利用組織微陣列技術及免疫組織化學染色技術分析
在口腔上皮性病變進程中Notch訊息傳遞路徑之表現

口腔鱗狀上皮細胞癌為具侵犯性的口腔黏膜惡性病變。口腔癌在癌化的進程中，為一種漸進式(multistep progress)的發展。在組織病理型態上，由正常口腔黏膜上皮癌化至鱗狀上皮細胞癌的進程中，可觀察到的組織變化，包括了正常口腔黏膜上皮(Normal mucosa)，口腔黏膜上皮增生(Hyperplasia)，低度至高度口腔黏膜上皮異生(Mild to moderate dysplasia)，口腔黏膜上皮原位癌(Carcinoma In Situ, CIS)及口腔黏膜鱗狀上皮細胞癌(Squamous cell carcinoma)。Notch 訊息傳遞路徑(Notch signal transduction pathway) 在許多脊椎動物及無脊椎動物的生長發育過程中，在調節細胞分化、增生，決定細胞命運，及維持早期細胞特性之中，扮演著極為重要的調控角色。而Notch 訊息傳遞與許多人類之疾病也有一定的相關性，包括白血病、子宮頸癌、大腸結腸癌、乳癌、Alagille syndrome、CADASIL syndrome、Spondylocostal dysostosis (SD) 、中風等疾病都有文獻 xxi 所提出。但在口腔癌的部分目前仍缺乏相關之實驗及證據。本實驗之研究目標為以組織微陣列技術及免疫組織化學染色技術，分析在口腔上皮性病變的癌化進程中，Notch 訊息傳導路徑中，Notch 1、Jagged 1、Delta 及RBP-Jk 的表現情形。實驗結果發現：1) 和正常黏膜組別相比，口腔黏膜上皮增生、口腔黏膜上皮異生和鱗狀上皮細胞癌組別，其 Notch 1、Jagged 1、Delta 及RBP-Jk 的表現都有顯著性的增加。2) 和口腔黏膜上皮增生組別比較，口腔黏膜上皮異生組別中Notch 1、Jagged 1、Delta 及RBP-Jk 的表現並無顯著性差異。3)和口腔黏膜上皮異生組別比較，鱗狀上皮細胞癌組別其Notch 1、Jagged 1、 Delta 及RBP-Jk 的表現有顯著性的增加。4)在口腔黏膜上皮異生組別之中，除了Notch 1 和口腔黏膜輕度上皮異生組別相較下，在口腔黏膜中度上皮異生組別有顯著性的下降之外，Jagged 1、Delta 及RBP-Jk 在口腔黏膜輕度上皮異生、口腔黏膜中度上皮異生及口腔黏膜重度上皮異生組別中，彼此之間並無顯著性差異。5)在鱗狀上皮細胞癌組別之中，除了Delta 和不良分化型鱗狀上皮細胞癌組別相較下，在中度分化型鱗狀上皮細胞癌組別有顯著性的上升之外，Notch 1、Jagged 1 及RBP-Jk 在良好分化型鱗狀上皮細胞癌、中度分化型鱗狀上皮細胞癌、和不良分化型鱗狀上皮細胞癌組別之間，其表現並無顯著性差異。因此，透過以組織微陣列技術及免疫組織化學染色技術，分析在口腔癌進程中Notch 訊息傳導路徑表現的實驗，可以發現Notch 訊息傳導路徑於口腔癌進程之中呈現正向調節(upregulated)的表現。若進一步了解其調控之機轉及機制，將有助於口腔癌癌化之研究，以及臨床上之意義和應用價值。

關鍵字

口腔黏膜上皮增生；口腔黏膜上皮異生；口腔黏膜上皮原位癌；口腔黏膜鱗狀上皮細胞癌； Notch 訊息傳導路徑；組織微陣列；免疫組織化學染色

並列摘要

Oral squamous cell carcinoma is a multistep progression of disease of oral squamous epithelium with development through a series of histopathological changes: through hyperplasia, mild dysplasia, moderate dysplasia, severe dysplasia to carcinoma in situ and then invasive disease. The Notch signaling pathway regulates multiple cellular processes during development and renewal of adult tissues. Recent studies also show that Notch signal transduction pathway also plays a multifaceted role in cancer and other diseases in human. However, it remains unclear how the Notch signaling pathway is involved in progression of oral squamous lesions. In this study, we used the tissue microarray technique associated with immunohistochemical assay to investigate the expression of Notch 1, Jagged 1, Delta, and RBP-Jk in a series of oral squamous lesions, including 30 normal mucosa, 44 epithelial hyperplasia, 83 epithelial dysplasia, 1 carcinoma in situ, and 72 squamous cell carcinomas. The results showed that there was significantly increased immunohistochemical expression of Notch 1, Jagged 1, Delta, and RBP-Jk in epithelial hyperplasia, epithelial dysplasia, and squamous cell carcinomas in comparison with normal mucosa. There is no significant difference between epithelial hyperplasia and epithelial dysplasia. The expression was significantly stronger in squamous cell carcinomas than in epithelial dysplasia. In conclusion, the results of our study indicated that Notch signaling pathway is upregulated during xxiii progression of oral squamous lesions. However, further study in investigating and understanding the mechanism of upregulation of Notch signal transduction pathway involved in the progression of oral squamous lesions is needed.

並列關鍵字

Notch signaling pathway ； epithelial hyperplasia ； epithelial dysplasia ； oral squamous cell carcinoma (OSCC) ； tissue microarray ； immunohistochemistry stain

參考文獻

1. Mashberg A, Samit A. Early diagnosis of asymptomatic oral and oropharyngeal

squamous cancers. CA Cancer J Clin 1995; 45: 328-351.

3. Kumar, V, Abbas, A.K., Fausto, N. Robbins and Cotran Pathologic Basis of Disease, 7th

diagnosis of cancer of the oral cavity. Br J Oral Maxillofac Surg. 2008; 46: 187-191.

Taiwan, R.O.C., 2009.

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利用組織微陣列技術及免疫組織化學染色技術分析在口腔上皮性病變進程中Notch訊息傳遞路徑之表現

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