探討WWOX於人類神經膠質瘤上的抑癌角色與臨床上預後因子變異分析

The role and the clinical implication of prognostic value of WWOX in human astrocytoma

蔡政宇(Cheng-Yu Tsai)

指導教授 ： 關皚麗

高雄醫學大學/醫學院/醫學研究所/碩士(2010年)

摘要

前言：
含雙色胺酸功能區氧化還原酶(WWOX)基因為在第十六對染色體上的16q23.3-24.1位置，而這個位置已經被確認為最容易引起基因脆裂的位置之一 (FRA16D)。而WWOX基因默化(gene silencing) 是經由同源對偶基因座的刪除以及基因啟動子的過度甲基化所造成，這樣的表現已經在許多不同種類的人類腫瘤上發現，例如：卵巢癌、前列腺癌、食道癌、肺癌、胰臟癌、胃癌以及肝癌，並且WWOX基因的默化與上列的人類腫瘤的侵犯性表現有著顯著的相關；然而WWOX基因對於人類神經膠質瘤之間的關係仍然是模糊不清的，因此本實驗的目的在於釐清WWOX基因於人類神經膠質瘤上的不活化機制以及這不活化的表現跟與臨床上預後因子之間的變異分析。
實驗方法：
我們收集了38位由高雄醫學大學附設中和醫院神經外科手術確定為神經膠質瘤的病人，使用回溯性方式來分析臨床上預測預後因子的分析。我們使用針對WWOX的多株抗體來測定WWOX蛋白於神經膠質瘤上的表現，並利用病理診斷上的強度與範圍來作為評分標準，之後再利用MSP 來測定WWOX啟動子的過度甲基化程度。

結果：
我們發現高度WWOX蛋白缺失的案例數有19位(50%，19/38)， 中度WWOX蛋白缺失的案例數有14位(36.8%，14/38)， 低度WWOX蛋白缺失的案例數有5位(13.2%，5/38)；WWOX啟動子的過度甲基化也顯著地呈現在部分案例上。然而我們發現WWOX蛋白質的表現並沒有與腫瘤惡性程度呈現相關性，而是在grade II的神經膠質瘤裡表現最明顯。
結論：
實驗結果顯示，WWOX基因默化確實在人類神經膠質瘤扮演相當重要的角色，並且WWOX基因默化程度與年齡、腫瘤位置、存活時間有緊密的正相關，但對於神經膠質瘤的惡性程度的相關性則非成正性相關而是推測屬於早期癌化的致病機轉。

關鍵字

雙色胺酸功能區氧化還原酶基因默化 ； 神經膠質瘤

並列摘要

Introduction：
WW domain-containing oxidoreductase (WWOX ) gene, located on chromosome 16q23.3-24.1, in the region recognized as the second common fragile site, FRA16D. WWOX silencing via homozygous deletion of its locus and/or promoter hypermethylaiton is observed in several human cancer types such as ovarian, prostate, esophageal, lung, pancreatic, gastric and hepatic carcinomas and correlates with aggressive phenotypes. However, in CNS tumor the relationship with WWOX is still unclear. The purpose of this study was tried to elucidate the frequencies of the various inactivating mechanisms of WWOX in astrocytoma and correlated its inactivation with important clinicopathological variables.
Materials and Methods：
In the present study, 38 patients with astrocytoma were retrospectively analysed. These 38 patients were received operation in Division of neurosurgery, Kaohsiung Medical University Hospital and diagnosed as astrocytoma. Immunohistochemically, a polyclonal antibody to WWOX was utilized and the level of WWOX protein expression was analysed by using a combined score system based on intensity and extent of immunoreactive tumor cells.
Results：
Highly WWOX protein reduced expression was observed in 19 cases (50%), moderately reduced was 14 cases (36.8%), without loss was 5 cases (13.2%). Furthermore, WWOX hyper-methylation status was significantly higher in our cases. However we found no association between loss of WWOX expression and tumor grade. Furthermore, we found loss of WWOX expression in grade II astrocytoma
Conclusion：
These results indicated that the WWOX gene inactivation is closely relevant to patient’s age, tumor locations and the progression of CNS tumors. Also we suggest that loss of WWOX expression is an early event in the pathogenesis of human astrocytoma.

並列關鍵字

WWOX ； gene silencing ； astrocytoma

參考文獻

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