Altered expression of endogenous soluble vascular endothelial growth factor receptor-2 is involved in the progression of esophageal squamous cell carcinoma

Abstract

Endogenous soluble vascular endothelial growth factor receptor-2 (esVEGFR-2), a new splicing variant of VEGFR-2, was shown to be the first endogenous specific inhibitor of lymphatic vessel growth. The expression of esVEGFR-2 and its clinicopathological roles in esophageal squamous cell carcinoma (ESCC) are unclear. In this article, quantitative RT-PCR was employed to detect the mRNA levels of esVEGFR-2 and VEGF-C in 90 paired primary ESCC tissues, along with immunohistochemical staining to measure esVEGFR-2 protein in 182 ESCC primary tissues. Correlations between esVEGFR-2 expression and clinicopathological features were also analyzed. Compared with the corresponding non-neoplastic esophageal mucosa tissues, the mRNA level of esVEGFR-2 was decreased, whereas the mRNA level of VEGF-C was increased in ESCCs. Downregulation of esVEGFR-2 mRNA level was significantly correlated with pTNM stages (χ(2) = 7.790, p=0.02). Immunohistochemical staining of esVEGFR-2 was inclined to be reduced in ESCC tissues; lower esVEGFR-2 protein expression was related to better prognosis (χ(2) = 6.366, p=0.012), whereas higher esVEGFR-2 protein accumulation in ESCC tissues was an independent prognostic factor for poor survival of patients (hazard ratio, 1.606; 95% confidence interval, 1.042-2.476; p=0.032). Taken together, altered expression of esVEGFR-2 is correlated with progression of ESCC. esVEGFR-2 might serve as a new independent prognostic marker for ESCC patients.

Figure 1.

Endogenous soluble vascular endothelial growth factor receptor-2 (esVEGFR-2) and vascular endothelial growth factor C (VEGF-C) mRNA relative expression in 90 patients with esophageal squamous cell carcinoma (ESCC) as measured by quantitative RT-PCR. β-Actin was applied as an internal reference. ^ΔΔCt method and Chi-square test were employed to analyze the results. Each bar is the log2^−ΔΔCt value of esVEGFR-2 or VEGFC expression level. (A) Statistically significant downregulation of esVEGFR-2. (B) Upregulation of VEGF-C. Bar indicates relative expression level.

Figure 2.

Immunohistochemical staining of endogenous soluble vascular endothelial growth factor receptor-2. Normal mucous membrane of esophagus (A), intense expression (B, score: 12), moderate expression in (C, score: 8), and mild expression in esophageal squamous cell carcinoma (D, score: 4). Scale bars: A, 100 µm; B–D, 50 µm.

Figure 3.

Kaplan-Meier survival curves for endogenous soluble vascular endothelial growth factor receptor-2 (esVEGFR-2) in patients with esophageal squamous cell carcinoma (ESCC). Patients were divided into two subgroups: low expression (bold line, score <9) and high expression (dotted line, score ≥9). Kaplan-Meier analysis of esVEGFR-2 expression in 182 patients with ESCC illustrated that survival was lower in 62 cases where esVEGFR-2 expression was high, as compared with 120 cases where esVEGFR-2 expression was low.