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Heparanase Is Involved in Angiogenesis in Esophageal Cancer through Induction of Cyclooxygenase-2

Authors' Affiliations: Departments of ¹ Gastroenterological Surgery, Transplant, and Surgical Oncology, ² Molecular Genetics, and ³ Oral Pathology and Medicine, Graduate School of Medicine and Dentistry, Okayama University, Okayama, Japan; ⁴ National Cardiovascular Center Research Institute, Osaka, Japan; and ⁵ Novartis Pharma Tsukuba Institute, Tsukuba, Japan

Requests for reprints: Yoshio Naomoto, Department of Gastroenterological Surgery, Transplant, and Surgical Oncology, Graduate School of Medicine and Dentistry, Okayama University, 2-5-1 Shikatacho, Okayama 700-8558, Japan. Phone: 81-86-235-7257; Fax: 81-86-221-8775; E-mail: ynaomoto{at}md.okayama-u.ac.jp.

Purpose: Both heparanase and cyclooxygenase-2 (COX-2) are thought to play critical roles for tumor malignancy, including angiogenesis, although it is unknown about their relationship with each other in cancer progression. We hypothesized that they may link to each other on tumor angiogenesis.

Experimental Design: The expressions of heparanase and COX-2 in 77 primary human esophageal cancer tissues were assessed by immunohistochemistry to do statistical analysis for the correlation between their clinicopathologic features, microvessel density, and survival of those clinical cases. Human esophageal cancer cells were transduced with heparanase cDNA and used for reverse transcription-PCR and Western blot to determine the expression of heparanase and COX-2. COX-2 promoter vector and its deletion/mutation constructs were also used along with transduction of heparanase cDNA for luciferase assay.

Results: Heparanase and COX-2 protein expression exhibited a similar pattern in esophageal tumor tissues, and their expression correlated with tumor malignancy and poor survival. Their expression also revealed a significant correlation with high intratumoral microvessel density. Up-regulation of COX-2 mRNA and protein was observed in esophageal cancer cells transfected with heparanase cDNA. COX-2 promoter was activated after heparanase cDNA was transduced and the deletion/mutation of three transcription factor (cyclic AMP response element, nuclear factor-B, and nuclear factor-interleukin-6) binding elements in COX-2 promoter strongly suppressed its activity.

Conclusion: Our results suggest that heparanase may play a novel role for COX-2-mediated tumor angiogenesis.

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