The meta-analysis investigates the associations between HIF-1α C1772 T polymorphism and cancer metastasis. We found that variant T allele significantly increased the risk of cancer metastasis.
Hypoxia-inducible factor1α (HIF-1α) is a transcription factor was first found as a regulator of renal production of erythropoietin (Epo) 
. It is a helix-loop-helix transcription factor that consists of α and β subunits. HIF-1α subunit is regulated by oxygen pressure and HIF-1 β is constitutively expressed 
. In normoxic conditions, HIF-1α is hydroxylated at specific proline residues. Under hypoxic conditions, HIF-1α is induced and combines with the β subunit, then removes to the nucleus and initiates gene transcription 
. The HIF-1α protein contains five functional domains: basic helix-loop-helix (bHLH), Per/Arnt/Sim (PAS), N-terminal (N-TAD), C-terminal (C-TAD), and oxygen-dependent degradation (ODD) 
HIF-1α is overexpressed in regional or distant metastases and is also expressed higher in preneoplastic and premalignant lesions, indicating that overexpression of HIF-1α can occur very early in carcinogenesis which may become a potential biomarker of predicting tumor progress 
and a good target for the detecting of tumor metastasis. HIF-1 activates the transcription of a large number of genes that for erythropoietin, vascular endothelial growth factor, endothelin-1, nitric oxide synthase, heme oxygenase-1, and insulin-like growth factor-2. However, the expression of vascular endothelial growth factor (VEGF) is an essential molecular event for tumor development and metastasis 
. It is known that HIF-1 induces erythropoiesis and angiogenesis, and is also involved in the regulation of both vascular tone and glucose metabolism 
. And HIF-1 transcriptional activity is regulated by the HIF-1α subunit. There were evidences indicate that HIF-1 plays an important role in cancer progression and metastasis 
. Higher expression levels of HIF-1α have been reported in human malignancies including colon, breast. HIF-1α polymorphism C1772T in human were initially identified in renal cell carcinoma patients which cause amino acid substitutions within the N-TAD, however, the difference in genotype distribution was not indicated between renal cell carcinoma cases and controls 
. It has been reported that the C1772T polymorphism T allele in HIF-1α represent higher transcriptional activity than that of wild-type C allele under both normoxic and hypoxic conditions 
. Therefore, the presence of this polymorphism might be associated with in cancer risk and cancer metastasis. However, the studies had controversial conclusions. A meta-analysis has proved that the HIF-1α C1772 T polymorphism is significantly associated with higher cancer risk 
. The aim of this study was to investigate the association between HIF-1α C1772 T polymorphism and cancer metastasis. In our analysis, we found that variant T allele significantly increased the risk of metastasis. Further, the associations were very stable, which did not change apparently when the sensitivity analyses were performed. The results indicated that T allele is a potential risk factor in cancer metastasis. There was a significant association between HIF-1α C1772 T polymorphism and cancer metastasis under the dominant model, while no association was found in the recessive model. One possible explanation is that the number of studies which investigate the TT genotype separately is too small. The results may also indicate that heterozygous T has a stronger effect on an individual's phenotype than homozygous T. It is mean that individuals with CT genotype may have a higher risk of metastasis than those with TT genotype. Further larger sample size and well-designed studies should be performed to testimony our results.
For the stratification analyses based on ethnicity and cancer types. There was an evidence to indicate that the HIF-1α C1772T polymorphism was significantly associated with increased risk of cancer metastasis among Asians and Caucasians only for dominant genetic model. However, no significant association was found between the C1772T polymorphism and cancer metastasis in colorectal cancer and breast cancer under dominant model. Further studies using larger sample size are needed to validate. Kuwai et al. 
indicated that the C1772T polymorphism in HIF-1α is not association with the progression and metastasis of colorectal cancer, while the study of patients with ESCC has a contrary result 
. It may because C1772T has different values in different kinds of tumors. The T/T genotype is rare in our study, thus, the absence of association between T/T and cancer metastasis may be due to chance. Extended epidemiological studies would be needed to determine if this genotype is associated with cancer metastasis. There is a previous founding reported that HIF-1α genetic variant increases risk of breast Lymph node metastasis 
, which is consistent with our subgroup analysis. It is likely that variations of sample sizes may account for contradictory results.
There are some limitations and potential bias that must be acknowledged in our meta-analysis. First, only published studies were included in our studies, many unpublished data have been ignored in the analysis. Therefore, potentially publication bias will be existed in our results, although the statistical data did not reflect it. Second, because of lacking of detailed analysis about age, gender, smoking, drinking and so on, those potential factors may influence our results. Third, the number of the included studies was not large enough. So the statistical power is weak to evaluate the association between HIF-1a polymorphisms and metastasis, especially in stratified analyses.
In summary, our meta-analysis reveal that the HIF-1α C1772T polymorphism can increase the risk of cancer metastasis. Although some results of the analysis are limited by the small number of studies. Our results suggest that the polymorphism is a potential risk factor. Large sample size and well-designed studies are needed to evaluate our finding.