Okawa Takaomi, Naomoto Yoshio, Nobuhisa Tetsuji, Takaoka Munenori, Motoki Takayuki, Shirakawa Yasuhiro, Yamatsuji Tomoki, Inoue Hiroyasu, Ouchida Mamoru, Gunduz Mehmet, Nakajima Motowo, Tanaka Noriaki
Department of Gastroenterological Surgery, Transplant, and Surgical Oncology, Okayama University, Okayama, Japan.
Clin Cancer Res. 2005 Nov 15;11(22):7995-8005. doi: 10.1158/1078-0432.CCR-05-1103.
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.
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.
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-kappaB, and nuclear factor-interleukin-6) binding elements in COX-2 promoter strongly suppressed its activity.
Our results suggest that heparanase may play a novel role for COX-2-mediated tumor angiogenesis.
乙酰肝素酶和环氧化酶-2（COX-2）均被认为在肿瘤恶性进展（包括血管生成）中发挥关键作用，尽管它们在癌症进展过程中的相互关系尚不清楚。我们推测它们可能在肿瘤血管生成方面相互关联。
通过免疫组织化学评估77例原发性人类食管癌组织中乙酰肝素酶和COX-2的表达，对其临床病理特征、微血管密度及这些临床病例的生存率之间的相关性进行统计分析。用乙酰肝素酶cDNA转导人食管癌细胞，并用于逆转录聚合酶链反应和蛋白质印迹法，以确定乙酰肝素酶和COX-2的表达。COX-2启动子载体及其缺失/突变构建体也与乙酰肝素酶cDNA转导一起用于荧光素酶测定。
乙酰肝素酶和COX-2蛋白表达在食管肿瘤组织中呈现相似模式，且它们的表达与肿瘤恶性程度及不良生存率相关。它们的表达还与肿瘤内微血管密度高显著相关。在用乙酰肝素酶cDNA转染的食管癌细胞中观察到COX-2信使核糖核酸和蛋白的上调。乙酰肝素酶cDNA转导后COX-2启动子被激活，且COX-2启动子中三个转录因子（环磷酸腺苷反应元件、核因子κB和核因子白细胞介素-6）结合元件的缺失/突变强烈抑制了其活性。
我们的结果表明，乙酰肝素酶可能在COX-2介导的肿瘤血管生成中发挥新作用。
