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研究生:黃暘凱
研究生(外文):Yang-Kai Huang
論文名稱: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
論文名稱(外文):Analysis of Expression of Notch Signaling Pathway inProgression of Oral Squamous Epithelial Lesionsby Tissue Microarray and Immunohistochemical Assay
指導教授:李勝揚李勝揚引用關係
指導教授(外文):Sheng-Yang Lee
學位類別:碩士
校院名稱:臺北醫學大學
系所名稱:牙醫學系碩博士班
學門:醫藥衛生學門
學類:牙醫學類
論文種類:學術論文
論文出版年:2010
畢業學年度:98
語文別:中文
論文頁數:64
中文關鍵詞: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
外文關鍵詞:Notch signaling pathwayepithelial hyperplasiaepithelial dysplasiaoral squamous cell carcinoma (OSCC)tissue microarrayimmunohistochemistry stain
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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。

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.

目錄
______________________________________________________________
頁數
標題....................................................................................................................... i
審定書.................................................................................................................. ii
上網授權書......................................................................................................... iii
國科會授權書..................................................................................................... iv
誌謝..................................................................................................................... vi
目錄.................................................................................................................... vii
表目錄................................................................................................................. xi
圖目錄............................................................................................................... xvi
中文摘要........................................................................................................... xxi
英文摘要.........................................................................................................xxiii
第一章 緒論
1.1 口腔癌在台灣...................................................................................... 1
1.2 口腔上皮病變之發展(Progression of oral cancer) ........................... 2
1.2.1 正常口腔黏膜上皮(Normal mucosa)...................................... 2
1.2.2 口腔黏膜上皮增生(Hyperplasia)............................................ 3
1.2.3 口腔黏膜上皮異生(Dysplasia) ............................................... 3
viii
1.2.4 口腔黏膜上皮原位癌(CIS)..................................................... 4
1.2.5 口腔黏膜鱗狀上皮細胞癌(Squamous cell carcinoma).......... 4
1.3 Notch 訊息傳導路徑(Notch signaling pathway) ............................... 4
1.3.1 簡介(Introduction) .................................................................... 4
1.3.2 Notch 受體蛋白(Notch receptor) ............................................. 5
1.3.3 DSL 標的物(DSL ligand) ......................................................... 6
1.3.4 Notch 訊息傳導路徑.................................................................. 7
1.4 組織微陣列(Tissue Microarray, TMA) ............................................. 8
第二章 研究目的.......................................................................................9
第三章 實驗假設.....................................................................................10
第四章 材料與方法
4.1 病患資料收集.................................................................................... 11
4.2 組織微陣列........................................................................................ 11
4.3 免疫組織化學染色............................................................................ 12
4.3.1 目標抗體選擇.......................................................................... 12
4.3.2 實驗藥品.................................................................................. 12
4.3.3 免疫組織化學染色步驟........................................................... 12
4.4 結果判定..................................................................................... 14
ix
4.5 統計方式..................................................................................... 14
第五章 結果
5.1 病患資料............................................................................................ 15
5.2 Notch 訊息傳遞路徑的免疫組織化學染色結果.............................. 15
5.2.1 Notch 1 在口腔黏膜正常鱗狀上皮和病變上皮的表現......... 15
5.2.2 Jagged 1 在口腔黏膜正常鱗狀上皮和病變上皮的表現....... 15
5.2.3 Delta 在口腔黏膜正常鱗狀上皮和病變上皮的表現............. 16
5.2.4 RBP-Jk 在口腔黏膜正常鱗狀上皮和病變上皮的表現......... 16
5.3 Notch 訊息傳遞蛋白質表現在口腔鱗狀上皮細胞病變的統計
分析.................................................................................................... 17
5.3.1 Notch1 在口腔黏膜上皮細胞不同病變的表現結果分析...... 17
5.3.2 Jagged 1 在口腔黏膜上皮細胞不同病變的表現結果分析... 17
5.3.3 Delta 在口腔黏膜上皮細胞不同病變的表現結果分析......... 18
5.3.4 RBP-Jk 在口腔黏膜上皮細胞不同病變的表現結果分析..... 18
第六章 討論
6.1 Notch 訊息傳遞路徑於上皮組織癌化過程中的表現變化及角色.. 19
6.2 Notch 訊息傳遞路徑於口腔黏膜癌化進程中的表現變化及角色.. 20
6.2.1 Notch 訊息傳遞路徑於正常口腔黏膜中的表現.................... 20
x
6.2.2 Notch 訊息傳遞路徑於口腔黏膜上皮增生中的表現變化.... 20
6.2.3 Notch 訊息傳遞路徑於口腔黏膜上皮異生中的表現變化.... 21
6.2.4 Notch 訊息傳遞路徑於口腔黏膜上皮原位癌中的表現
變化............................................................................................ 22
6.2.5 Notch 訊息傳遞路徑於口腔鱗狀上皮細胞癌中的表現
變化............................................................................................ 22
6.3 Notch 訊息傳導路徑於口腔黏膜癌化進程中的未來研究方向及應用
價值..................................................................................................... 23
第七章 結論.............................................................................................25
參考文獻..................................................................................................26
附錄..........................................................................................................32

1. Mashberg A, Samit A. Early diagnosis of asymptomatic oral and oropharyngeal
squamous cancers. CA Cancer J Clin 1995; 45: 328-351.
2. de Visser KE, Korets LV, Coussens LM. De novo carcinogenesis promoted by chronic
inflammation is B lymphocyte dependent. Cancer Cell 2005; 7(5):411-23.
3. Kumar, V, Abbas, A.K., Fausto, N. Robbins and Cotran Pathologic Basis of Disease, 7th
ed. 2005;Ch. 16; 773-795.
4. Sargeran K, Murtomaa H, Safavi SM, Vehkalahti MM, Teronen O. Survival after
diagnosis of cancer of the oral cavity. Br J Oral Maxillofac Surg. 2008; 46: 187-191.
5. Taiwan area main causes of death 2008, Department of Health, The executive Yuan,
Taiwan, R.O.C., 2009.
6. Genomic imbalances in precancerous tissues signal oral cancer risk. Garnis C, Chari R,
Buys TP, Zhang L, Ng RT, Rosin MP, Lam WL. Mol Cancer 2009; 23;8:50.
7. Lippman SM, Hong WK. Molecular markers of the risk of oral cancer. Engl J Med 2001;
26;344(17):1323-6.
8. Batsakis JG, Suarez P, el-Naggar AK. Proliferative verrucous leukoplakia and its related
lesions. Oral Oncol 1999; 35(4):354-9.
9. Warnakulasuriya S, Reibel J, Bouquot J, Dabelsteen E. Oral epithelial dysplasia
classification systems: predictive value, utility, weaknesses and scope for improvement.
J Oral Pathol Med 2008; 37(3):127-33.
10. Reibel J. Prognosis of oral premalignant lesions: significance of clinical,
histopathological, and molecular biological characteristics. Crit Rev Oral Biol Med 2003;
14: 47-62.
11. Warnakulasuriya S. Histological grading of oral epithelial dysplasia: revisited. J Pathol
2001; 194: 294-7.
12. Warnakulasuriya S, Johnson NW, Van der Wall I. Nomenclature and classification of
potentially malignant disorders of the oral mucosa. J Oral Pathol Med 2007; 36:
27
575-580.
13. Squier CA. The permeability of oral mucosa. Crit Rev Oral Biol Med 1991;2(1):13-32.
14. Dale BA, Salonen J, Jones AH. New approaches and concepts in the study of
differentiation of oral epithelia. Crit Rev Oral Biol Med 1990;1(3):167-90.
15. World Health Organization Classification of Tumours. Pathology & genetics. Head and
neck tumours. International Agency for Research on Cancer (IARC). In: Barnes L,
Eveson JW, Reichart P, Sidransky D, eds. Head and neck tumors. Lyon: IARC Press,
2005; 177–80.
16. Warnakulasuriya KAAS, MacDonald DG. Epithelial cell kinetics in oral leukoplakia. J
Oral Pathol Med 1995; 24: 165–9.
17. Pindborg JJ, Reichart P, Smith CJ, Van der Waal I. World Health Organization:
histological typing of cancer and precancer of the oral mucosa. Berlin: Springer-Verlag,
1997.
18. Bouquot J, Speight PM, Farthing PM. Epithelial Dysplasia of the Oral Mucosa –
diagnostic problems and prognostic features. Current Diagnostic Pathology 2006; 12:
11-22
19. Brothwell DJ, Lewis DW, Bradley G, Leong I, Jordan RC, Mock D, Leake JL.
Observeragreement in the grading of oral epithelial dysplasia. Community Dent Oral
Epidemiol 2003; 31:300-5
20. Ilagan MX, Kopan R. SnapShot: notch signaling pathway. Cell 2007; 23;128(6):1246.
21. Artavanis-Tsakonas S, Matsuno K, Fortini ME. Notch signaling. Science 1995; 14;
268(5208): 225-32. Review.
22. Kimble J, Simpson P. The LIN-12/Notch signaling pathway and its regulation. Annu Rev
Cell Dev Biol 1997; 13:333-61.
23. Fiúza UM, Arias AM. Cell and molecular biology of Notch. J Endocrinol 2007; 194(3):
459-74.
28
24. Morgan T. The theory of the gene. Am Nat 1917; 51:513–44.
25. Fehon RG, Kooh PJ, Rebay I, Regan CL, Xu T, Muskavitch MA & Artavanis-Tsakonas
S 1990 Molecular interactions between the protein products of the neurogenic loci Notch
and Delta, two EGF-homologous genes in Drosophila. Cell 61 523–534.
26. Artavanis-Tsakonas S, Simpson P. Choosing a cell fate: a view from the Notch locus.
Trends Genet. 1991;7(11-12):403-8. Review.
27. Campos-Ortega JA. Genetic mechanisms of early neurogenesis in Drosophila
melanogaster. J Physiol Paris 1994;88(2):111-22.
28. Artavanis-Tsakonas S, Delidakis C, Fehon RG. The Notch locus and the cell biology of
neuroblast segregation. Annu Rev Cell Biol 1991;7:427-52.
29. Palomero T, Ferrando A. Therapeutic targeting of NOTCH1 signaling in T-cell acute
lymphoblastic leukemia. Clin Lymphoma Myeloma 2009; 9 Suppl 3:S205-10. Review.
30. Srivastava S, Ramdass B, Nagarajan S, Rehman M, Mukherjee G, Krishna S. Notch1
regulates the functional contribution of RhoC to cervical carcinoma progression. Br J
Cancer 2010; 5;102(1):196-205.
31. Katoh M, Katoh M. Notch signaling in gastrointestinal tract (review). Int J Oncol 2007;
30(1):247-51. Review.
32. Robbins J, Blondel BJ, Gallahan D, Callahan R. Mouse mammary tumor gene int-3: a
member of the notch gene family transforms mammary epithelial cells. J Virol 1992;
66(4):2594-9.
33. Boyer-Di Ponio J, Wright-Crosnier C, Groyer-Picard MT, Driancourt C, Beau I,
Hadchouel M, Meunier-Rotival M. Biological function of mutant forms of JAGGED1
proteins in Alagille syndrome: inhibitory effect on Notch signaling. Hum Mol Genet
2007; 16(22):2683-92.
29
34. Joutel A, Corpechot C, Ducros A, Vahedi K, Chabriat H, Mouton P, Alamowitch S,
Domenga V, Cécillion M, Marechal E, Maciazek J, Vayssiere C, Cruaud C, Cabanis EA,
Ruchoux MM, Weissenbach J, Bach JF, Bousser MG, Tournier-Lasserve E. Notch3
mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia.
Nature 1996;383(6602):707-10.
35. Turnpenny PD, Whittock N, Duncan J, Dunwoodie S, Kusumi K, Ellard S. Novel
mutations in DLL3, a somitogenesis gene encoding a ligand for the Notch signalling
pathway, cause a consistent pattern of abnormal vertebral segmentation in
spondylocostal dysostosis. J Med Genet 2003; 40(5):333-9.
36. Arboleda-Velasquez JF, Zhou Z, Shin HK, Louvi A, Kim HH, Savitz SI, Liao JK,
Salomone S, Ayata C, Moskowitz MA, Artavanis-Tsakonas S. Linking Notch signaling
to ischemic stroke. Proc Natl Acad Sci U S A 2008; 105(12):4856-61.
37. Ellisen LW, Bird J, West DC, Soreng AL, Reynolds TC, Smith SD, Sklar J. TAN-1, the
human homolog of the Drosophila notch gene, is broken by chromosomal translocations
in T lymphoblastic neoplasms. Cell 1991; 23;66(4):649-61.
38. Yochem J, Weston K & Greenwald I. The Caenorhabditis elegans lin-12 gene encodes a
transmembrane protein with overall similarity to Drosophila Notch. Nature 1988; 335;
547–550.
39. Lubman OY, Korolev SV, Kopan R. Anchoring notch genetics and biochemistry;
structural analysis of the ankyrin domain sheds light on existing data. Mol Cell 2004;
12;13(5):619-26.
40. Lardelli M, Dahlstrand J, Lendahl U. The novel Notch homologue mouse Notch 3 lacks
specific epidermal growth factor-repeats and is expressed in proliferating
neuroepithelium. Mech Dev 1994;46(2):123-36.
30
41. Bigas A, Martin DI, Milner LA. Notch1 and Notch2 inhibit myeloid differentiation in
response to different cytokines. Mol Cell Biol 1998;18(4):2324-33.
42. Roehl H, Bosenberg M, Blelloch R, Kimble J. Roles of the RAM and ANK domains in
signaling by the C. elegans GLP-1 receptor. EMBO J 1996; 15(24):7002-12.
43. Radhakrishnan R, Solomon M, Satyamoorthy K, Martin LE, Lingen MW. Tissue
microarray - a high-throughput molecular analysis in head and neck cancer. J Oral
Pathol Med 2008;37(3):166-76. Review.
44. Kononen J, Bubendorf L, Kallioniemi A, et al. Tissue microarrays for high throughput
molecular profiling of tumor specimens. Nat Med 1998; 4: 844–7.
45. Battifora H. The multitumor (sausage) tissue block: Novel method for
immunohistochemical antibody testing. Lab Invest 1986; 55: 244–8.
46. Kallioniemi OP, Wagner U, Kononen J, Sauter G. Tissue microarray technology for
high-throughput molecular profiling of cancer. Hum Mol Genet 2001; 10: 657–62.
47. D''Souza B, Miyamoto A, Weinmaster G. The many facets of Notch ligands. Oncogene
2008;27(38):5148-67. Review.
48. Roy M, Pear WS, Aster JC. The multifaceted role of Notch in cancer. Curr Opin Genet
2007; 17(1):52-9. Review
49. Panelos J, Tarantini F, Paglierani M, Di Serio C, Maio V, Pellerito S, Pimpinelli N,
Santucci M, Massi D. Photoexposition discriminates Notch 1 expression in human
cutaneous squamous cell carcinoma. Mod Patho. 2008; 21(3):316-25.
50. Hansson EM, Lendahl U, Chapman G. Notch signaling in development and disease.
Semin Cancer Biol 2004; 14(5):320-8. Review.
51. Lowell S, Jones P, Le Roux I, Dunne J, Watt FM. Stimulation of human epidermal
differentiation by delta-notch signalling at the boundaries of stem-cell clusters. Curr Biol
31
2000;10:491–500.
52. Nicolas M, Wolfer A, Raj K, Kummer JA, Mill P, van Noort M, et al. Notch1 functions
as a tumor suppressor in mouse skin. Nat Genet 2003; 33:416–21.
53. Hijioka H, Setoguchi T, Miyawaki A, Gao H, Ishida T, Komiya S, Nakamura N.
Upregulation of Notch pathway molecules in oral squamous cell carcinoma. Int J Oncol
2010; 36(4):817-22
54. Rangarajan A, Talora C, Okuyama R, Nicolas M, Mammucari C, Oh H, et al. Notch
signaling is a direct determinant of keratinocyte growth arrest and entry into
differentiation. EMBO J 2001;20:3427-36.
55. Lin JT, Chen MK, Yeh KT, Chang CS, Chang TH, Lin CY, Wu YC, Su BW, Lee KD,
Chang PJ. Association of High Levels of Jagged-1 and Notch-1 Expression with Poor
Prognosis in Head and Neck Cancer. Ann Surg Oncol 2010 Jun 2.

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