Heparanase is involved in angiogenesis in esophageal cancer through induction of cyclooxygenase-2

Takaomi Okawa, Yoshio Naomoto, Tetsuji Nobuhisa, Munenori Takaoka, Takayuki Motoki, Yasuhiro Shirakawa, Tomoki Yamatsuji, Hiroyasu Inoue, Mamoru Ouchida, Mehmet Gunduz, Motowo Nakajima, Noriaki Tanaka

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Abstract

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 c DNA was transduced and the deletion/mutation of three transcription factor (cyclic AMP response element, nuclear factor-κB, 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.

Original languageEnglish
Pages (from-to)7995-8005
Number of pages11
JournalClinical Cancer Research
Volume11
Issue number22
DOIs
Publication statusPublished - Nov 15 2005

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Okawa, T., Naomoto, Y., Nobuhisa, T., Takaoka, M., Motoki, T., Shirakawa, Y., Yamatsuji, T., Inoue, H., Ouchida, M., Gunduz, M., Nakajima, M., & Tanaka, N. (2005). Heparanase is involved in angiogenesis in esophageal cancer through induction of cyclooxygenase-2. Clinical Cancer Research, 11(22), 7995-8005. https://doi.org/10.1158/1078-0432.CCR-05-1103