The Clinicopathological Significance of Tissue Levels of Hypoxia-Inducible Factor-1α and Vascular Endothelial Growth Factor in Gastric Cancer
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Background/Aims: Hypoxia-inducible factor-1α (HIF- 1α) is a mediator of tumor progression. Vascular endothelial growth factor (VEGF) is the most potent angiogenic factor known to be induced by HIF-1α. We investigated the clinicopathological significance of HIF-1α and VEGF levels in biopsied gastric cancer tissue. Methods: Endoscopic biopsy specimens from 67 patients with gastric carcinoma who underwent surgery were available for this study. Semiquantitative RT-PCR was applied to biopsied tumors and normal tissues to determine the expressions of HIF-1α and VEGF. The expression levels of HIF-1α and VEGF were evaluated using the tumor:normal (T/N) ratios of HIF-1α and VEGF mRNA. The clinicopathological variables were reviewed retrospectively. Results: The T/N ratios of HIF-1α mRNA showed significant correlation with lymph-node metastases, distant metastases, stage, and recurrence within 3 years (p＜0.05). The T/N ratios of VEGF mRNA showed significant correlation with lymph-node metastases and distant metastases (p＜0.05). There was a significant correlation between the T/N ratios of HIF-1α and VEGF mRNA (r=0.72, p＜0.01). Conclusions: The increased expression of HIF-1α and VEGF mRNA could reflect aggressive tumor behavior, including the recurrence of gastric cancer. Examination of HIF-1α mRNA in biopsy specimens by RT-PCR assay might provide useful preoperative information on tumor aggressiveness.
Abstract
Background/Aims: Hypoxia-inducible factor-1α (HIF- 1α) is a mediator of tumor progression. Vascular endothelial growth factor (VEGF) is the most potent angiogenic factor known to be induced by HIF-1α. We investigated the clinicopathological significance of HIF-1α and VEGF levels in biopsied gastric cancer tissue. Methods: Endoscopic biopsy specimens from 67 patients with gastric carcinoma who underwent surgery were available for this study. Semiquantitative RT-PCR was applied to biopsied tumors and normal tissues to determine the expressions of HIF-1α and VEGF. The expression levels of HIF-1α and VEGF were evaluated using the tumor:normal (T/N) ratios of HIF-1α and VEGF mRNA. The clinicopathological variables were reviewed retrospectively. Results: The T/N ratios of HIF-1α mRNA showed significant correlation with lymph-node metastases, distant metastases, stage, and recurrence within 3 years (p＜0.05). The T/N ratios of VEGF mRNA showed significant correlation with lymph-node metastases and distant metastases (p＜0.05). There was a significant correlation between the T/N ratios of HIF-1α and VEGF mRNA (r=0.72, p＜0.01). Conclusions: The increased expression of HIF-1α and VEGF mRNA could reflect aggressive tumor behavior, including the recurrence of gastric cancer. Examination of HIF-1α mRNA in biopsy specimens by RT-PCR assay might provide useful preoperative information on tumor aggressiveness.
참고문헌 (36)
- Kuwai T, "Expression of hypoxia inducible factor 1alpha is associated with tumor vascularization in human colorectal carcinoma", Int J Cancer, 105, pp.176~181 (2003)
- Stoeltzing O, "Role of hypoxia-inducible factor 1alpha in gastric cancer cell growth,angiogenesis, and vessel maturation", J Natl Cancer Inst, 96, pp.946~956 (2004)
- Livingston DM, "Toward mechanism-based cancer care", JAMA, 285, pp.588~593 (2001)
- Takahashi R, "Hypoxia-inducible factor-1alpha expression and angiogenesis in gastrointestinal stromal tumor of the stomach", Oncol Rep, 10, pp.797~802 (2003)
- Talks KL, "The expression and distribution of the hypoxia-inducible factors HIF-1alpha and HIF-2alpha in normal human tissues, cancers, and tumor-associated macrophages", Am J Pathol, 157, pp.411~421 (2000)
- Yang-Sook Chun, "Oxygen-Dependent and -Independent Regulation of HIF-1alpha", Journal of Korean Medical Science, 17(5), pp.581~588 (2002), 대한의학회
- Shi YH, "Hypoxia-inducible factor-1 in tumor angiogenesis", World J Gastroenterol, 10, pp.1082~1087 (2004)
- Zhong H, "Increased expression of hypoxia inducible factor-1 alpha in rat and human prostate cancer", Cancer Res, 58, pp.5280~5284 (1998)
- Stroka DM, "HIF-1 is expressed in normoxic tissue and displays an organ-specific regulation under systemic hypoxia", FASEB J, 15, pp.2445~2453 (2001)
- Semenza G, "Signal transduction to hypoxia-inducible factor 1", Biochem Pharmacol, 64, pp.993~998 (2002)
- Chen WT, "Hypoxia-inducible factor-1alpha is associated with risk of aggressive behavior and tumor angiogenesis in gastrointestinal stromal tumor", Jpn J Clin Oncol, 35, pp.207~213 (2005)
- Mizokami K, "Clinicopathologic significance of hypoxia-inducible factor 1alpha overexpression in gastric carcinomas", J Surg Oncol, 94, pp.149~154 (2006)
- Yoshikawa T, "Up-regulation of hypoxia-inducible factor-1 alpha and VEGF mRNAs in peritoneal dissemination of patients with gastric cancer", Anticancer Research, 26, pp.3849~3854 (2004)
- Fukuda R, "Vascular endothelial growth factor gene expression in colon cancer cells exposed to prostaglandin E2 is mediated by hypoxia-inducible factor 1", Cancer Res, 63, pp.2330~2334 (2003)
- Koshikawa N, "Constitutive upregulation of hypoxia-inducible factor-1alpha mRNA occurring in highly metastatic lung carcinoma cells leads to vascular endothelial growth factor overexpression upon hypoxic exposure", Oncogene, 22, pp.6717~6724 (2003)
- Iyer NV, "Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1alpha", Genes Dev, 12, pp.149~162 (1998)
- Carmeliet P, "Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis", Nature, 394, pp.485~490 (1998)
- Reinmuth N, "Biology of angiogenesis in tumors of the gastrointestinal tract", Microsc Res Tech, 60, pp.199~207 (2003)
- Takahashi Y, "Expression of vascular endothelial growth factor and its receptor, KDR, correlates with vascularity, metastasis, and proliferation of human colon cancer", Cancer Res, 55, pp.3964~3968 (1995)
- Aoyagi K, "VEGF significance in peritoneal recurrence from gastric cancer", Gastric Cancer, 8, pp.155~163 (2005)
- Sumiyoshi Y, "Overexpression of hypoxia-inducible factor 1alpha and p53 is a marker for an unfavorable prognosis in gastric can", Clin Cancer Res, 12, pp.5112~5117 (2006)
- Urano N, "Overexpression of hypoxia- inducible factor-1alpha in gastric adenocarcinoma", Gastric Cancer, 9, pp.44~49 (2006)
- Griffiths EA, "Hypoxiainducible factor-1alpha expression in the gastric carcinogenesis sequence and its prognostic role in gastric and gastro- oesophageal adenocarcinomas", Br J Cancer, 96, pp.95~103 (2007)
- Giatromanolaki A, "Relation of hypoxia inducible factor 1alpha and 2alpha in operable non-small cell lung cancer to angiogenic", molecular profile of tumours and survival, 2001, pp.85, 881~890
- Zhong H, "Overexpression of hypoxia inducible factor 1alpha in common human cancers and their metastases", Cancer Res, 59, pp.5830~5835 (1999)
- Matsuyama T, "Expression of hypoxia-inducible factor-1alpha in esophageal squamous cell carcinoma", Cancer Sci, 96, pp.176~182 (2005)
- Kitadai Y, "Quantitative analysis of lymphangiogenic markers for predicting metastasis of human gastric carcinoma to lymph nodes", Int J Cancer, 115, pp.388~392 (2005)
- Mori M, "Detection of cancer micrometastases in lymph nodes by reverse transcriptasepolymerase chain reaction", Cancer Res, 55, pp.3417~3420 (1995)
- Mizukami Y, "Hypoxia-inducible factor-1-independent regulation of vascular endothelial growth factor by hypoxia in colon cancer", Cancer Res, 64, pp.1765~1772 (2004)
- Griffiths EA, "Is the hypoxia-inducible factor pathway important in gastric cancer?", Eur J Cancer, 41, pp.2792~2805 (2005)
- Krishnamachary B, "Regulation of colon carcinoma cell invasion by hypoxia-inducible factor 1", Cancer Res, 63, pp.1138~1143 (2003)
- Beasley NJ, "Hypoxia-inducible factors HIF-1alpha and HIF-2alpha in head and neck cancer: relationship to tumor biology and treatment outcome in surgically resected patients", Cancer Res, 62, pp.2493~2497 (2002)
- Hachisuka T, "High lymphatic vessel density correlates with overexpression of VEGF-C in gastric cancer", Oncol Rep, 13, pp.733~737 (2005)
- Onogawa S, "Expression of vascular endothelial growth factor (VEGF)-C and VEGF-D in early gastric carcinoma: correlation with clinicopathological parameters", Cancer Lett, 226, pp.85~90 (2005)
- Takahashi Y, "Significance of vessel count and vascular endothelial growth factor and its receptor (KDR) in intestinal-type gastric cancer", Clin Cancer Res, 2, pp.1679~1684 (1996)
- Soon-Sun Hong, "HIF-1alpha: a Valid Therapeutic Target for Tumor Therapy", Cancer Research and Treatment, 36(6), pp.343~353 (2004), 대한암학회