Expression of hypoxia-inducible factor 1α in gastric cancer and its clinical signficance

Abstract

To explore the expression level and location of hypoxia-inducible factor 1α (HIF-1α) in gastric cancer (GC) tissues and their relationship with clinicopathological features and clinical outcomes. From July to September 2015, 27 pairs of fresh paired GC tissues and adjacent normal tissues were gathered from the Eighth Department of General Surgery of the First Affiliated Hospital of Anhui Medical University. Quantitative real-time PCR (qRT-PCR) and Western blot were performed to detect the expression of HIF-1α mRNA and protein in these tissues. A total of 191 GC tissues and 46 randomly selected adjacent normal gastric tissues were consecutively collected between December 2006 and September 2008 from Department of General Surgery of the same hospital. Immunohistochemistry were performed on them to detect the expression of HIF-1α and CD34[described in terms of microvessel density (MVD)], and correlation of different locations of HIF-1α (in cytoplasm or nucleus) with MVD, clinicopathological features, and clinical prognosis was analyzed. The average relative expression level of HIF-1α mRNA in GC tissues (0.625±0.170) was significantly higher than in normal adjacent tissues (0.218±0.036, t=2.336, P=0.023) by qRT-PCR. From the results of Western blot, the expression level of HIF-1α protein increased in GC tissues compared with its corresponding normal tissues. Immunohistochemistry results revealed that positive HIF-1α staining was observed in 67.54% GC tissues and 45.65% normal tissues, with significant difference (P=0.006). And 35.08% in GC and 45.65% in normal tissues were cytoplasmic positive (P=0.138); while 37.17% in GC and only 2.17% in normal tissues were nuclear positive, with significant difference (P<0.001). High differentiation group and TNM clinical early stage (Ⅰ+ Ⅱ) group had significantly higher cytoplasmic HIF-1α expression positive rate compared with low differentiation group (P=0.008) and TNM clinical intermediate-advanced stage (Ⅲ+ Ⅳ) group (P=0.019); whereas low differentiation group had significantly higher nuclear HIF-1α expression positive rate compared with high differentiation group (P=0.043). The mean MVD in the nuclear HIF-1α positive GC group (115.6 ± 7.8) was higher than that in the cytoplasmic HIF-1α positive GC group (93.1±7.5, t=2.077, P=0.040). The median follow-up time was 56(3-81)months. Kaplan-Meier survival analysis and Log-Rank test results showed that nuclear HIF-1α positive patients had a shorter survival time (median 45 months) than cytoplasmic HIF-1α positive patients (median 64 months, P<0.001). Multivariate Cox regression analysis revealed that differentiation (HR=1.713; 95% CI: 1.019-2.882), depth of invasion (tumor stage, HR=6.137; 95% CI: 1.832-20.556) and lymph node metastasis (HR=2.788; 95% CI: 1.313-5.920) were independent prognostic factors for GC (all P<0.05). Different location of HIF-1α protein may be realted to the tumorigenesis and progression of GC, and may become a potential prognostic indicator of GC.