Abstract
摘要:約百分之五十的原發性腦瘤是源自神經膠細胞,為稱神經膠瘤。依據世界衛生組織的分類,此腫瘤可分為高惡度神經膠瘤與低惡度神經膠瘤,其中,高惡度神經膠瘤佔所有顱內腫瘤的40%以上。縱使,近年來成功地以多重處理與多重治療模式針對腦瘤進行治療,然而,惡性神經膠瘤病患的存活期仍相當有限,癌症分期制度依舊是目前預測惡性神經膠瘤病患預後的主要方式。最近,由於病患對於放射系治療與烷基化療藥物產生抗性,使得神經膠瘤病患的預後不佳。微型核醣核酸(microRNA)是一種長度約18-25 核苷酸的內生性核醣核酸,它可以透過轉錄後機制抑制數以百計下游基因的蛋白質表現。最近研究顯示,微型核醣核酸的異常表現與許多種的癌症的某些特徵有關連性,如癌症轉移、癌症生成、分化程度、抗藥性與病人的存活率,顯示微型核醣核酸可以扮演致癌基因或是癌症抑制基因,其表現在癌症的發生及進程上扮演重要的角色。微型核醣核酸的表現可以提供一個更準確的方法作為癌症的分類、預測病患的預後和預測病患的治療療效。在先前的研究中,我們發現微型核醣核酸-328 與高惡度神經膠瘤(GBM)存活率的延長有顯著相關。因為惡性神經膠瘤在分子層次上存在相當的異質性,但是微型核醣核酸-328 是否可以預測除了惡性神經膠瘤以外的其他腦癌的存活率。在這次的計畫中,我們將全面性的研究微型核醣核酸-328 在腦癌上的功能與臨床應用。我們探討微型核醣核酸-328 是否可以作為其不同他種腦癌的預後標記,同時研究微型核醣核酸-328 之所以影響癌細胞轉移、癌症生成與抗藥性的分子訊息路徑。在這個三年計畫中,我們提出六個研究目標,1. 評估微型核醣核酸-328 對不同種類的腦癌的影響。2. 尋找在神經膠瘤中的微型核醣核酸-328 的標的基因。3. 於體外及活體研究方法探討微型核醣核酸-328 對於神經膠瘤各項腫瘤性狀的影響。4. 剖析微型核醣核酸-328 之所以影響神經膠瘤腫瘤性狀的分子訊息路徑。5. 建立活體異種原位老鼠模式用以評估神經膠瘤的侵襲性。6. 探索微型核醣核酸-328 的上游調控機制。經過我們這些努力,我們預期可以找到微型核醣核酸-328 的標的基因以及微型核醣核酸-328 負責腦癌進程與抗藥性的訊息路徑。這些發現或許將來有機會發展出腦癌預後標記與新的治療方式。
Abstract: Approximately 50% primary brain tumors arise from glial cells, which are named asgliomas. Gliomas are categorizes by the World Health Organization (WHO) as eitherlow-grade or high-grade. High-grade glioma (HGG) comprises more than 40% of allintracranial tumors. Despite recent successes in the treatment of cancer withmultidisciplinary multimodal treatment approaches, the duration of survival for patientswith malignant glioma remains limited. The most important determinant of prognosis inmalignant glioma is largely its grading. Recently, undesirable prognosis for patients withmalignant glioma has been attributed to resistance to radiotherapy and alkylatingchemotherapeutic agents. MicroRNAs are endogenous small non-protein-coding RNAs(18-25 nucleotides) that conduct the post-transcriptional repression of hundreds of theirtarget proteins. Recent evidence has shown that deregulation of microRNAs correlates withcertain features of diverse cancers (such as metastasis、tumorigenesis、differentiation status,drug resistance and outcome of tumor patients) and indicates that microRNAs can act asoncogenes or tumor suppressors and alterations in microRNA expression may play a criticalrole in the cancer initiation and progression. The expression level of microRNAs canprovide a more accurate method for classifying cancer subtype, predicting patients’outcome and predicting therapeutic efficacy. In our previous study, we found thatmicroRNA-328 (miR-328) is correlated with prolonged survival of glioblastomamultiforme (GBM). Because malignant glioma is molecularly heterogeneous, it is unclearwhether miR-328 can predict patients’ survival of brain tumors other than GBM. In thisproject, we will comprehensively study the functions and clinical applications of miR-328in brain tumor. We will explore whether the prognostic activity of miR-328 can extent toother types of brain tumors and investigate miR-328 mediated molecular signalingpathways involved in metastasis, tumorigenesis and drug resistance in brain tumors. Wepropose six specific aims in this three-year proposal, 1. surveying the impact of miR-328 ondifferent kinds of brain tumors, 2. identification of miR-328 targets in gliomas, 3.characterizing the functions of miR-328 on cancerous phenotypes of gliomas in vitro and invivo, 4. elucidating miR-328 mediated signaling pathways involved in glioma progression,5. establishing an in vivo orthotopic xenograft mouse model for evaluating glioma invasionand 6. exploring the upstream regulation of miR-328. Through our efforts, we anticipatethat we can identify miR-328 targets and miR-328 mediated signaling pathways responsiblefor progression and drug resistance of brain tumors. These findings might develop aprognostic marker and new therapeutic strategies for the treatment of this devastatingdisease in the future.
Keyword(s)
微型核醣核酸-328
預後標記
抗藥性
微型核醣核酸標的基因
miR-328
prognosis marker
drug resistance
microRNA target