Elsevier

Oral Oncology

Volume 45, Issue 12, December 2009, Pages e222-e226
Oral Oncology

The association between hypoxia inducible factor-1α gene polymorphisms and increased susceptibility to oral cancer

https://doi.org/10.1016/j.oraloncology.2009.07.015Get rights and content

Summary

The aim of this study was to estimate the relations between hypoxia inducible factor-1α (HIF-1α) gene polymorphisms, C1772T and G1790A, to the susceptibility and clinicopathological status of oral cancer. A total of 521 subjects, including 347 controls and 174 oral cancer patients, were recruited in this study and subjected to polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) to analyze the impact of these two polymorphic variants on oral cancer. A significant association between oral cancer susceptibility and G1790A polymorphism was demonstrated since individuals with heterozygotes, that is GA, had a higher risk for oral cancer, compared to GG genotypes after adjusting for other confounders (AOR = 3.31; 95%CI = 1.27–8.61). Compared to individuals with both C1772C and G1790G homozygotes, individuals with at least one of either C1772T or G1790A of HIF-1α gene had a risk of 2.17-folds (95% CI = 1.0–4.75) to develop oral cancer. Moreover, results also revealed the presence of synergistic effect between gene polymorphisms of HIF-1α and environmental risk factors, such as tobacco and betel nut consumptions while there was no significant association between HIF-1α gene polymorphism and clinicopathological parameters of oral cancer. Genetic polymorphism, including C1772T and G1790A, of HIF-1α is an important factor for the susceptibility to oral cancer.

Introduction

The capability of tumor cells to sense hypoxia for enhancing cells proliferation, invasion, and metastasis is one of the critical components for cancer development.1, 2, 3, 4, 5 Stimulation of angiogenesis 1, 2, 6 and cell proliferation 7 are highly dependent on the function of hypoxia inducible factor-1-alpha (HIF-1α). HIF-1α associates with the nuclear HIF-1β subunit, this dimeric complex acts as a transcription factor to bind the promoters of hypoxia-inducible genes such as vascular endothelial growth factor (VEGF), erythropoietin (Epo), and nitric oxide synthase 2 (NOS2) genes, which code for proteins involved in embryogenesis, angiogenesis, cell proliferation, cell invasion, and metastasis, during the cellular response to hypoxia.8, 9, 10, 11, 12, 13, 14, 15

Oral cancer is the most common malignant disease with poor prognosis and is the sixth leading cause of cancer death in Taiwan.16 More than 85–90% of oral cancer cases are oral squamous cell carcinoma (OSCC).17 Significant over expression of HIF-1α was found in OSCC,18, 19, 20 and highly correlated with angiogenesis as well as tumor progress of OSCC by modulating cancer cells to be more invasive and aggressive phenotype.20 Moreover, increased expression of HIF-1α is associated with the expression of matrix metalloproteinase (MMP) and CXCR4, both associated with metastasis, in OSCC under hypoxic conditions.3, 4, 21 It suggested that HIF-1α may play a crucial role in regulation of cancer cells proliferation and metastasis of oral cancer.

Previous studies suggested that except for environmental carcinogens, such as alcohol,22, 23 tobacco consumption,22, 23, 24 and betel nut,22, 25, 26 genetic effects 2, 22, 27, 28, 29, 30 also contributed to the development of oral cancer. HIF-1α gene is located on chromosome 14q21-24.31 The polymorphisms of C1772T coding for P582S and G1790A coding for A588T were demonstrated in the N-transactivating domain of HIF-1α gene.32 Moreover, some in vitro studies have demonstrated that those genetic variations resulted in significantly enhanced transcription activities under both normoxic and hypoxic condition,1, 33 and the infiltrations of blood vessels as well as the relative levels of HIF-1α were significantly increased in tumors from head and neck squamous cell carcinoma patients with heterozygous alleles.1, 19 We hypothesized that the gene variants C1772T and G1790A of HIF-1α could contribute to the susceptibility and clinicopathological development of oral cancer. Since the effect of these two gene polymorphisms C1772T and G1790A of HIF-1α in oral cancer has not been clarified, the purpose of this study was to estimate the influence of genetic polymorphisms of HIF-1α on the susceptibility and clinicopathological characteristics of oral cancer.

Section snippets

Subjects and specimen collection

Among a total of 521 subjects recruited in this study, 174 patients who were diagnosed with oral cancer, according to the characteristic criteria of national guidelines for oral cancer 16 between April, 2007 and April, 2009 were recruited from Chung Shan Medical University Hospital (Taichung) and Show Chwan Memorial Hospital (Changhua, Taiwan). Meanwhile, 347 race- and ethnic group-matched individuals were randomly selected from the same geographic area to act as the controls.

This study has

Results

The demographical data are shown in Table 1. There were significantly difference distribution of age, gender, betel nut chewing, and tobacco consumption between oral cancer patients and controls.

In our recruited control group, the frequencies of C1772T (p > 0.05, χ2 value: 0.125) and G1790A (p > 0.05, χ2 value: 0.145) of HIF-1α gene were in Hardy–Weinberg equilibrium, respectively. The genotype distributions as well as the association between oral cancer and gene polymorphisms of C1772T and G1790A

Discussion

In this study, we provided novel information of the effects of C1772T and G1790A single nucleotide polymorphisms of HIF-1α on the susceptibility and clinicopathological development of oral cancer.

It has been reported that over expression of hypoxia inducible factor-1α is significantly associated with cell proliferation, tumor size development, lymph node metastasis, and prognosis of oral squamous cell carcinoma.21, 35 Furthermore, genetic polymorphisms at C1772T and G1790A of HIF-1α have been

Conflict of Interest Statement

None declared.

Acknowledgment

This study was supported by a research Grant from National Science Council, Taiwan (NSC95-2314-B-040-014) and Changhua Christian Hospital (98-CCH-IRP-24).

References (43)

  • K.C. Lai et al.

    Genetic damage in cultured human keratinocytes stressed by long-term exposure to areca nut extracts

    Mutat Res

    (2006)
  • S. Ramachandran et al.

    Single nucleotide polymorphisms of DNA repair genes XRCC1 and XPD and its molecular mapping in Indian oral cancer

    Oral Oncol

    (2006)
  • D.T. Bau et al.

    Oral cancer and genetic polymorphism of DNA double strand break gene Ku70 in Taiwan

    Oral Oncol

    (2008)
  • G.L. Semenza et al.

    Assignment of the hypoxia-inducible factor 1alpha gene to a region of conserved synteny on mouse chromosome 12 and human chromosome 14q

    Genomics

    (1996)
  • P. Silva et al.

    Prognostic significance of tumor hypoxia inducible factor-1alpha expression for outcome after radiotherapy in oropharyngeal cancer

    Int J Radiat Oncol Biol Phys

    (2008)
  • J.L. Roh et al.

    The prognostic value of hypoxia markers in T2-staged oral tongue cancer

    Oral Oncol

    (2009)
  • K. Tanimoto et al.

    Hypoxia-inducible factor-1alpha polymorphisms associated with enhanced transactivation capacity, implying clinical significance

    Carcinogenesis

    (2003)
  • X. Liang et al.

    Hypoxia inducible factor-alpha expression correlates with vascular endothelial growth factor-C expression and lymphangiogenesis/angiogenesis in oral squamous cell carcinoma

    Anticancer Res

    (2008)
  • Y. Miyazaki et al.

    The effect of hypoxic microenvironment on matrix metalloproteinase expression in xenografts of human oral squamous cell carcinoma

    Int J Oncol

    (2008)
  • T. Ishikawa et al.

    Hypoxia enhances CXCR4 expression by activating HIF-1 in oral squamous cell carcinoma

    Oncol Rep

    (2009)
  • W. Lam et al.

    Effect of hypoxia on the expression of phosphoglycerate kinase and antitumor activity of troxacitabine and gemcitabine in non-small cell lung carcinoma

    Mol Cancer Ther

    (2009)
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    The first two authors contributed equally to this article.

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