WEE1蛋白於台灣口腔鱗狀細胞癌之表現狀態與臨床病理指標之分析

Abstract

口腔癌占台灣十大癌症死因中第五位，特別在男性中為第四位，而當中超過九成的口腔癌為口腔鱗狀細胞癌。全球近年來研究發現口腔鱗狀細胞癌中，腫瘤抑制基因的突變機率高於致癌基因的活化性突變機率。已知TP53為口腔鱗狀細胞癌中最常突變之基因並且其亦為有力的G1細胞週期檢查點，因此當TP53產生突變而喪失正常功能時，細胞會代償性地更加依賴G2檢查點。WEE1蛋白即為一種G2檢查點調節蛋白，他可以磷酸化周期蛋白依賴性激酶1(CDK1) 酪氨酸15的位置 (tyrosine 15)，從而抑制其活性，使得細胞週期停止，無法繼續進入有絲分裂。本實驗之目的為釐清台灣口腔鱗狀細胞癌中WEE1蛋白之表現狀況及其與各癌症臨床病理表現之關聯，同時也比較與其受質磷酸化周期蛋白依賴性激酶1之間的相關性。選用從2006年至2010年共75例頭頸部鱗狀細胞癌中腫瘤及周圍非腫瘤的部分，並且使用WEE1及磷酸化周期蛋白依賴性激酶1免疫組織化學染色法，分析二者的表現，發現WEE1於腫瘤細胞中有減少的趨勢，而且與其受質磷酸化周期蛋白依賴性激酶1在分布的位置上大致吻合。經由統計結果分析發現，WEE1及磷酸化周期蛋白依賴性激酶1兩者間呈現中度正相關性，進一步比較與各個癌症臨床病理表現間的相關性發現，WEE1與腫瘤的復發呈現負相關而磷酸化周期蛋白依賴性激酶1則與腫瘤的大小以及臨床分期呈現負相關。在五年存活率的分析上，二者均無顯著的相關性存在，這顯示磷酸化周期蛋白依賴性激酶1的降低可能會造成腫瘤的進展，而失去WEE1的表現則有可能會促成癌症復發。合併這二者在口腔鱗狀細胞癌中的表現，未來有可能可以進一步發展成為臨床預後的指標。

An immunohistochemical study was conducted to investigate the expression of WEE1 and phosphorylated cyclin-dependent kinase 1 (CDK1) in oral squamous cell carcinomas (OSCC) in Taiwan. Seventy-five cases of OSCC were enrolled (67 males and 8 females). Age ranged from 23 to 82 years and the location of OSCC included tongue (n=27, 36%), buccal mucosa (n=23, 31%), gingiva (n=17, 23%), palate (n= 4, 5%), lip (n=2, 3%), floor of mouth (n=1, 1%) and alveolar mucosa (n=1, 1%). Normal-appearing tissue from adjacent, non-tumor area was harvested as the control group. We concluded that: (1) the mean labeling index of WEE1 in OSCC neoplastic cells was 22.5% and the median was 21 %. High expression of WEE1 (higher than 21% WEE1-positive cells) was observed in 38 out of 75 patients (50.67%) and low expression of WEE1 was observed in 37 out of 75 patients (49.33%). The mean and median labeling indices of WEE1 in normal epithelia were 37.97% and 35.5% respectively. (2) The mean labeling index of nuclear phosphorylated CDK1 was 11.1% and the median was 10%. High nuclear phosphorylated CDK1 was observed in 39 out of 75 patients (52%). (3) Statistically, the relation between WEE1 and phosphorylated CDK1 was a moderately positive correlation and also the immunostaining of phosphorylated CDK1 was also colocalized with that of WEE1 staining. In respect of clinical-pathological correlation, the WEE1 expression was significantly associated with the recurrence rate inversely. Decreased phosphorylated CDK1 expression was significantly associated with advanced T stage and clinical staging. In survival analysis, both WEE1 and phosphorylated CDK1 carried no significance to survival. To summarize, decreased phosphorylation of CDK1 may promote tumor progression and absence of WEE1 expression was associated with poor prognosis in OSCC. Therefore, combined WEE1 and phosphorylated CDK1 expression in OSCC could be a significant prognostic indicator. In the future, it merits further investigation of the potential molecular mechanism of WEE1 in OSCC.