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. 2007 Mar 21;13(11):1680-6.
doi: 10.3748/wjg.v13.i11.1680.

Upregulation of hypoxia inducible factor 1alpha mRNA is associated with elevated vascular endothelial growth factor expression and excessive angiogenesis and predicts a poor prognosis in gastric carcinoma

Jie Ma  1 , Li Zhang, Guo-Qing Ru, Zhong-Sheng Zhao, Wen-Juan Xu
Affiliations

Upregulation of hypoxia inducible factor 1alpha mRNA is associated with elevated vascular endothelial growth factor expression and excessive angiogenesis and predicts a poor prognosis in gastric carcinoma

Jie Ma et al. World J Gastroenterol. .

Abstract

Aim: To investigate the implication of the hypoxia inducible factor HIF-1alpha mRNA in gastric carcinoma and its relation to the expression of vascular endothelial growth factor (VEGF) protein, tumor angiogenesis invasion/metastasis and the patient's survival.

Methods: In situ hybridization was used to examine expression of HIF-1alpha mRNA, and immunohistochemical staining was used to examine expression of VEGF protein and CD34 in 118 specimens from patients with gastric carcinoma.

Results: The positive rates of HIF-1alpha mRNA and VEGF protein were 49.15% and 55.92%, respectively. Positive expressions of HIF-1alpha and VEGF in stage T3-T4 tumors and those with vessel invasion, lymph node metastasis and distant metastasis were dramatically stronger than stage T1-T2 cases and those without vessel invasion, lymph node metastasis and distant metastasis. The mean microvascular density (MVD) in stage T3-T4 tumors and those with vessel invasion, lymph node metastasis and distant metastasis was significantly higher than stage T1-T2 tumors and those without vessel invasion, lymph node metastasis and distant metastasis. The mean MVD in tumors with positive HIF-1alpha and VEGF expression was significantly higher than that in tumors with negative HIF-1alpha and VEGF expression. The expression of HIF-1alpha was positively correlated with VEGF protein. There were positive correlations between MVD and expression of HIF-1alpha and VEGF. The mean survival time and the 5-year survival rate in cases with positive expression HIF-1alpha and VEGF and MVD value >or= 41.5/0.72 mm2 were significantly lower than those with negative expression of HIF-1alpha and VEGF and MVD value < 41.5/0.72 mm2.

Conclusion: Overexpression of HIF-1alpha is found in gastric carcinoma. HIF-1alpha may induce the angiogenesis in gastric carcinoma by upregulating the transcription of VEGF gene, and take part in tumor invasion and metastasis. They can be used as prognostic markers of gastric cancer in clinical practice.

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Figures

Figure 1
Figure 1
The expression of HIF-1α mRNA in gastric cancer tissue. A: HIF-1α mRNA was negative (-) in nontumorous gastric epithelial mucous. In situ hybridization and visualization with DBA. Magnification × 120; B: Moderately differentiated adenocarcinoma was involved with muscular layer. HIF-1α mRNA was positively expressed (+++). In situ hybridization and visualization with DAB. Magnification × 180; C: Moderately differentiated adenocarcinoma was involved with serosa layer. HIF-1α mRNA was positively expressed (++). In situ hybridization and visualization with DAB. Magnification × 210; D: Moderately differentiated adenocarcinoma was involved with great omentum. HIF-1α mRNA was positively expressed (++). In situ hybridization and visualization with DAB. Magnification × 240.
Figure 2
Figure 2
The expression of VEGF protein in gastric cancer tissue. A: VEGF was negative (-) in nontumorous gastric epithelial mucous. In situ hybridization and visualization with DBA. Magnification × 120; B: Poorly differentiated adenocarcinoma was involved with muscular layer. VEGF was positively expressed (+++). In situ hybridization and visualization with DAB. Magnification ×180; C: Moderately differentiated adenocarcinoma was involved with serosa layer. HIF-1αmRNA was positively expressed (+++). In situ hybridization and visualization with DAB. Magnification × 200; D: Poorly differentiated adenocarcinoma was involved with great omentum. VEGF was positively expressed (++). In situ hybridization and visualization with DAB. Magnification × 220.
Figure 3
Figure 3
Relationship between HIF-1α mRNA, VEGF protein, MVD and prognosis. A: Survival curves by the Kaplan-Meier method. Log-rank test revealing a significant difference between negative and positive expression of HIF-1α mRNA (P < 0.05); B: Survival curves based on the Kaplan-Meier method. Log-rank test revealing a significant difference between negative and positive expression of VEGF (P < 0.05); C: Survival curves by the Kaplan-Meier method. There was a significant difference in Log-rant test between patients with MVD value < 41.5/0.72 mm2 and those with MVD value ≥ 41.5/0.72 mm2.
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