Gustafsson Annika, Hansson Elisabeth, Kressner Ulf, Nordgren Svante, Andersson Marianne, Wang Wenhua, Lönnroth Christina, Lundholm Kent
Department of Surgery, Surgical Metabolic Research Laboratory at Lundberg Laboratory for Cancer Research, Sahlgrenska University Hospital, Göteborg University, Göteborg, Sweden.
Int J Cancer. 2007 Jul 15;121(2):232-40. doi: 10.1002/ijc.22582.
The importance of prostaglandins in tumor growth and progression is well recognized, including antineoplastic activities by cyclooxygenase (COX) inhibitors. Variation in treatment response to COX inhibition has questioned differences in expression of cell surface and nuclear membrane receptors among tumors with different disease progression. The purpose of this study was to evaluate whether EP(1-4) subtype, PPAR gamma receptor and COX-1/COX-2 expression in colorectal cancer are related to tumor-specific mortality. Reverse transcription-polymerase chain reaction and immunohistochemistry were used to demonstrate expression and protein appearance in tumor tissue compared with normal colon tissue. EP(1) and EP(2) subtype receptor protein was highly present in tumor cells, EP(3) occurred occasionally and EP(4) was not visible. PPAR gamma, EP(2) and EP(4) mRNA were significantly higher in normal colon tissue compared with tumor tissue, without any distinct relationship to Dukes A-D tumor stage. Multivariate analyses indicated that increased tumor tissue EP(2) and COX-2 expression predicted poor survival (p<0.001). COX-1 expression was significantly higher than COX-2 expression in normal colon tissue. Average COX-2 mRNA was not increased in tumor tissue compared with normal colon. However, most tumor cells stained positive for COX-2 protein, which was low or undetectable in normal mucosa cells. COX-1 protein was preferentially visible in stroma. EP(1-4) subtype receptor mRNAs were generally positively correlated to both COX-1 and COX-2 in tumor tissue, but not in normal colon. Our results imply that both prostaglandin production (COX-2) and signaling via EP(1-4) subtype receptors, particularly EP(2), predict disease-specific mortality in colorectal cancer.
前列腺素在肿瘤生长和进展中的重要性已得到充分认识，包括环氧合酶（COX）抑制剂的抗肿瘤活性。对COX抑制治疗反应的差异引发了对不同疾病进展肿瘤中细胞表面和核膜受体表达差异的质疑。本研究的目的是评估结直肠癌中EP（1 - 4）亚型、过氧化物酶体增殖物激活受体γ（PPARγ）受体以及COX - 1/COX - 2的表达是否与肿瘤特异性死亡率相关。与正常结肠组织相比，采用逆转录 - 聚合酶链反应和免疫组织化学方法来证明肿瘤组织中的表达和蛋白质出现情况。EP（1）和EP（2）亚型受体蛋白在肿瘤细胞中高度存在，EP（3）偶尔出现，而EP（4）不可见。与肿瘤组织相比，正常结肠组织中PPARγ、EP（2）和EP（4）的mRNA显著更高，与杜克A - D期肿瘤分期无明显关系。多变量分析表明，肿瘤组织中EP（2）和COX - 2表达增加预示着生存不良（p<0.001）。正常结肠组织中COX - 1的表达显著高于COX - 2的表达。与正常结肠相比，肿瘤组织中平均COX - 2 mRNA没有增加。然而，大多数肿瘤细胞COX - 2蛋白染色呈阳性，而在正常黏膜细胞中该蛋白含量低或无法检测到。COX - 1蛋白在基质中更易见。肿瘤组织中EP（1 - 4）亚型受体mRNA通常与COX - 1和COX - 2呈正相关，但在正常结肠中并非如此。我们的结果表明，前列腺素产生（COX - 2）以及通过EP（1 - 4）亚型受体，特别是EP（2）的信号传导，可预测结直肠癌的疾病特异性死亡率。
