Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/92206
標題: 缺氧誘導因子 HIF2α 藉轉錄調控因子 Bmi1 路徑 促進鼠腦中多形性神經膠質瘤細胞生長
HIF2α promotes Glioblastoma Multiforme tumor development in mouse brain via direct regulation of Bmi1 expression
作者: 陳建彰
Chien-Chang Chen
關鍵字: 無;no
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摘要: 
在各種腦瘤當中,多形性神經膠質母細胞瘤(Glioblastoma multiforme, GBM)是最惡性的腦部腫瘤,大多數患者存活時間短於兩年。多形性神經膠質母細胞瘤的特徵包含腫瘤細胞具高度侵蝕性、血管新生、腫瘤組織內部壞死及缺氧等現象。就細胞生理而言,缺氧狀態可啟動細胞內的缺氧誘導因子(Hypoxia inducible factors,HIFs)以調控缺氧反應基因表現。先前研究指出 HIF1α 缺氧誘導因子在 GBM 患者檢體中穩定作用並影響腫瘤轉移,而 HIF2α 缺氧誘導因子和多種缺氧反應基因也被發現在膠質瘤腫瘤幹細胞中表現 此點顯示 HIF2α 缺氧誘導因子對 GBM 腫瘤的,發展可能扮演十分重要的角色。藉由基因轉染實驗可觀察到表現 HIF2α 的 GBM 細胞外觀明顯改變,實驗也證明 HIF2α 和 Bmi1 基因存在直接的作用關係,即 Bmi1基因是受 HIF2α 控制的缺氧反應基因。實驗結果中可發現 HIF2 直接結合至 Bmi1基因並調控基因表現,而表現 HIF2α 的 GBM 細胞會有較強的細胞移動能力、生長速度及腫瘤幹細胞的特性 動物實驗中也有發現移植表現 HIF2α 的 GBM 細胞後,個體存活率較差,生成的腫瘤體積和腫瘤侵蝕範圍也有明顯增加。在臨床檢體中也發現有約 40%病人同時高表現 HIF2α 和 BMI1 蛋白 統計分析結果也說明 HIF2α和 BMI1 蛋白在臨床上對 GBM 腫瘤的發展具高度相關。在本研究中發現 Bmi1 基因受 HIF2 調控表現,為缺氧反應基因其中一員。HIF2 缺氧誘導因子調控 Bmi1 基因表現而增進腫瘤細胞 EMT(epithelial-mesenchymal transition)現象,維持腫瘤幹細胞的特性並增進腫瘤生長,此點可導致 GBM 患者預後狀況較差。

Glioblastoma multiforme (GBM) is the most malignancy in brain tumors with the GBM characteristic of intratumoral hypoxia. The hypoxia condition can stabilize hypoxia inducible factors (HIFs) to activate hypoxic responsive genes expression to induce epithelial-mesenchymal transition (EMT) and maintain tumor cells stemness.Previous studies indicated that HIF1α was stable in GBM samples and regulate tumor metastasis. HIF2α and multiple hypoxia responsive genes were found to be expressed in glioma stem cells (GCGs). Role of HIF2α may be also important in GBM tumor progression.From the result of EPAS1 gene transfection experiment, HIF2α-overexpessed GBM cells showed the alteration of phenotype. A direct HIF2α and Bmi1 interaction was found from immunoblotting experiment and was further proved by luciferase reporter assay and immunoprecipitation assay. We observed that HIF2 protein directly bound to Bmi1 promoter and regulated Bmi1 gene expression. The interaction between HIF2 protein and Bmi1 gene expression provide the evidence that Bmi1 gene is also one of hypoxia responsive genes. Wound healing assay showed that HIF2α-overexpressed GBM cells could increase the migration ability in vitro. An extended tumor growth of HIF2α-overexpressed GBM cells can be observed from in vivo study. HIF2α and BMI1 over-expressed phenomena can also be found in clinical GBM patients. Therefore, the results of this project clearly showed that the role of HIF2α in Bmi1 direct gene regulation and promotion of GBM tumor progression
URI: http://hdl.handle.net/11455/92206
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