臺灣博碩士論文加值系統

本研究利用鏈黴菌卵白素-生物素免疫組織化學染色法，探討細胞凋亡相關蛋白BCL-2、BCL-XL、MCL-1、BAX、BAK 和P53於69例口腔鱗狀細胞癌（OSCC，實驗組），26例上皮過度角化、43例上皮變異（疾病對照組），及16例正常口腔黏膜（正常對照組）的表現。同時分析這些細胞凋亡相關蛋白於口腔鱗狀細胞癌中的表現和口腔鱗狀細胞癌患者臨床病理參數和預後之相關性。
BCL-2在正常口腔黏膜、上皮過度角化、上皮變異和口腔鱗狀細胞癌標本中之陽性染色率，分別為0.0%、0.0%、20.9% 和4.4%。上皮變異之BCL-2表現率較上皮過度角化之BCL-2表現率為高（p<0.05, odds ratio=16.6）；鱗狀細胞癌之BCL-2表現率較上皮變異之BCL-2表現率為低（p<0.05, odds ratio=0.172）。BCL-2於OSCC的表現與患者之每日飲酒量有顯著相關（p=0.0307）。
BCL-XL在正常口腔黏膜、上皮過度角化、上皮變異和口腔鱗狀細胞癌標本中之陽性染色率，分別為43.8%、30.8%、74.4% 和21.7%。上皮變異之BCL-XL表現率較正常口腔黏膜之BCL-XL表現率為高（p<0.05, odds ratio=3.74）、也較上皮過度角化之BCL-XL表現率為高（p<0.05, odds ratio=6.545）、鱗狀細胞癌之BCL-XL表現率較上皮變異之BCL-XL表現率為低（p<0.05, odds ratio=0.095）。BCL-XL於OSCC之表現和臨床分期（p=0.0098）及每日吸菸量（p=0.0359）有顯著相關。臨床分期第三期及第四期口腔癌患者之BCL-XL陽性染色勝算比（odds ratio = 0.093）約減少為第一期及第二期口腔癌患者的十分之一倍；每日多吸一包菸，BCL-XL的陽性染色勝算比約減少為0.18倍。
MCL-1在正常口腔黏膜、上皮過度角化、上皮變異和口腔鱗狀細胞癌標本中之陽性染色率，分別為81.2%、100.0%、95.3%和68.1%。上皮過度角化之MCL-1表現率較正常口腔黏膜之MCL-1表現率為高（p<0.05, odds ratio=13.74）、鱗狀細胞癌之MCL-1表現率較上皮過度角化之MCL-1表現率為低（p<0.05, odds ratio=0.0）、也較上皮變異之MCL-1表現率為低（p<0.05, odds ratio=0.10）。MCL-1於OSCC之表現與腫瘤大小、局部淋巴結狀況、嚼檳榔總時間有顯著相關（p<0.05）。T3及T4患者其MCL-1呈陽性染色之勝算比約增加為T1及T2患者的42.6倍（odds ratio = 42.646）。有局部淋巴結轉移患者其MCL-1的陽性染色勝算比約減少為無局部淋巴結轉移患者的0.07倍（odds ratio = 0.066）。每多嚼一年的檳榔，MCL-1的陽性染色勝算比約增加為1.1倍（odds ratio =1.135）。
BAX在正常口腔黏膜、上皮過度角化、上皮變異和口腔鱗狀細胞癌標本中之陽性染色率，分別為43.8%、69.2%、86.0%和87.0%。上皮變異之BAX表現率較正常口腔黏膜之BAX表現率為高（p<0.05, odds ratio=7.92）、鱗狀細胞癌之BAX表現率也較正常口腔黏膜之BAX表現率為高（p<0.05, odds ratio=8.57）。BAX於OSCC的表現與臨床病理參數之間均無統計學上有意義的相關。
BAK在正常口腔黏膜、上皮過度角化、上皮變異和口腔鱗狀細胞癌標本中之陽性染色率，分別為75.0%、100.0%、97.7% 和97.1%。上皮過度角化之BAK表現率較正常口腔黏膜之BAK表現率為高（p<0.05, odds ratio=19.08）、上皮變異之BAK表現率較正常口腔黏膜之BAK表現率為高（p<0.05, odds ratio=14.0）、鱗狀細胞癌之BAK表現率也較正常口腔黏膜之BAK表現率為高（p<0.05, odds ratio=11.2）。BAK於OSCC的表現與臨床病理參數之間均無統計學上有意義的相關。
P53在正常口腔黏膜、上皮過度角化、上皮變異和口腔鱗狀細胞癌標本中之陽性染色率，分別為12.5%、0.0%、16.3% 和33.3%。鱗狀細胞癌之P53表現率較正常口腔黏膜之P53表現率為高（p<0.05, odds ratio=3.5）、較上皮過度角化之P53表現率為高（p<0.05, odds ratio=26.78），也較上皮變異之P53表現率為高（p<0.05, odds ratio=2.57）。同時上皮變異之P53表現率較上皮過度角化之P53表現率為高（p<0.05, odds ratio=10.89）。P53於OSCC的表現與患者年齡有統計學上有意義之相關，每增加一歲，P53的陽性染色勝算比約減少為0.9倍（odds ratio=0.933, p=0.0209）。
各臨床病理參數和細胞凋亡相關蛋白於口腔癌之表現與口腔癌患者預後的關係，若僅就單一變項來看（以Wilcoxon test檢定），發現腫瘤大小、局部淋巴結的轉移與否、臨床分期、有無接受化學治療、有無接受放射線治療、和MCL-1的表現，與患者存活率有顯著相關（p<0.05）。若以Cox regression model分析，則局部淋巴結的轉移與否，MCL-1、BAX、P53於OSCC的表現與口腔癌患者的預後有顯著相關（p<0.05）。有局部淋巴結轉移患者比無局部淋巴結轉移患者之死亡危險性約增加為13倍（hazard ratio = 12.7）。MCL-1陽性患者比MCL-1陰性患者之死亡危險性約增加為5倍（hazard ratio=5.141）。BAX陽性口腔癌患者比BAX陰性口腔癌患者的死亡危險性約減少了77%（hazard ratio=0.228）。P53陽性口腔癌患者比P53陰性口腔癌患者的死亡危險性約增加為4倍（hazard ratio=3.867）。
在細胞凋亡相關蛋白於實驗組及控制組之表現中，任何兩者之間的相關性方面，發現在正常口腔黏膜組織中，BAX與BCL-XL、BAX與BAK 、BAK與BCL-XL成中度正相關（p<0.05）。在上皮變異及上皮過度角化的標本中沒有任何兩者之間有統計學上有意義之相關。在鱗狀細胞癌中，BAK與BCL-2成低度負相關、MCL-1與BCL-XL成低度正相關（p<0.05）。
在我們的OSCC病例中，MCL-1與BCL-XL之陽性染色率分別為68.1% 和21.7%，而BCL-2之陽性染色率則只有4.4%，此表示於我們的OSCC病例中，癌細胞主要以表現MCL-1和BCL-XL而非BCL-2之方式來逃避BAX和BAK所誘導的細胞凋亡，以延長癌細胞之存活時間。而低的BCL-2陽性染色率（4.4%）和較高的BAX陽性染色率（87.0%）和P53陽性染色率（33.3%），也顯示於我們的OSCC病例中，P53蛋白可能大部分為具有功能的野生型（wide type），而非突變型P53蛋白。此論點也支持我們過去的研究結果--－在我們的OSCC病例中p53基因之突變率只有5.4%。在預測OSCC患者的預後（存活率）方面，局部淋巴結轉移或MCL-1的表現可以作為一個獨立的預測預後因子。

In this study, we used the streptavidin-biotin immunohisto-chemical method to study the expressions of the apoptosis-associated proteins（BCL-2、BCL-XL、MCL-1、BAX、BAK and P53）in 69 cases of oral squamous cell carcinoma（OSCC）（experimental group）, 26 cases of epithelial hyperkeratosis（EH）, 43 cases of epithelial dysplasia（ED）（disease control groups）, and 16 cases of normal oral mucosa（NOM）（normal control group）. The expressions of the apoptosis-associated proteins in OSCCs were further correlated with the clinicopathological parameters and the prognosis of the OSCC patients.
We found that the positive staining rates of the BCL-2 in the NOM, EH, ED and OSCC specimens were 0.0%, 0.0%, 20.9% and 4.4%, respectively. The BCL-2 expression rate in ED specimens was significantly greater than that in EH specimens（p<0.05, odds ratio=16.6）. The BCL-2 expression rate in OSCC specimens was significantly lower than that in ED specimens（p<0.05, odds ratio=0.172）. The expression of the BCL-2 in OSCCs was significantly correlated with the patients’ daily consumption of the alcohol（p=0.0307）.
The positive staining rates of the BCL-XL in the NOM, EH, ED and OSCC specimens were 43.8%, 30.8%, 74.4% and 21.7%, respectively. The BCL-XL expression rate in ED specimens was significantly greater than that in NOM specimens（p<0.05, odds ratio=3.74）and that in EH specimens（p<0.05, odds ratio=6.545）. The BCL-XL expression rate in OSCC specimens was significantly lower than that in ED specimens（p<0.05, odds ratio=0.095）. The expression of the BCL-XL in OSCCs was significantly correlated with the clinical staging of the cancer（p=0.0098）and the patients’ daily consumption of the cigarettes（p=0.0359）. The odds in favor of the positive staining rate of the BCL-XL for the stage III and IV OSCCs decreased to approximately 0.1 time as large as that of the stage I and II OSCCs（odds ratio = 0.093）. If the daily consumption of the cigarettes increases one pack, then the odds in favor of the positive staining rate of the BCL-XL decrease to approximately 0.18 times.
The positive staining rates of the MCL-1 in the NOM, EH, ED and OSCC specimens are 81.2%, 100.0%, 95.3% and 68.1%, respectively. The MCL-1 expression rate in EH specimens was significantly greater than that in NOM specimens（p<0.05, odds ratio=13.74）. The MCL-1 expression rate in OSCC specimens was significantly lower than that in EH specimens（p<0.05, odds ratio=0.0）and that in ED specimens（p<0.05, odds ratio=0.10）. The expression of the MCL-1 in OSCCs was significantly correlated with the T status、N status, and the patients’ duration of chewing betel quids（p<0.05）. The odds in favor of the positive staining rate of the MCL-1 for T3 and T4 OSCCs increased to 42.6 times as large as that of T1 and T2 OSCCs（odds ratio=42.646）. The adjusted odds ratio for the regional lymph node metastasis on the positive staining rate of the MCL-1 in OSCCs with regional lymph node metastasis was about 0.07 times（odds ratio=0.066）. If the duration of chewing betel quids increases one year, then the odds in favor of the positive staining rate of the MCL-1 increase to 1.1 times（odds ratio=1.135）.
The positive staining rates of the BAX in the NOM, EH, ED and OSCC specimens were 43.8%, 69.2%, 86.0% and 87.0%, respectively. The BAX expression rate in ED specimens was significantly greater than that in NOM specimens（p<0.05, odds ratio=7.92）. The BAX expression rate in OSCC specimens was significantly larger than that in NOM specimens（p<0.05, odds ratio=8.57）. There was no statistically significant correlation between the expression of the BAX in OSCCs and the clinicopathological parameters of the patients.
The positive staining rates of the BAK in the NOM, EH, ED and OSCC specimens were 75.0%, 100.0%, 97.7% and 97.1%, respectively. The BAK expression rate in EH specimens（p<0.05, odds ratio=19.08）, in ED specimens（p<0.05, odds ratio=14.0）or in OSCC specimens（p<0.05, odds ratio=11.2）was significantly greater than that in NOM specimens. The expression of the BAK in OSCCs was not significantly correlated with any of the clinicopathological parameters of the patients.
The positive staining rates of the P53 in the NOM, EH, ED and OSCC specimens were 12.5%, 0.0%, 16.3% and 33.3%, respectively. The P53 expression rate in OSCC specimens was significantly greater than that in NOM specimens（p<0.05, odds ratio=3.5）, that in EH specimens（p<0.05, odds ratio=26.78）, and that in ED specimens（p<0.05, odds ratio=2.57）. The P53 expression rate in ED specimens was significantly larger than that in EH specimens（p<0.05, odds ratio=10.89）. There was a statistically significant correlation between the expression of P53 in OSCCs and the age of the patients. If the age increases one year, then the odds in favor of the positive staining rate of the P53 decrease to 1.1 times（odds ratio=1.135）.
The correlations between the clinicopathological parameters or the expression of the apoptosis-associated proteins in OSCCs and prognosis of the patients were analyzed statistically. We found that there were statistically significant correlations between the survival rates of the OSCC patients and the T status, N status, clinical staging, with or without chemotherapy or radiotherapy, or the MCL-1 expression in the OSCCs（p<0.05, Wilcoxon test）. Using the Cox regression analysis, we also found statistically significant correlations between the survival rates of the OSCC patients and N status or the MCL-1、BAX or P53 expression in the OSCCs. The hazard ratio for the patients with regional lymph node metastasis was about 13 times greater than that for the patients without regional lymph node metastasis（hazard ratio = 12.7）. The hazard ratio for the patients with MCL-1-positive OSCC was 5 times greater than that for the patients with MCL-1-negative OSCC （hazard ratio = 5.141）. The hazard ratio for the patients with BAX- positive OSCC versus the patients with BAX-negative OSCC decreased to about 77%（hazard ratio = 0.228）. The hazard ratio for the patients with P53-positive OSCCs increased to about 4 times as large as that for the patients with P53- negative OSCCs（hazard ratio =3.867）.
Regarding the relationship between the expressions of any two apoptosis-associated proteins in the experimental and control groups, there was a moderate positive correlation between the expressions of the BAX and BCL-XL, between the expressions of the BAX and BAK, and between the expressions of the BAK and BCL-XL（p<0.05）in the NOM specimens. In the EH and ED specimens, there was no statistically significant correlation between the expressions of any two apoptosis-associated proteins. In the OSCC specimens, there was a low negative correlation between expressions of the BAK and BCL-2 as well as a low positive correlation between the expressions of the MCL-1 and BCL-XL（p<0.05）.
In our OSCC cases, the positive staining rates of the MCL-1 and BCL-XL were 68.1% and 21.7%, respectively. However, the positive staining rate of the BCL-2 was only 4.4%. This suggests that in our OSCC cases cancer cells express MCL-1 and BCL-XL , but not BCL-2, to counteract the BAX- and BAK-induced apoptosis and to prolong their survival time. The lower BCL-2 positive staining rate （4.4%）as well as the higher BAX positive staining rate（87.0%）and the P53 positive staining rate（33.3%）also indicate that the majority of the P53 proteins in our OSCCs are the functional wide-type form and not the mutant form. This also supports the result of our previous study － the mutation rate of the p53 gene in our OSCCs is only 5.4%. The regional lymph node metastasis or the MCL-1 expression in OSCCs can be an independent factor for the prediction of the patients’ prognosis or survival rates.

頁次
目錄.....................................................I
表目錄.................................................III
圖目錄..................................................IV
中文摘要................................................1
ABSTRACT................................................5
第一章 前言...........................................10
第一節 研究動機......................................10
第二節 研究目的......................................11
第二章 文獻回顧.......................................12
第一節 台灣口腔癌....................................12
第二節 台灣口腔癌前病變..............................18
第三節 細胞凋亡......................................21
第四節 BCL-2家族.....................................24
第五節 P53...........................................39
第三章 材料與方法.....................................45
第一節 標本取樣......................................45
第二節 標本之處理....................................45
第三節 實驗方法......................................46
第四章 結果...........................................57
第一節 實驗組及對照組之臨床與組織病理學發現..........57
第二節 BCL-2蛋白之免疫組織化學染色結果...............59
第三節 BCL-XL蛋白之免疫組織化學染色結果..............61
第四節 MCL-1蛋白之免疫組織化學染色結果...............62
第五節 BAX蛋白之免疫組織化學染色結果.................64
第六節 BAK蛋白之免疫組織化學染色結果.................65
第七節 P53蛋白之免疫組織化學染色結果.................66
第八節 細胞凋亡相關蛋白於實驗組及控制組之表現中，任何兩者之 間的相關性.............................................68
第九節 臨床病理參數和細胞凋亡相關蛋白於口腔癌之表現與口腔癌患者預後的關係...........................................68
第五章 討論...........................................73
第一節 細胞凋亡相關蛋白於OSCC之表現與臨床病理參數之相關性之討論.....................................................73
第二節 細胞凋亡相關蛋白於實驗組及控制組之表現中，任何兩者之間的相關性...............................................78
第三節 尋找一個預後因子..............................79
第六章 結論...........................................81
附表...................................................86
附圖..................................................101
參考文獻..............................................122

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