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題 名 | Deregulation of p53 and RB Transcriptional Control Leads to Overexpression of DNA Methyltransferases in Lung Cancer=p53及RB異常轉錄調控導致DNA甲基轉移酵素過度表現 |
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作 者 | 湯硯安; 蔡侑庭; 林若凱; 許瀚水; 陳志毅; 王憶卿; | 書刊名 | 臺灣癌症醫學雜誌 |
卷 期 | 1:1 2014.06[民103.06] |
頁 次 | 頁14-27 |
分類號 | 415.138 |
關鍵詞 | DNA甲基轉移酵素; 轉錄調控; 肺癌; DNMT; p53; RB; Transcription; Lung cancer; |
語 文 | 英文(English) |
中文摘要 | 背景:抑癌基因的啟動子被過度甲基化時,會導致基因不表達進而使腫瘤生成;此甲基 化現象主要是由 DNA 甲基轉移酵素(DNA methyltransferases,DNMTs)所調控,DNMTs 主要有 DNMT1、DNMT3A 以及 DNMT3B,文獻指出,在很多癌症中發現 DNMTs 有過 度表達的情形,然而造成此現象的詳細機制仍不清楚。 目的:文獻顯示 p53 及 RB 抑癌蛋白可以負調控許多基因表現,其上游蛋白 MDM2 則可 抑制 p53 及 RB 蛋白表現,因此本篇研究以肺癌細胞及臨床模式探討 p53/RB/MDM2 調控 路徑參與 DNMT 其轉錄調控異常之機制。 方法:在細胞層次上,由報導基因冷光酵素活性分析(luciferase assay)與染色質免疫沈 澱(chromatin immunoprecipitation)觀察抑癌蛋白 p53 及 RB 是否對 DNMTs 扮演負轉 錄調控因子的角色。在臨床研究上,以免疫組織染色法(immunohistochemistry)及 DNA 定序分析非小細胞肺癌病人組織中 DNMT 與 RB 蛋白及 p53 突變之相關性。 結果:在癌細胞株中大量表現 p53 及 RB 後,會抑制 DNMT1 及 DNMT3A 啟動子的活性 及 mRNA 表現量;以 siRNA 降低 p53 及 RB 的表現量後,DNMT1 及 DNMT 3A 啟動子的 活性及 mRNA 表現量上升,顯示 p53 及 RB 的確能負轉錄調控 DNMT3A 的基因表現。在 臨床研究上,以免疫組織染色法及 DNA 定序分析 100 位非小細胞肺癌病人組織,發現 DNMT1、DNMT3A 及 DNMT3B 蛋白過度表現且 RB 蛋白低表現或 p53 突變有顯著負相關 性(P 值為 0.016~0.024),且其抑癌基因多為啟動子過度甲基化;此外,病人存活率分析 資料指出:DNMT3A、RB 與 MDM2 蛋白皆正常表現的病人,與其他病人相較,有較好的 預後(P 值為 0.049)。 結論: 由以上細胞及臨床模式實驗結果顯示,p53 及 RB 蛋白會負轉錄調控 DNMT 的啟動 子,進而降低 DNMT 的 mRNA 及蛋白質表現,但此 p53 及 RB 轉錄負調控 DNMT 的作用 可被 MDM2 蛋白所拮抗。臨床資料顯示 DNMT3A、RB 與 MDM2 蛋白的表現程度可做為 肺癌病人預後的指標。 |
英文摘要 | Background: Overexpression of DNA 5’-cytosine-methyltransferases (DNMTs), which silence genes including tumor suppressor genes, is involved in many cancers. However, the mechanism of DNMT overexpression remains mostly unclear. Objectives: The tumor suppressor p53 and RB proteins, which repress gene transcription, are often inactivated by gene mutation or overexpression of the E3 ubiquitin ligase MDM2 in cancer cells. Therefore, this study aims to examine whether the transcriptional regulation of DNMT1, 3A and 3B genes is controlled by p53/RB/MDM2 pathway in lung cancer using cell and clinical studies. Methods: The interaction and regulation between p53 or RB with DNMT1, 3A and 3B promoters were detected by promoter activity assay and chromatin immunoprecipitation. Transcriptional repression of DNMT1, 3A and 3B by p53 and RB was confirmed using siRNA-mediated knockdown or overexpression of p53/RB. Immunohistochemistry for p53, RB, MDM2, and DNMTs protein expression and DNA sequencing for p53 mutation were performed on tumor tissues from lung cancer patients. Results: p53 and RB suppressed the promoter activity and mRNA/protein expression of DNMT1, 3A and 3B through binding to their promoter. The suppression could be attenuated by knocking down of RB and p53. Importantly, co-transfection of both p53 and RB expression constructs showed additional inhibition of DNMT protein expression. In clinical study, functional RB and p53 inversely correlated with DNMT1, 3A and 3B expressions in samples from lung cancer patients (P=0.016~0.024). Lung cancer patients with low RB expression or p53 mutation resulting in DNMTs overexpression showed promoter hypermethylation in multiple tumor suppressor genes. Patients with normal expression of DNMT3A, RB and MDM2 was associated with better prognosis compared to other patients (P=0.049). Conclusions: This study provides cell and clinical evidence that p53 and RB pathways transcriptionally repress DNMT expression. Normal expression of DNMT3A, RB and MDM2 proteins can be a biomarker for good prognosis in lung cancer. |
本系統中英文摘要資訊取自各篇刊載內容。