biosystems Taqman RT reagent kit and Sybr Green PCR master mix. Briefly, 2 µg of DNase treated RNA from a single 100-mm plate were reverse transcribed in a 20-µl reaction containing 5.5 mM MgCl2, 500 µM each dNTP, 2.5 µM oligo d(T)16, 0.4 units/µl RNase inhibitor, and 1.25 units/µl Multiscribe reverse transcriptase. The reactions were incubated at 25°C for 5 min, 48° for 30 min, and then 95°C for 5 min.

Five µl of each RT reaction were used to amplify MMP-1 mRNA in triplicate real-time PCR reactions and 2 µl of each RT reaction were used to amplify GAPDH mRNA in duplicate reactions. To enable quantitative comparisons between PCR assays, standard curves were generated with every assay. Serial log dilutions ranging from 1 ng to 100 fg of American Type Culture Collection plasmids pSP6-MMP-1 and pCMV sport6 were used as standards for MMP-1 and GAPDH, respectively. Sequences for the MMP-1 primers were 5'-AGCTAGCTCAGGATGACATTGATG-3' (sense) and 5'-GCCGATGGGCTGGACAG-3' (antisense); and GAPDH primers were 5'-CGACAGTCAGCCGCATCTT-3' (sense) and 5'-CCCCATGGTGTCTGAGCG-3' (antisense). The PCRs contained 200 nM each primer and were incubated on a Molecular Dynamics Opticon thermal cycler at 95°C for 10 min, followed by 50 PCR cycles of 95°C for 15 s, and 60°C for 1 min, and a plate read. The PCR cycles were followed by a Sybr green melting curve from 55°C to 90°C. MMP-1 mRNA expression was normalized to GAPDH mRNA expression and is reported as mean copies of MMP-1 message per 500 ng of total RNA ± the SD.

Genotyping HFFs.
DNA was harvested from the 100-mm plates of HFFs using Gentra Systems DNA extraction kit. A segment of the MMP-1 promoter containing the 1G/2G polymorphism was amplified by the PCR using 5'-AACCTATTAACTCACCCTTGT-3' as the forward primer and 5'-CCTCCATTCAAAAGATCTTATTTAGCATCTCCT-3' as the reverse primer. Each PCR reaction contained 0.2 mM each dNTP, 1.5 mM MgCl2, 200 nM each primer, 1 unit platinum TaqDNA polymerase (Invitrogen), and 1x PCR buffer (Invitrogen). The reactions were subjected to a hot start of 94°C for 2 min followed by 35 cycles of 94°C for 30s, 55°C for 30 s, and 72°C for 1 min. The PCR product was purified using a Qiagen PCR purification kit, and then the product was sequenced using a nested primer (5'-AGTGTTCTTTGGTCTCTGC-3') and the Applied Biosystems dig dye terminator sequencing kit.

Statistical Methods.
Random coefficient regression was used to model the relationship between MMP-1 expression and the cell genotype and treatment applied. Log transformation was applied to the MMP-1 expression values for variance stabilization. 95% CIs are given for all model-based estimates. The formula used for calculating the upper fence was the upper quartile + 1.5 * (upper quartile - lower quartile). The formula for calculating the lower fence was the lower quartile - 1.5 * (upper quartile - lower quartile).


   Results and Discussion
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results and Discussion
REFERENCES
 
The HFFs were primary isolates from normal tissue; therefore, it was assumed that they were diploid cell lines. Distribution of genotypes in the 34 HFF cell lines isolated agrees with our previous findings (3) . Approximately 25% of the cells were homozygous for the 1G polymorphism, ~25% were homozygous for the 2G allele, and ~50% were heterozygous (Table 1)Citation . Also in keeping with our previous report (3) , expression of MMP-1 mRNA in unstimulated HFF cell lines was low. Analysis of MMP-1 expression in HFFs by real time RT-PCR revealed the average basal expression for 1G homozygotes to be ~144 ± 290 (mean ± SD) copies of MMP-1 message/500 ng RNA, 2G homozygotes averaged 377 ± 726 copies of MMP-1 message/500 ng RNA, and homozygotes produced an average of nearly 157 ± 233 copies of MMP-1 message/500 ng RNA (Table 1)Citation . Although these findings are suggestive of a biological trend in which the average basal expression is higher in cells homozygous for the 2G allele, variations in the level of expression among the samples precluded statistical significance (P > 0.05).


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  		Table 1 Mean, SD, median, and upper quartiles of HFF MMP-1 expression levels in copies of MMP-1 mRNA/500 ng total RNA

 
HFFs treated with EGF, IL-1, or FGF had statistically significant increases in mean MMP-1 expression, confirming earlier published results (Table 2Citation ; Refs. 2 , 13 ). A comparison of MMP-1 expression among genotypes revealed that mean MMP-1 expression in EGF-stimulated 2G homozygous cells was greater than the corresponding expression in 1G homozygous cells (3,309 ± 5,700 copies of MMP-1 mRNA/500 ng total RNA and 1,228 ± 2,393 copies of MMP-1 mRNA/500 ng total RNA, respectively; Table 1Citation ). Likewise, mean MMP-1 expression in IL-1-stimulated HFFs was greater for the 2G homozygous population than for the 1G homozygous population (7,786 ± 12,199 copies of MMP-1 mRNA/500 ng total RNA and 2,883 ± 7,281 copies of MMP-1 mRNA/500 ng total RNA, respectively). However, after bFGF treatment, homozygous 2G cells had lower average MMP-1 expression (8,848 ± 13,826 copies of MMP-1 mRNA/500 ng total RNA) than did 1G homozygous cells (11,827 ± 31,257 copies of MMP-1 mRNA/500 ng total RNA). Similar to basal MMP-1 expression, stimulated MMP-1 expression varied widely among cell lines, and none of these differences in expression were statistically significant with respect to the 1G versus 2G allele (P > 0.05). Similar variability in MMP-1 production that was related to the 1G/2G polymorphism was recently described in amnion cells from patients with preterm premature rupture of fetal membranes (14) . This variability in SNP expression is commonly seen and has been attributed to environmental and physiological factors that complicate the analysis of genetic differences from individual to individual (15) .


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  		Table 2 Fold increase of MMP-1 expression after treatments

Fold increase and Ps are calculated from the log transformed model-based estimates of mean expression.

 
Although the presence of a 2G MMP-1 promoter does not significantly affect mean MMP-1 expression levels, it does influence the dispersion of MMP-1 expression levels within a population of cell lines (Table 1Citation ; Fig. 1Citation ). The upper quartiles of MMP-1 expression in HFFs clearly demonstrate this. Heterozygous EGF-, bFGF-, and IL-1-treated HFFs had upper quartiles that were 2.5, 4, and 3 times greater than their respective quartiles in 1G homozygous HFF cells. The presence of an additional 2G allele (the 2G homozygotes) increases the extremes of MMP-1 expression further. In the EGF-, bFGF-, and IL-1 treated 2G homozygous cell populations, the upper quartiles were 6.5, 9.3, and 11 times greater than their respective quartiles in 1G homozygous cells. The presence of more individual cell lines with higher MMP-1 mRNA expression in the populations containing a 2G allele suggests that, although the MMP-1 promoter genotype is not predictive of the mean MMP-1 expression level of a population, there may be a greater potential for a given individual with a 2G polymorphism to have higher MMP-1 expression.



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  		Fig. 1. Box plots of the distribution of MMP-1 expression levels in 1G homozygous (G), 2G homozygous (GG), or heterozygous (H) cell populations incubated in serum free DMEM containing 0.2% LH, 10 ng/ml EGF, 10 ng/ml FGF, or 5 ng/ml IL-1. Each box represents the interquartile range (25th-75th percentile) of the population. The line within each box, the median value. +, the mean of each population. Data points lying beyond the upper fences (vertical lines above the boxes) are considered outliers (*). (See "Methods" for an explanation of this calculation.) The number beneath each plot, the number of outliers beyond the scale of the plots.

 
A positive correlation has been established between the presence of the 2G polymorphism and the incidence or invasiveness of five different cancers (5, 6, 7, 8, 9) . Additionally, two of these studies demonstrated higher MMP-1 expression in tumor tissues containing the 2G polymorphism compared with tumor tissues that contained only the 1G polymorphism (6 , 7) . The differences between findings in studies on cancer and our findings may be explained by the differences in the cell types being examined. The HFF lines described here represent an unselected population of normal cells derived from individuals and tissues not involved with disease. In contrast, Kanamori et al. and Nishioka et al. measured the association of MMP-1 expression and the 2G allele in tumor tissues from a population selected for the presence of disease (6 , 7) . It is possible the perturbation of transcription in neoplastic cells, such as those examined by Kanamori et al. and Nishioka et al., potentiates the observed influence of the 2G polymorphism on high levels of MMP-1 expression. This argument implies that the MMP-1 polymorphism affects only neoplastic cell MMP-1 expression. However, there is some evidence suggesting that stromal cells associated with neoplastic cells are different from stromal cells in other regions of the body (12) , and therefore, our findings in foreskin fibroblasts might not be predictive of the findings of a similar study in tumor-associated fibroblasts (16) . Additionally, a potential role for the MMP-1 polymorphism in a nonneoplastic disease was recently established by Fujimoto et al. (14) when they found that there is a modest but significant increased risk for the development of preterm premature rupture of fetal membranes in African-American women with a 2G polymorphism in their MMP-1 promoter. Future, quantitative examinations of the influence of the 2G MMP-1 promoter genotype and MMP-1 expression in neoplastic cells and tumor-associated fibroblasts may further clarify how the 2G polymorphism is involved in the development and invasiveness of cancer.


   ACKNOWLEDGMENTS
 
We thank the staff at the Dartmouth Hitchcock Memorial Hospital Birthing Pavilion for helping us obtain the foreskins.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Supported by Grants AR-26599, CA-27667, Department of Defense DAMD17-00-1-0221, and from the Scleroderma Research Foundation (to C. E. B.); a predoctoral fellowship, Department of Defense DAMD17-00-1-0223 (to C. A. W.); and a Cancer Center Support Grant P30 CA23108-24 to the Norris Cotton Cancer Center. Back

2 To whom requests for reprints should be addressed, at Dartmouth Medical School, Hanover, NH 03755-3833. Phone: (603) 650-1609; Fax: (603) 650-1128; E-mail: brinckerhoff{at}dartmouth.edu Back

3 The abbreviations used are: ECM, extracellular matrix; MMP, matrix metalloproteinase; RT, reverse transcription; EGF, epidermal growth factor; FGF, fibroblast growth factor; bFGF, basic FGF; IL, interleukin; SNP, single nucleotide polymorphism; HFF, human foreskin fibroblast; LH, lactalbumin hydrolysate; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; CI, confidence interval. Back

Received 9/ 3/02. Accepted 10/30/02.


   REFERENCES
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results and Discussion
 REFERENCES
 

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