The role of genetic polymorphisms in the promoters of the matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-2 genes in head and neck cancer
Introduction
HNSCC is among the top ten most common cancers worldwide.1 In the Western world HNSCCs represent 5% of newly diagnosed cancers, but the incidence accounts for up to 40% of all malignancies in Thailand and South East Asia. Although tobacco smoke, alcohol use and nutritional deficiency play a major role in the etiology of these malignancies, only a fraction of exposed individuals develop the disease, suggesting a genetic susceptibility in the general population. It has been shown that first degree relatives of head and neck cancer patients have a 2-fold elevated risk over the general population,2 most of which cannot be explained by germ line mutation. Although some of the familial risk may be due to shared environmental factors, there may be other common, low penetrance genetic variants affecting susceptibility to head and neck cancer. In addition, the inherited genetic factors in some HNSCC patients may be responsible for a more aggressive disease. The ability to identify such high-risk individuals will have major influence in the cancer prevention and treatment programs in the future.
The MMPs, a family of >20 extracellular endopeptidases with enzymatic activity against almost all protein components of the ECM, have been implicated in the invasion and metastasis of HNSCC.3 Most MMPs are synthesized not only by the genetically altered cancer cells but also by adjacent and intervening stromal cells. Recent work has suggested that, in addition to promoting invasion and metastasis, MMPs also play an important role in almost every step of cancer development.4 Among the MMPs, MMP-2 (gelatinase A) is a member of the MMP family that primarily hydrolyzes type IV collagen, the major structural component of basement membrane. Numerous studies have shown that MMP-2 is overexpressed and plays critical roles in invasion and metastasis of HNSCC.3, 5, 6, 7 Although somatic mutation of MMP2 in cancer has not been reported so far, several single nucleotide polymorphisms (SNPs) in the MMP2 promoter region have been identified.8 Among them, a C → T transition located at nucleotide −1306 abolishes the Sp1-binding site (CCACC) and consequently diminishes promoter activity. Transient transfection experiments showed that reporter gene expression driven by the C allelic MMP2 promoter was significantly greater than reporter gene expression driven by the T allelic counterpart in both epithelial cells and in macrophages, indicating the functional significance of this polymorphism.8 It is likely that CC genotype may be associated with the high transcriptional and enzyme activity of MMP-2, and eventually affect individual susceptibility to neoplasms.
The expression of MMP activity can be controlled at the level of gene transcription, pro-enzyme activation and by both broad spectrum and specific inhibitors, including a family of anti-proteinases known as tissue inhibitors of metalloproteinases (TIMPs). Of the four members in the TIMP family, TIMP-2 is particularly interesting because it is an important inhibitor of MMP-2 and other active MMPs.9 The local balance of MMP-2/TIMP-2 appears to be a crucial factor in tumour invasion and metastasis. Recently, a functional polymorphism (−418G → C) has been identified in the promoter region of TIMP2.10 This G → C substitution which is located within the consensus sequence for the Sp1-binding site (GAGGCTGGG) in the promoter region may down-regulate the transcriptional activity and lead to an imbalance between the activities of TIMP-2 and MMP-2.
Although recent molecular epidemiological studies have suggested that genetically determined matrix-degrading capacity may contribute to the risk and progression of some tumor types,11, 12, 13, 14, 15, 16 so far the role of MMP2 and TIMP2 polymorphisms in HNSCC remained inconclusive. The objective of this study was to examine the possible contribution of MMP2 and TIMP2 promoter polymorphisms to the risk and aggressiveness of HNSCC in an ethnic Thai population. We compared the frequency of each allele in DNAs from HNSCC patients with normal control samples. We also examined whether the genotypes affected expression of the MMP2 and TIMP2 in both cell lines and tissues. Finally, we determined whether the MMP2 and TIMP2 genotypes correlated with various clinicopathological parameters.
Section snippets
Patient materials
Two hundred and thirty-nine newly diagnosed, previously untreated patients with HNSCC at the Department of Head and Neck Surgery, Siriraj Hospital, Thailand were recruited between September 2002–August 2004. Those with second primary HNSCC, primaries of the nasopharynx or sinonasal tract or primaries outside the upper aerodigestive tract, cervical metastasis of unknown origin and histopathological diagnoses other than squamous cell carcinoma were excluded. Two hundred and fifty control subjects
MMP2 and TIMP2 genotypes in cases and controls
Table 1 displays the selected characteristics of 239 HNSCC cases and 250 controls from Thai population screened for MMP2 and TIMP2 genotypes. By study design, there were no statistically significant differences between the cases and controls by age, gender, smoking or drinking status.
The allele frequencies and genotype distributions of MMP2 and TIMP2 in patients and controls are shown in Table 2, Table 3 respectively. The allele frequencies for the MMP2 −1306C and −1306T were 93.1% and 6.9% in
Discussion
In the present study, we examined the relationship between the functional polymorphisms in the promoters of MMP2 and TIMP2 and levels of gene expression, cancer susceptibility, and cancer progression using both in vitro and clinical models of HNSCC. On the basis of analysis with 239 cases with HNSCC and 250 controls, we found that subjects carrying the MMP2 CC genotype had an increased risk for developing HNSCC and more aggressive disease. In addition, it appeared that the polymorphisms of MMP2
Acknowledgements
We are grateful to Vachiraya Puangwattana and Narawan Pungram for their excellent technical assistance, Kampanart Nimpoonsri for data collection and Prida Malasit for providing laboratory support. This work is supported in part by grants from the Siriraj Grant for Research and Development (to Pornchai O-charoenrat) and the Thailand Research Fund Senior Scholar (to Prida Malasit).
References (26)
- et al.
Identification of novel, functional genetic variants in the human matrix metalloproteinase-2 gene: role of Sp1 in allele-specific transcriptional regulation
J Biol Chem
(2001) - et al.
Preferential inhibition of 72- and 92-kDa gelatinase by tissue inhibitor of metalloproteinases-2
J Biol Chem
(1991) - et al.
A single nucleotide polymorphism in the matrix metalloproteinase-2 promoter is associated with colorectal cancer
Biochem Biophys Res Commun
(2004) - et al.
Tumour thickness predicts cervical nodal metastases and survival in early oral tongue cancer
Oral Oncol
(2003) - et al.
The transcription factors Sp1, Sp3, and AP-2 are required for constitutive matrix metalloproteinase-2 gene expression in astroglioma cells
J Biol Chem
(1999) - et al.
Global Cancer Statistics, 2002
CA Cancer J Clin
(2005) - et al.
Family history of cancer is a risk factor for squamous cell carcinoma of the head and neck in Brazil: a case-control study
Int J Cancer
(1995) - et al.
Expression of matrix metalloproteinases and their inhibitors correlates with invasion and metastasis in squamous cell carcinoma of the head and neck
Arch Otolaryngol Head Neck Surg
(2001) - et al.
New functions for the matrix metalloproteinases in cancer progression
Nat Rev Cancer
(2002) - et al.
Possible contribution of active MMP2 to lymph-node metastasis and secreted cathepsin L to bone invasion of newly established human oral-squamous-cancer cell lines
Int J Cancer
(1997)
Expression of matrix metalloproteinases (MMP-1 and -2) and their inhibitors (TIMP-1, -2 and -3) in oral lichen planus, dysplasia, squamous cell carcinoma and lymph node metastasis
Br J Cancer
Expression of MMPS, MT-MMP, and TIMPs in squamous cell carcinoma of the oral cavity: correlations with tumor invasion and metastasis
Head Neck
Tissue inhibitor of metalloproteinases-2 gene polymorphisms in chronic obstructive pulmonary disease
Eur Respir J
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