The association between hypoxia inducible factor-1α gene polymorphisms and increased 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)
- et al.
Hypoxia response element of the human vascular endothelial growth factor gene mediates transcriptional regulation by nitric oxide: control of hypoxia-inducible factor-1 activity by nitric oxide
Blood
(2000) - et al.
Identification of hypoxia-inducible factor 1 ancillary sequence and its function in vascular endothelial growth factor gene induction by hypoxia and nitric oxide
J Biol Chem
(2001) HIF-1, O(2), and the 3 PHDs: how animal cells signal hypoxia to the nucleus
Cell
(2001)- et al.
Expression of type 2 nitric oxide synthase and vascular endothelial growth factor in oral dysplasia
J Oral Maxil Surg
(2002) - et al.
Expression of nitric oxide synthase-2 in cutaneous squamous cell carcinoma of the head and neck
Br J Oral Maxil Surg
(2002) - et al.
Hypoxia-inducible factor and its biomedical relevance
J Biol Chem
(2003) - et al.
Hypoxia-induced tumor angiogenic pathway in head and neck cancer: an in vivo study
Cancer Lett
(2005) - et al.
Clinicopathologic significance of tumor cell-lined vessel and microenvironment in oral squamous cell carcinoma
Oral Oncol
(2008) - et al.
Hypoxia induces resistance to 5-fluorouracil in oral cancer cells via G(1) phase cell cycle arrest
Oral Oncol
(2009) - et al.
Cigarette smoke condensate induces cytochromes P450 and aldo-keto reductases in oral cancer cells
Toxicol Lett
(2006)
Genetic damage in cultured human keratinocytes stressed by long-term exposure to areca nut extracts
Mutat Res
Single nucleotide polymorphisms of DNA repair genes XRCC1 and XPD and its molecular mapping in Indian oral cancer
Oral Oncol
Oral cancer and genetic polymorphism of DNA double strand break gene Ku70 in Taiwan
Oral Oncol
Assignment of the hypoxia-inducible factor 1alpha gene to a region of conserved synteny on mouse chromosome 12 and human chromosome 14q
Genomics
Prognostic significance of tumor hypoxia inducible factor-1alpha expression for outcome after radiotherapy in oropharyngeal cancer
Int J Radiat Oncol Biol Phys
The prognostic value of hypoxia markers in T2-staged oral tongue cancer
Oral Oncol
Hypoxia-inducible factor-1alpha polymorphisms associated with enhanced transactivation capacity, implying clinical significance
Carcinogenesis
Hypoxia inducible factor-alpha expression correlates with vascular endothelial growth factor-C expression and lymphangiogenesis/angiogenesis in oral squamous cell carcinoma
Anticancer Res
The effect of hypoxic microenvironment on matrix metalloproteinase expression in xenografts of human oral squamous cell carcinoma
Int J Oncol
Hypoxia enhances CXCR4 expression by activating HIF-1 in oral squamous cell carcinoma
Oncol Rep
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
Cited by (54)
Association of hypoxia inducible factor-1 alpha exon 12 mutation in diabetic patients with and without diabetic foot ulcer
2018, International Journal of Biological MacromoleculesTumor hypoxia and role of hypoxia-inducible factor in oral cancer
2024, World Journal of Surgical Oncology
- 1
The first two authors contributed equally to this article.