Abstract
Hypoxia-inducible factor-2α (HIF-2α) plays an important role in tumor progression and metastasis. A number of studies have evaluated the correlation between HIF-2α overexpression and clinical outcome in cancer patients but yielded inconsistent results. To comprehensively and quantitatively summarize the evidence on the capability of HIF-2α to predict the prognosis of cancer patients with solid tumors, a meta-analysis was carried out. Renal cell carcinoma (CC-RCC) was separately analyzed due to an alternative mechanism of regulation. Systematic literature searches were performed in PubMed and Embase databases for relevant original articles until February 2018. Forty-nine studies with 6,052 patients were included in this study. The pooled hazard ratios (HRs) with corresponding confidence intervals were calculated to assess the prognostic value of HIF-2α protein expression in tumor cells. The meta-analysis revealed strong significant negative associations between HIF-2α expression and five endpoints: overall survival [HR = 1.69, 95% confidence interval (95% CI) 1.39–2.06], disease-free survival (HR = 1.87, 95% CI 1.2–2.92), disease-specific survival (HR = 1.57, 95% CI 1.06–2.34), metastasis-free survival (HR = 2.67, 95% CI 1.32–5.38), and progression-free survival (HR = 2.18, 95% CI 1.25–3.78). Subgroup analyses revealed similar associations in the majority of tumor sites. Overall, these data demonstrate a negative prognostic role of HIF-2α in patients suffering from different types of solid tumors.
Highlights
Hypoxia is a common feature of most of solid tumors resulting from an imbalance between oxygen supply and consumption by tumor cells
We found that the pooled hazard ratios (HRs) for metastasis-free survival (MFS) was 2.67, indicating that HIF2α expression is a negative prognostic factor for MFS in patients with prostate and salivary gland cancer (Figure 7)
In view of its role in regulating oncogenic processes triggered by hypoxia, the evaluation of its prognostic value in cancer is of great clinical importance, which may lead to a more accurate patient prognosis and the generation of targeted therapies in the future
Summary
Hypoxia is a common feature of most of solid tumors resulting from an imbalance between oxygen supply and consumption by tumor cells. Hypoxia triggers important cellular stress responses allowing tumor cells to survive under extreme conditions, including the stabilization of the hypoxia-inducible factor (HIF) proteins [9, 10]. Prolyl-hydroxylation promotes HIF-α degradation via the von Hippel–Lindau (VHL) ubiquitin/proteasome pathway. Under hypoxia, this regulation is HIF2 Expression in Cancer suppressed, leading to the stabilization of three independent HIF-α subunits (HIF-1α, HIF-2α, and HIF-3α) that dimerize with the constitutively expressed HIF-1β and activate the transcription of genes via hypoxia responsive elements in their promoter region. Specific activity of HIF-2α differently contributes to total HIF target gene expression among many types of cancers, which may influence the characteristics of these tumors and the outcome of patients [15]. Hypoxia-induced HIF-2α expression and its subsequent chain of events make this protein a relevant marker of tumor hypoxia and a promising target for anticancer therapies with novel inhibitors
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