Department of Biochemistry and Molecular Biology, Poznań University of Medical Sciences, Poznań, Poland.
Int J Oncol. 2012 Mar;40(3):860-6. doi: 10.3892/ijo.2011.1183. Epub 2011 Sep 1.
The development of cervical cancer requires genetic and epigenetic factors which result in the persistence of a malignant phenotype. Cervical cancer exhibits also some unique differences from other solid tumors. Normal cervical stratified epithelia have characteristics of hypoxic tissue with over-expression of HIF-1 (hypoxia-inducible factor-1) transcription factor, which targets the transcription of over 70 genes involved in many aspects of cancer biology. One of the genes, which could be induced by HIF-1 is chemokine (C-X-C motif) receptor 4 (CXCR4). CXCR4 could also be epigenetically regulated by methylation of CpG dinucleotides located in the promoter region. Here, we examined the CXCR4, DNMT3A, DNMT3B and DNMT1 transcript levels in cancer tissue (n=30) and non-cancer, normal uterine cervical tissue (n=30) from a Polish cohort. We also compared the methylation status of CXCR4 promoter region in cancer and normal tissue samples. Our result showed significantly higher levels of CXCR4, DNMT3A, DNMT3B and DNMT1 transcript (p=0.0058, 0.0163, 0.0003 and <0.0001, respectively) levels in cancer tissue as compared to normal samples. We did not observe DNA methylation in the CXCR4 promoter region in either control or cancer tissue samples. CXCR4 has a functional hypoxia response element (HRE) in the promoter region, located -1.3 kb from the transcription start site. Our work shows for the first time that HIF-1A could promote the induction of CXCR4 gene expression (Spearman's correlation coefficient = 0.515, p=0.003) in patients with primary advanced uterine cervical carcinoma.
宫颈癌的发展需要遗传和表观遗传因素，这些因素导致恶性表型的持续存在。宫颈癌也表现出一些与其他实体瘤不同的独特特征。正常宫颈分层上皮具有缺氧组织的特征，过度表达 HIF-1（缺氧诱导因子-1）转录因子，该因子靶向参与癌症生物学多个方面的 70 多个基因的转录。HIF-1 可以诱导的一个基因是趋化因子（C-X-C 基序）受体 4（CXCR4）。CXCR4 也可以通过位于启动子区域的 CpG 二核苷酸的甲基化进行表观遗传调控。在这里，我们检查了波兰队列中 30 例癌症组织和 30 例非癌症、正常子宫颈组织中的 CXCR4、DNMT3A、DNMT3B 和 DNMT1 转录本水平。我们还比较了癌症和正常组织样本中 CXCR4 启动子区域的甲基化状态。我们的结果显示，与正常样本相比，癌症组织中的 CXCR4、DNMT3A、DNMT3B 和 DNMT1 转录本水平显著升高（p=0.0058、0.0163、0.0003 和 <0.0001，分别）。我们没有观察到 CXCR4 启动子区域在对照或癌症组织样本中的 DNA 甲基化。CXCR4 在启动子区域有一个功能性缺氧反应元件（HRE），位于转录起始位点的-1.3 kb 处。我们的工作首次表明，HIF-1A 可以促进原发性晚期子宫颈癌患者 CXCR4 基因表达的诱导（Spearman 相关系数=0.515，p=0.003）。
