HIF-1 alpha overexpression correlates with poor overall survival and disease-free survival in gastric cancer patients post-gastrectomy

Abstract

Background: Overall, gastric cancer prognosis remains poor. Detailed characterization of molecular markers that govern gastric cancer pathogenesis is warranted to establish innovative therapeutic options. HIF-1α overexpression has been linked to poor gastric cancer prognosis. However, though researched for years, the prognostic role of HIF-1α in gastric cancer is still controversial. Hence, the objective of the present study was to analyze the prognostic values of HIF-1α, TGF-β, VEGF and pERK1/2 in gastric cancer patients following gastrectomy.

Methods: This study included 446 patients with confirmed gastric cancer who underwent gastrectomy in a single Chinese Cancer Center between 2005 and 2006. Clinicopathologic features, as well as immunohistochemical analysis of TGF-β, HIF-1α, VEGF and pERK1/2 were determined. Long-term survival of these patients was analyzed using univariate and multivariate analyses.

Results: HIF-1α overexpression was more frequent in patients with hepatic metastases (71.6% versus 43.0% in those without hepatic metastases, P = 0.000, χ2 = 23.086) and more frequent in patients with peritoneum cavity metastasis (62.3% versus 43.0% in those without such metastasis, P = 0.000, χ2 = 13.691). In univariate analysis, patients with HIF-1α overexpression had a shorter disease-free survival (DFS) and overall survival (OS) than patients with weak-expression (DFS: NA VS. 16.8 m, P = 0.000, χ2 = 74.937; OS: NA VS. 25.5 m, P = 0.000, χ2 = 90.594). Importantly, HIF-1α overexpression was a promising prognostic marker for poor survival by multivariate analysis (DFS: HR 2.766, 95%CI 2.136-2.583, P = 0.000; OS: HR 3.529, 95%CI 2.663-4.667, P = 0.000).

Conclusions: HIF-1α overexpression could be considered a useful independent prognostic biomarker in gastric cancer after gastrectomy, and is correlated to both a poor overall survival and disease-free survival in these patients. HIF-1α expression can be used to stratify patients at higher risk for poor prognosis, and is potentially an important therapeutic target in gastric cancer patients.

Figure 1. Immunohistochemical staining of TGF-β, HIF-1α, VEGF and pERK 1/2 expression in gastric cancer.

A. Immunohistochemical staining of TGF-β was located mainly in the cytoplasm of tumor cells (positive expression ×400); B. TGF-β original magnification ×100; C. HIF-1α was located mainly in the nucleus of tumor cells (positive expression ×400); D. HIF-1α original magnification ×100; E. VEGF was located mainly in the cytoplasm of tumor cells (positive expression ×400); F. VEGF original magnification×100; G. pERK1/2 was located in the cytoplasm and nucleus of tumor cells (positive expression ×400); H. pERK1/2 original magnification ×100.

Figure 2. Kaplan-Meier curves for disease-free survival.

TGF-β, HIF-1α, VEGF and pERK 1/2 overexpression were divided into an overexpression group and a weak-expression group. A log-rank test was used to calculate significance. A. Disease-free survival curves stratified by TGF-β expression (P = 0.053). B. Disease-free survival curves stratified by HIF-1α expression (P = 0.000). C. Disease-free survival curves stratified by VEGF expression (P = 0.161). D. Disease-free survival curves stratified by pERK 1/2 expression (P = 0.107).

Figure 3. Kaplan-Meier curves for overall survival.

TGF-β, HIF-1α, VEGF and pERK 1/2 overexpression were divided into an overexpression group and a weak-expression group. A log-rank test was used to calculate significance. A. Overall survival curves stratified by TGF-β expression (P = 0.139). B. Overall survival curves stratified by HIF-1α expression (P = 0.000). C. Overall survival curves stratified by VEGF expression (P = 0.217). D. Overall survival curves stratified by pERK 1/2 expression (P = 0.018).