Clinical and Prognostic Significance of HIF-1α, PTEN, CD44v6, and Survivin for Gastric Cancer: A Meta-Analysis

<div><p>Purpose</p><p>This study was to quantitatively summarize published data for evaluating the clinical and prognostic significance of four proteins involved in hypoxia-inducible factor-1 (HIF-1α) regulation of the metastasis cascade.</p><p>Methods</p><p>Searches were performed using the MEDLINE, EMBASE, Cochrane Library, and Chinese Biomedicine databases without any language restrictions. Studies were pooled and either the summary risk ratio (RR) or odds ratio (OR) was calculated. Potential sources of heterogeneity were sought out <i>via</i> subgroup and sensitivity analyses, and publication bias was also performed.</p><p>Results</p><p>Seventeen studies evaluated HIF-1α, 20 studies evaluated phosphatase and tensin homolog (PTEN), 20 studies evaluated Survivin, and 16 studies evaluated CD44v6. Our results showed that increased HIF-1α expression was linked to a poor 5-year overall survival (RR = 1.508; 95% confidence interval (CI) 1.318–1.725; P<0.001). Decreased survival was heavily influenced by advanced tumor invasion (OR = 3.050; 95% CI 2.067–4.501; P<0.001), lymph node metastasis (1415 patients; OR = 3.486, 95% CI 2.737–4.440; P<0.001), distant metastasis (OR = 6.635; 95% CI 1.855–23.738; P = 0.004), vascular invasion (OR = 2.368; 95% CI 1.725–3.252; P<0.001), dedifferentiation (OR = 2.112; 95% CI 1.410–3.163; P<0.001), tumor size (OR = 1.921; 95% CI 1.395–2.647; P<0.001), and a higher TNM stage (OR =  2.762; 95% CI 1.941–3.942; P<0.001). Similarly, aberrant expression of PTEN, CD44v6, and Survivin were also observed in tumors that correlated with poor OS. The higher ORs of death at 5 years were 1.637 (95% CI = 1.452–1.845; P<0.001), 1.901 (95% CI = 1.432–2.525; P<0.001), and 1.627 (95% CI = 1.384–1.913; P<0.001), respectively, with an OR>2 for the main stratified meta-analyses of clinical factors.</p><p>Conclusions</p><p>Our findings indicate that HIF-1α/PTEN/CD44v6/Survivin, as measured by immunohistochemistry, can be used to predict the prognosis and potential for invasion and metastasis in Asian patients with gastric cancer. The development of strategies against this subset of proteins could lead to new therapeutic approaches.</p></div

Meta-analyses of Surviving and Cd44v6 expressions on gastric cancer.

<p>NS, number of studies, NP, number of patients; OR, odd ratio; RR, risk ratio; CI, confidence interval.</p

Meta-analysis on the relation between Survivin expression and 5-year overall survival (OS).

<p>The summary RR and 95% CIs were shown (fixed-effect model analysis).</p

Hypoxia regulation of the metastasis cascade.

<p>Hypoxia regulation of the metastasis cascade.</p

Meta-analysis on the relation between PTEN expression and 5-year overall survival (OS).

<p>The summary RR and 95% CIs were shown (fixed-effect model analysis).</p

Main characteristics of the 73 studies included in the final meta-analyses.

<p>Pub, publication; Exp, expression; RR, risk ratio; OS, overall survival; Positive, inverse relationship between specific protein expression and survival; Negative, no relationship. ‘Reader’ are readers of the histologic slides, ‘blinded reading’ means that readers of the slides without knowledge of the clinical outcome, and ‘−’ corresponds to missing data.</p

Meta-analyses of HIF-1α/PTEN/CD44v6/Survivin expressions on gastric cancer.

<p>NS, number of studies, NP, number of patients; OR, odd ratio; RR, risk ratio; CI, confidence interval.</p

Meta-analysis on the relation between CD44v6 expression and 5-year overall survival (OS).

<p>The summary RR and 95% CIs were shown (random-effect model analysis).</p

Meta-analysis on the relation between HIF-1α expression and 5-year overall survival (OS).

<p>The summary RR and 95% CIs were shown (fixed-effect model analysis).</p