Association of hypoxia-inducible factor-1α (HIF1α) 1790G/A gene polymorphism with renal cell carcinoma and prostate cancer susceptibility: a meta-analysis

Renal cell carcinoma (RCC) is one of the most commonly occurring types of tumors in the urogenital system and accounts for ~ 85% of all kidney tumors [1‐4]. RCC is not sensitive to conventional chemotherapy and radiotherapy, and its prognosis remains poor [1]. Prostate cancer (PCa) is a complex disease, and is the fifth leading cause of cancer death in men worldwide [5]. The screening projection for PCa is still unclear and recent large clinical trials have failed to exert notable reduction in the prostate-specific mortality and the all-cause mortality [6]. The current evidence shows that RCC and PCa are Von Hippel-Lindau tumor suppressor (VHL)-related cancers [7‐10]. VHL protein is an E3 ubiquitin ligase that targets hypoxia inducible factor 1α (HIF1α) to the proteasome for degradation [11]. The current literature indicates that genetic factors are significant contributors to cancers risk [12‐15].

Hypoxia inducible factor 1α (HIF1α) is the central regulator of the cellular response to low oxygen, and the activity of HIF1α is down-regulated in various human pathologies [16, 17]. During hypoxia, reduced oxygen availability can inhibit these HIF hydroxylase enzymes, and lead to HIF1α protein accumulation, which may translocate to the cell nucleus, bind to the HIF1β, and induce the transcription of some HIF target genes [18]. HIF1α regulates tumor cell proliferation, invasion, migration, and resistance to radiotherapy [16, 19]. Consequently, given the importance of HIF signaling in disease, there is considerable interest in developing strategies to modulate HIF1α activity and to induce down-stream signaling events. HIF1α 1790G/A (rs11549467) gene polymorphism is one of the most important gene polymorphism for certain cancers, such as PCa, and RCC. However, the available evidence is inadequate due to inconsistencies between studies and an overall lack of data. This meta-analysis was performed to investigate whether the HIF1α 1790G/A (rs11549467) gene polymorphism is associated with RCC, PCa susceptibility.

In this in-depth meta-analysis, the results indicate that the AA genotype of HIF1α 1790G/A is positively associated with the risk of RCC in overall populations and Caucasians, but not for Asians. The G allele and GG genotype are not associated with the susceptibility of RCC in overall populations, Caucasians, and Asians. The G allele is negatively associated with PCa susceptibility in overall populations and Asians, but not for Caucasians. The GG genotype is negatively associated with PCa susceptibility in Asians, but not for overall populations or Caucasians. However, the HIF1α 1790G/A AA genotype is not associated with PCa susceptibility in overall populations, Caucasians or Asians.

Previous, related meta-analyses have been conducted. Li et al. [28] reported that for the 1790G/A polymorphism, the G allele was significantly associated with a higher risk of urinary cancers in Asians. Anam et al. [29] conducted a meta-analysis using the genome wide association method including 19 case-control studies with a total sample size 10,654, and reported that the HIF1α 1790 G/A gene polymorphism significantly increased the risk of cancer in both Asian and Caucasian populations. Zhou et al. [30] performed a meta-analysis of 28 case-control studies of the relationship between the HIF1α G1790A gene polymorphism and the risk of cancer, and reported that the G with A of HIF-1α G1790A gene polymorphism is a notable risk factor of cancer, especially for RCC, lung cancer, pancreatic cancer, and head and neck cancer. These meta-analyses did not assess the relationship between the HIF1α 1790G/A gene polymorphism and RCC and PCa susceptibility by races. Our results indicate that AA genotype of HIF1α 1790G/A was positively associated with RCC risk in overall populations and Caucasians. Furthermore, the G allele was negatively associated with PCa susceptibility in overall populations and Asians, and the GG genotype was negatively associated with PCa susceptibility in Asians. However, the sample sizes were small and these results need to be treated with caution.

Considering our results and the available literature, we suspected that the G allele and GG genotype were negatively associated with PCa susceptibility, and that the AA genotype was a risk factor to induce the onset of RCC. The hypothesis was as follows: Under both normoxic conditions and hypoxia, the HIF-1α G1790A gene polymorphism would be associated with increased transcription activities and enhanced angiogenesis compared to the wild type [31, 32]. The cause of the enhance transactivation capacity could be the alteration of stability of variant proteins or the enhanced recruitment of transcriptional co-factors such as SRC-1 and CBP/p300 that interact with HIF-1α [33]. HIF-1α G1790A gene polymorphism has been detected within the oxygen-dependent degradation/pVHL binding domain in exon 12 of the HIF-1α gene, which induces increased transcription activity compared to wild type [31]. In addition, regulatory region mutations may interfere with different post-translational modifications of HIF-1α and result in enhanced protein stability [34, 35]. HIF-1α G1790A has been associated with enhanced tumor-produced HIF-1α and cancer progression [36]. BHLHE41 is a specific transcriptional target of HIF-1α, and the HIF-1α G1790A polymorphism creates a HIF-binding site to mediate the upregulation of BHLHE41 [37]. However, there was rare study to detect the functional roles of the G, GG, and AA genotypes in the transcription and other related activities of HIF-1α. In this study, we found that the negative association of G allele with susceptibility of prostate cancer in Asians. We suspected that G allele of HIF-1α G1790A might be associated with low levels of HIF-1α and might be negative association of G allele with prostate cancer risk. However, more studies should be performed to confirm it.

There were some limitations in our meta-analysis, as the study sample sizes were low, and we did not explore sources of variability between studies such as adjusting variables, age distribution, and sources of controls. These results should be treated with caution.

The present results support the hypothesis that the AA genotype of HIF1α 1790G/A is positively associated with RCC risk in overall populations and Caucasians. Furthermore, the G allele is negatively associated with PCa susceptibility in overall populations and Asians, and the GG genotype is negatively associated with PCa susceptibility in Asians. However, additional investigations are required to confirm these relationships.