Expression of hypoxia-inducible factor (HIF)-1alpha is associated with vascular endothelial growth factor expression and tumour angiogenesis in human oesophageal squamous cell carcinoma.

The purpose of this study was to examine the relationship between hypoxia inducible factor (HIF)-1alpha expression, vascular endothelial growth factor (VEGF) expression, and tumour vascularity in squamous cell carcinoma of the oesophagus. Expression of HIF-1alpha and VEGF was examined in two oesophageal squamous cell carcinoma cell lines (TE2, TE3) and 82 archival surgical specimens of human oesophageal squamous cell carcinoma tissue. In both cell lines, the levels of HIF-1alpha protein and VEGF mRNA were increased under hypoxic conditions. Thirty-two of the 82 (39%) tumour specimens showed high levels of HIF-1alpha immunoreactivity in the nuclei and/or cytoplasm of cancer cells. HIF-1alpha expression correlated significantly with venous invasion, VEGF expression, and microvessel density. Among the 47 patients who did not receive pre-operative chemotherapy, the outcome of those with high HIF-1alpha-expressing tumours was significantly poorer than that of those with low HIF-1alpha-expressing tumours. These results suggest that HIF-1alpha and VEGF expression are important determinants of survival in squamous cell carcinoma of the oesophagus.

Kimura S ，Kitadai Y ，Tanaka S ，Kuwai T ，Hihara J ，Yoshida K ，Toge T ，Chayama K ... -  《EUROPEAN JOURNAL OF CANCER》

[Expression of hypoxia-inducible factor-1alpha and vessel endothelial growth factor in esophageal squamous cell carcinoma and clinico-pathological significance thereof].

To investigate the expression of hypoxia-inducible factor (HIF)-1alpha and vessel endothelial growth factor (VEGF) and their relations with the clinicopathological features of esophageal squamous cancer. Esophageal squamous cancer tissues and normal end squamous epithelium tissues were collected from 42 patients during operation. Real-time quantitative PCR was used to detect the mRNA expression of HIF-1alpha and VEGF and immunohistochemistry was used to detect the protein expression of HIF-1alpha and VEGF. The relations between the expression of HIF-1alpha, VEGF and depth of tumor invasion, histological grade, lymphatic invasion, and lymph node metastasis were evaluated. The HIF-1alpha mRNA expression level was 5.88 + 1.12 in the esophageal squamous cancer tissue, higher, but not significantly, than that in normal end squamous epithelium tissue 4.76 +/- 1.26 (P = 0.014). The VEGF mRNA expression level in the esophageal squamous cancer tissue was 12.79 +/- 2.51, higher, but not significantly, than that in the normal end squamous epithelium tissue (10.92 +/- 2.23, P = 0.010). The HIF-1alpha and VEGF protein positive rates in esophageal squamous cancer tissue were 50% (21/42) and 76% (32/42) respectively, significantly higher than those in the normal esophageal tissue [14% (6/42) and 33% (14/42) respectively, P = 0.001, P = 0.000]. The expression of HIF-1alpha mRNA and VEGF mRNA in the esophageal squamous cancer were correlated with lymph node metastasis (including lymphatic invasion) (P = 0.063 and P = 0.073 respectively). HIF-1alpha immunoreactivity was localized in the nucleus and/or cytoplasm of the cancer cells. The expression of HIF-1alpha protein was correlated with lymph node metastasis and histological grade (P = 0.013 and P = 0.028 respectively). No correlation was found between HIF-1alpha mRNA and VEGF protein. HIF-1alpha may be regulated at transcription and post-transcription levels in addition to protein level. It also plays an important role in lymphatic metastasis of esophageal squamous cancer and tumor malignancy degree. So HIF-1alpha and VEGF may serve as predictors of progression in esophageal squamous cell carcinoma and as potential targets for anti-angiogenesis therapy of esophageal squamous cell carcinoma.

Yu ZT ，Zhao HF ，Shang XB 《-》

Correlation of hypoxia inducible factor-1alpha with lymphatic metastasis via vascular endothelial growth factor-C in human esophageal cancer.

Hypoxia inducible factor (HIF)-1alpha is a transcription factor that regulates the transcription of genes associated with cell proliferation and vascular development. In various cancer tissues, HIF-1alpha is associated with clinicopathological factors, such as the tumor size, histological grade, and lymph node status. Although HIF-1alpha plays a critical role in tumor growth by inducing vascular endothelial growth factor (VEGF), it is unclarified whether HIF-1alpha affects lymphatic metastasis. The purpose of this study is to clarify the correlation of HIF-1alpha protein expression with lymph node metastasis in esophageal squamous cell carcinoma (ESCC). The expressions of HIF-1alpha and VEGF-C, which is one of the main lymphangiogenic factors, were examined in five ESCC cell lines and 48 surgical specimens of ESCC. HIF-1alpha and VEGF-C mRNAs were expressed in all the five ESCC cell lines as determined by RT-PCR analysis. Immunohistochemically, 34 of the 48 patients (70.8%) were positive for HIF-1alpha and 29 patients (60.4%) were positive for VEGF-C. Clinicopathologically, HIF-1alpha expression correlated with lymphatic invasion and VEGF-C expression (P = 0.003 and P = 0.01, respectively). Furthermore, HIF-1alpha expression tended to correlate with lymph node metastasis (P = 0.09). These findings suggest that HIF-1alpha plays a role in lymphatic invasion and lymph node metastasis through the induction of VEGF-C in ESCC.

Katsuta M ，Miyashita M ，Makino H ，Nomura T ，Shinji S ，Yamashita K ，Tajiri T ，Kudo M ，Ishiwata T ，Naito Z ... -  《EXPERIMENTAL AND MOLECULAR PATHOLOGY》

Effect of endothelial PAS domain protein 1 and hypoxia inducible factor 1alpha on vascular endothelial growth factor expression in human pancreatic carcinoma.

Transcription factors hypoxia inducible factor 1alpha (HIF 1alpha) and endothelial PAS domain protein 1 (EPAS1) promote the transcription of vascular endothelial growth factor (VEGF). VEGF enhances angiogenesis and vascular permeability of tumours, which promotes tumour growth and facilitates entry of cancer cells into blood circulation and metastasizing. This study examined whether HIF 1alpha and EPAS1 stimulated angiogenesis through activation of VEGF in human pancreatic carcinoma. Specimens from pancreatic carcinoma and healthy parts of same pancreas were taken from 60 patients. Real time quantitative reverse transcription polymerase chain reaction estimated expression of HIF 1alpha, EPAS1, and VEGF mRNAs. Western blotting and immunohistochemical, streptavidin peroxidase method assessed expression of HIF 1alpha, EPAS1, and VEGF proteins. Microvessel density (MVD) was assessed. Highly significant increases in expression of EPAS1, VEGF, and MVD were found in pancreatic carcinoma tissue but not in normal pancreatic tissue: VEGF at mRNA and protein levels (t = 17.32, P = 0.0001; t = 98.41, P = 0.0001); EPAS1 protein level (t = 22.51, P = 0.0001). Expression of HIF 1alpha was similar in pancreatic carcinoma and normal pancreatic tissues at both mRNA and protein levels. Significant correlations were observed between EPAS1 and VEGF (r = 0.736, P = 0.0041), between VEGF and MVD (r = 0.858, P = 0.0001), and between EPAS1 and MVD (r = 0.641, P = 0.0003). No significant correlations were observed between HIF 1alpha and VEGF, or between HIF 1alpha and MVD. MVD and expression of EPAS1 and VEGF were significantly related with TNM staging, so was EPASI and VEGF with size of tumour. EPAS1 and VEGF, but not HIF1alpha, are overexpressed in pancreatic carcinoma. The expression of EPAS1 is correlated with that of VEGF and MVD. EPAS1 may be involved in the angiogenesis of pancreatic carcinoma by upregulating the expression of VEGF. Targeting EPAS1 may be a new method of antiangiogenic tumour therapy for pancreatic carcinoma.

Zhu DM ，Li DC ，Zhang ZX ，Zhang XY ... -  《-》

Expression of p53 protein in esophageal squamous cell carcinoma: relation to hypoxia-inducible factor-1alpha, angiogenesis and apoptosis.

Hypoxia-inducible factor (HIF)-1 is important in the control of transcription of several genes related to angiogenesis. We have previously reported that expression of HIF-1alpha correlates with venous invasion and clinical outcome in esophageal squamous cell carcinoma. p53 has been reported to interact with HIF-1alpha and induce ubiquitin-mediated proteosomal degradation of HIF-1alpha. The purpose of this study was to clarify whether the expression of p53 is associated with that of HIF-1alpha. Expression of p53, HIF-1alpha and vascular endothelial growth factor (VEGF) was examined in 81 archival surgical specimens of human esophageal squamous cell carcinoma tissue. CD34 and single-stranded DNA were used to evaluate angiogenesis and apoptosis. Forty-seven of the 81 (58.0%) tumor specimens showed high levels of nuclear p53 immunoreactivity. Overexpression of p53 was observed in the early clinical stage of tumor development. Expression of p53 was not correlated with HIF-1alpha or VEGF expression, angiogenesis or apoptosis in esophageal carcinoma. These results suggest that mutations in p53 play a role in carcinogenesis but not in the progression of esophageal squamous cell carcinoma. HIF-1alpha may not only be regulated by p53 but also by other factors.

Kimura S ，Kitadai Y ，Kuwai T ，Tanaka S ，Hihara J ，Yoshida K ，Toge T ，Chayama K ... -  《PATHOBIOLOGY》