Breast Cancer Res 2011 ;13 (2): R26. [IF:5.785]
Pro-oncogene Pokemon promotes breast cancer progression by upregulating survivin expression.
Zu X , Ma J , Liu H , Liu F , Tan C , Yu L , Wang J , Xie Z , Cao D , Jiang Y .
Guangdong Provincial Key Laboratory of Chemical Biology, Graduate School at Shenzhen, Tsinghua University, Lishui Road, Shenzhen 518055, People's Republic of China. jiangyy@sz.tsinghua.edu.cn.
清华大学，广东省化学生物学重点实验室，深圳研究生院
Abstract
Pokemon is an oncogenic transcription factor involved in cell growth, differentiation and oncogenesis, but little is known about its role in human breast cancer. In this study, we aimed to reveal the role of Pokemon in breast cancer progression and patient survival and to understand its underlying mechanisms. Tissue microarray analysis of breast cancer tissues from patients with complete clinicopathological data and more than 20 years of follow-up were used to evaluate Pokemon expression and its correlation with the progression and prognosis of the disease. DNA microarray analysis of MCF-7 cells that overexpress Pokemon was used to identify Pokemon target genes. Chromatin immunoprecipitation (ChIP) and site-directed mutagenesis were utilized to determine how Pokemon regulates survivin expression, a target gene. Pokemon was found to be overexpressed in 158 (86.8%) of 182 breast cancer tissues, and its expression was correlated with tumor size (P = 0.0148) and lymph node metastasis (P = 0.0014). Pokemon expression led to worse overall (n = 175, P = 0.01) and disease-related (n = 79, P = 0.0134) patient survival. DNA microarray analyses revealed that in MCF-7 breast cancer cells, Pokemon regulates the expression of at least 121 genes involved in several signaling and metabolic pathways, including anti-apoptotic survivin. In clinical specimens, Pokemon and survivin expression were highly correlated (n = 49, r = 0.6799, P < 0.0001). ChIP and site-directed mutagenesis indicated that Pokemon induces survivin expression by binding to the GT boxes in its promoter. Pokemon promotes breast cancer progression by upregulating survivin expression and thus may be a potential target for the treatment of this malignancy.
摘要：
引言：Pokemon是一个与细胞生长、分化及肿瘤发生相关的致癌性转录因子，而大家对它在人类乳腺癌中所起的作用却知之甚少。因此，本项研究致力于揭示其对乳腺癌进展及患者生存情况的影响，也希望洞悉其潜在机制。
方法：运用组织微阵列法分析具有完整临床病理资料的乳腺癌患者的癌组织，结合20多年的随访数据评估Pokemon的表达水平及其与乳腺癌的进展和预后的关系。使用DNA微阵列法分析高表达Pokemon的MCF-7细胞，以此鉴定Pokemon的靶基因。应用染色质免疫沉淀法（ChIP）和定点突变技术来展示Pokemon对其靶基因——生存素基因的调控作用。
结果：在182例乳腺癌组织中，有158例组织中的Pokemon出现高表达，即86.8%的乳腺癌组织中Pokemon高表达。并且，其表达水平与肿瘤的大小和淋巴侵袭密切相关。Pokemon的表达致使患者总体生存状况及疾病关联生存状况变得更差。对MCF-7乳腺癌细胞进行DNA微阵列分析发现Pokemon至少调控121个基因的表达，涉及多条信号转导和代谢通路，其中就包括生存素这种凋亡抑制基因。临床样本分析结果显示：Pokemon的表达水平与生存素基因的表达水平高度相关。染色质免疫沉淀和定点突变实验提示：Pokemon是通过与生存素基因启动子区的GT盒结合来诱导其表达的。
结论：Pokemon通过上调生存素基因的表达水平使乳腺癌进展加速，因而Pokemon可能成为治疗这种恶性肿瘤的一个潜在靶点。
