Prognostic Value of Hypoxia-Inducible Factor 1α in Solid Malignancies: A Meta-Analysis

Numerous studies have reported the prognostic role of Hypoxia-Inducible Factor 1α(HIF-1α)and solid malignancies, but the data of different reports remains controversial. To accurately evaluate the prognostic value of HIF-1α expression in solid malignancies, a meta-analysis based on published studies was conducted. Relevant studies from 34 observational articles with 3828 patients were collected via PubMed, Embase. These studies were chosen for the meta-analysis based on requisite criteria and the quality was evaluated using the Newcastle Ottawa Quality Assessment Scale. Hazard ratios (HRs) and 95% confidence interval (CIs) were pooled from studies on overall survival (OS) and disease-free survival (DFS) to estimate the association. The pooled HRs (95% CIs) of HIF-1α for OS and DFS were 1.94 [1.74, 2.16] and 2.16 [1.71, 2.74], respectively. The overall data of the shown meta-analysis suggested that the high expression of HIF-1α is correlated with poor survival outcome in solid


Introduction
Accumulating evidence shows that hypoxia is a common trait of solid malignancies, and tumors outgrow their own vasculature scale out a certain size could lead to hypoxia. Hypoxia-inducible factor 1 (HIF-1), a heterodimer composing of hypoxia-inducible factor 1α and hypoxia-inducible factor 1β subunits, is a major transcription factor regulating the tumorigenic response to hypoxia in micro-environmental oxygenation [1,2]. HIF-1α has been found to be up-regulated in many types of human malignancies, leading to a more aggressive phenotype with increased proliferation, invasiveness, metastases, epithelial-mesenchymal transition and stem-cell maintenance [3][4][5]. The expression of HIF-1α is regulated by the oxygen level, whereas the β subunit is constitutively expressed. Under hypoxic conditions, the degradation of HIF-1α is suppressed and the expression of HIF-1α would increase [1,6].
HIF-1α could bind to hypoxia response elements The studies enrolled in this meta-analysis were all cohort studies. Newcastle-Ottawa Scale (NOS) was applied to evaluate the quality of each included study.
Scores ranged from 0 (lowest) to 9 (highest) to assess the quality of article, and studies with scores of 6 or more were regarded as high quality. A consensus NOS score for each item was achieved.
Hazard ratios (HR) and their 95% CI were used for analysis of the effects of HIF-1α expression on prognosis. Outcome endpoints were divided into two groups, OS and DFS, according to the data acquired in the current or previous studies. We extracted the statistical variables directly when data were described in the study. Otherwise, calculated from available numerical data in the articles based the methods described by Tierney [8]. The data from Kaplan-Meier survival curves were read by Engauge Digitizer version 4.1, and two researchers read the curves to reduce reading variability independently.
Heterogeneity among studies was determined by Chi square-based Q test and I 2 statistics. P value higher than 0.05 for the Q test and I 2 value less than 50 % were considered to be of no noteworthy heterogeneity, the fixed effects model was adopted (P > 0.05, I 2 < 50%); If not, the random effects model was applied.
The publication bias was evaluated by funnel plot.
All the statistical tests were two-sided, and P < 0.05 was considered as statistically significant publication bias.

Eligible studies
The initial search yielded 4237 references were retrieved from PubMed and Embase databases using

Demographic characteristics of included studies
These enrolled studies were published from 2004 to 2015. The detailed clinical characteristics of patients and other publication information have been extracted in Table 1. NOS=Newcastle-Ottawa Scale.

Survival outcomes
Thirty-three studies, including 3778 patients, provided eligible data for OS analysis. Figure 2 showed that the pooled HR (95% CI) of these studies All above meta-analysis results were reviewed in Table 2 Nine studies, including 874 patients, provided eligible data for DFS analysis.

Potential publication bias
Funnel plots was adopted to visualize the publication bias. (Figure 4)

Discussion
HIF1α plays a critical role in hypoxia to improve glycolysis, oxygen delivery, and angiogenesis for tumor cells [43]. Recent studies have demonstrated that HIF1α is over-expressed in various human malignancies and intimately correlates with tumorgenesis, tumor progression, metastasis potential, treatment failure and increased mortality in many malignancies [44][45][46]. Dysregulation of HIF1α expression and HIF1α signal pathway in tumor microenvironment may serve as a key factor in human cancer development [46,47]. In view of its role in regulating tumor pathophysiology, evaluating its prognostic value in malignancies is of great clinical importance, which may lead to better patient stratification and targeted therapies in the future.
The prognostic role of HIF-1α expression has been proven in the recent meta-analysis in gastric cancer [48], hepatocellular carcinoma [49], lung cancer [50] and some other tumors. In conclusion, over-expression of HIF-1α was correlated with poor survival in patients with solid malignancies. These findings suggested that HIF-1α inhibition therapy could be an important method in malignancies, and that HIF-1α might be routinely detected to predict prognosis in solid malignancies.
However, more literatures need to be adopted for further verification of our results.

None
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