Effects of hypoxia‐inducible factor‐1α and hypoxia‐inducible factor‐2α overexpression on hepatocellular carcinoma survival: A systematic review with meta‐analysis

Background and Aim The role of hypoxia‐inducible factor‐1α (HIF‐1α) and hypoxia‐inducible factor‐2α (HIF‐2α) has been implicated in the clinical prognosis of hepatocellular carcinoma (HCC), but the results remain controversial. We aim to investigate the association of HIF‐1α and HIF‐2α overexpression with the prognosis and clinicopathological features of HCC. Methods A systematic search was conducted in PubMed, Embase, Scopus, Web of Science, and Cochrane Library until June 20, 2020. Meta‐analysis was conducted to generate combined HRs with 95% confidence intervals (CI) for overall survival (OS) and disease‐free survival (DFS). Odds ratios (ORs) with 95% CI were also derived by fixed or random effect model. Results Twenty‐two studies involving 3238 patients were included. Combined data suggested that overexpression of HIF‐1α in HCC was not only correlated with poorer OS [HR = 1.75 (95% CI: 1.53–2.00)] and DFS [HR = 1.64 (95% CI: 1.34–2.00)] but was also positively associated with vascular invasion [OR = 1.83 (95% CI: 1.36–2.48)], tumor size [OR = 1.36 (95% CI: 1.12–1.66)], and tumor number [1.74 (95% CI: 1.34–2.25)]. In contrast, HIF‐2α overexpression was not associated with the prognosis and clinicopathological features of HCC. Conclusion Our data provided compelling evidence of a worse prognosis of HCC in HIF‐1α overexpression patients but not HIF‐2α overexpression ones.