Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, Sahlgrenska University Hospital, Gothenburg, Sweden.
BMC Cancer. 2011 Jun 13;11:238. doi: 10.1186/1471-2407-11-238.
Increased cyclooxygenase activity promotes progression of colorectal cancer, but the mechanisms behind COX-2 induction remain elusive. This study was therefore aimed to define external cell signaling and transcription factors relating to high COX-2 expression in colon cancer tissue.
Tumor and normal colon tissue were collected at primary curative operation in 48 unselected patients. COX-2 expression in tumor and normal colon tissue was quantified including microarray analyses on tumor mRNA accounting for high and low tumor COX-2 expression. Cross hybridization was performed between tumor and normal colon tissue. Methylation status of up-stream COX-2 promoter region was evaluated.
Tumors with high COX-2 expression displayed large differences in gene expression compared to normal colon. Numerous genes with altered expression appeared in tumors of high COX-2 expression compared to tumors of low COX-2. COX-2 expression in normal colon was increased in patients with tumors of high COX-2 compared to normal colon from patients with tumors of low COX-2. IL1β, IL6 and iNOS transcripts were up-regulated among external cell signaling factors; nine transcription factors (ATF3, C/EBP, c-Fos, Fos-B, JDP2, JunB, c-Maf, NF-κB, TCF4) showed increased expression and 5 (AP-2, CBP, Elk-1, p53, PEA3) were decreased in tumors with high COX-2. The promoter region of COX-2 gene did not show consistent methylation in tumor or normal colon tissue.
Transcription and external cell signaling factors are altered as covariates to COX-2 expression in colon cancer tissue, but DNA methylation of the COX-2 promoter region was not a significant factor behind COX-2 expression in tumor and normal colon tissue.
环氧化酶活性的增加促进结直肠癌的进展，但 COX-2 诱导的机制仍不清楚。因此，本研究旨在确定与结肠癌组织中 COX-2 高表达相关的外部细胞信号和转录因子。
在 48 例未经选择的患者的初次根治性手术中收集肿瘤和正常结肠组织。对肿瘤和正常结肠组织中的 COX-2 表达进行定量分析，包括对肿瘤 mRNA 的微阵列分析，以评估肿瘤 COX-2 表达的高低。对肿瘤和正常结肠组织进行杂交。评估 COX-2 启动子区上游的甲基化状态。
与正常结肠相比，COX-2 高表达的肿瘤显示出基因表达的巨大差异。与 COX-2 低表达的肿瘤相比，高 COX-2 表达的肿瘤中出现了许多表达改变的基因。与 COX-2 低表达的肿瘤相比，高 COX-2 表达的肿瘤中的正常结肠 COX-2 表达增加。IL1β、IL6 和 iNOS 转录本在外源细胞信号因子中上调；9 种转录因子（ATF3、C/EBP、c-Fos、Fos-B、JDP2、JunB、c-Maf、NF-κB、TCF4）表达增加，5 种（AP-2、CBP、Elk-1、p53、PEA3）表达减少在高 COX-2 肿瘤中。COX-2 基因启动子区在肿瘤或正常结肠组织中未显示一致的甲基化。
转录和外部细胞信号因子作为结直肠癌组织中 COX-2 表达的协变量发生改变，但 COX-2 启动子区的 DNA 甲基化不是肿瘤和正常结肠组织中 COX-2 表达的重要因素。
