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Carcinogenesis文章:Krüppel样因子4表观修饰异常及其在肾细胞癌中抑癌基因功能

Krüppel样因子4 (Krüppel-like factor 4, KLF4)是多功能转录因子,其功能异常可见于多种恶性肿瘤疾病中,但在肾细胞癌中该转录因子表达及作用尚不清楚。来自华中科技大学同济医学院的研究者检测了KLF4在肾细胞癌中表观遗传学异常改变并确定了其在肿瘤发病中的作用。研究者检测了原发的肾细胞癌组织和配对正常组织中KLF4在mRNA和蛋白表达改变,同时采用甲基化特异性PCR和Sequenom MassARRAY技术检测甲基化修饰状态改变。采用卡普兰-梅耶生存曲线(Kaplan-Meier curve)和log-rank test进行生存分析。通过上调肾细胞癌细胞系中KLF4表达后评估KLF4对细胞生长和表皮-间质转移能力的影响。通过稳定转染KLF4的肾癌细胞的体内实验模型评估抗肿瘤活性。研究结果发现,相对于正常肾脏组织,不同病理类型的肾癌组织KLF4表达显著降低,这种表达降低与肾切除术后生存不良有关。体外实验表明,上调肾细胞癌细胞系中KLF4表达能够抑制肿瘤发生和肾癌转移。本项研究结果提示KLF4是一个肿瘤抑制基因,在肾细胞癌中通过该基因启动子区CpG高甲基化修饰造成的表观静息机制促进肿瘤发生,并且KLF4具有指示肾细胞癌进展的诊断价值。该研究已经发表在2013年Carcinogenesis杂志上。本研究中使用的Sequenom甲基化检测工作由博奥生物集团有限公司完成。


原文摘要:
Epigenetic alterations of Krüppel-like factor 4 and its tumor suppressor function in renal cell carcinoma
Krüppel-like factor 4 (KLF4) is a transcription factor that can have divergent functions in different malignancies. The expression and role of KLF4 in renal cell cancer remain unclear. The purpose of this study is to determine epigenetic alterations and possible roles of KLF4 in renal cell carcinoma. The KLF4 expression in primary renal cell cancer tissues and case-matched normal renal tissues was determined by protein and messenger RNA analyses. The epigenetic alterations were detected by methylation-specific PCR and Sequenom MassARRAY. Kaplan–Meier curves and the log-rank test were used for the survival analysis. The effects of KLF4 on cell growth and epithelial-to-mesenchymal transition (EMT) were determined in renal cancer cell lines after viral-based and RNA activation-mediated overexpression of KLF4. In vivo antitumor activity of KLF4 was evaluated by using stably KLF4-transfected renal cancer cells. KLF4 expression was dramatically decreased in various pathological types of renal cancer and associated with poor survival after nephrectomy. Hypermethylation of KLF4 promoter mainly contributed to its expression suppression. In vitro assays indicated that KLF4 overexpression inhibited renal cancer cell growth and survival. KLF4 overexpression also suppressed renal cancer cell migration and invasion by altering the EMT-related factors. In vivo assay showed that ectopic expression of KLF4 also inhibited tumorigenicity and metastasis of renal cancer. Our results suggest that KLF4 is a putative tumor suppressor gene epigenetically silenced in renal cell cancers by promoter CpG methylation and that it has prognostic value for renal cell progression.
 
原文出处:

http://carcin.oxfordjournals.org/content/early/2013/07/01/carcin.bgt189.abstract