口腔癌是世界上最常見的十大癌症之一。口腔鱗狀細胞癌是其中最常見的癌症型態，儘管它可以經手術切除以及放射線治療來控制，但癌細胞轉移至淋巴結以及遠端器官可能會導致治療失敗和患者死亡。近來，我們利用次世代定序分析結果發現，八支膠原蛋白相關基因 (COL1A1、COL1A2、COL3A1、COL4A1、COL5A1、COL5A2、COL6A1和COL11A1) 可能與口腔鱗狀細胞癌的腫瘤新生與惡化相關。因此，本研究目的為驗證八支膠原蛋白相關基因的訊息RNA及蛋白質的表現量與口腔鱗狀細胞癌的腫瘤新生和惡化的關聯性。我們使用定量即時聚合酶連鎖反應評估八支膠原蛋分別於23位頰黏膜鱗狀細胞癌患者以及11位舌頭鱗狀細胞癌患者其配對組織(腫瘤比正常)中訊息RNA的表現量；再利用免疫組織化學染色法評量八支膠原蛋白於484位口腔鱗狀細胞癌患者 (其中包含176位頰黏膜鱗狀細胞癌、246位舌頭鱗狀細胞癌及62位唇鱗狀細胞癌)在組織微陣列中蛋白表現量。結果發現，在頰黏膜鱗狀細胞癌組織中，所有膠原蛋白的訊息RNA及蛋白表現程度顯著高於腫瘤鄰近正常組織，除了COL5A2的訊息RNA與蛋白質是正常組織高於腫瘤組織。我們由免疫組織化學染色結果得知，頰黏膜鱗狀細胞癌組織中的COL1α1、COL1α2、COL4α1、COL5α1、COL5α2、COL6α1和COL11α1之蛋白表現中位數分別為4、2、2、4、3、3和3。此外在舌頭鱗狀細胞癌、唇鱗狀細胞癌和口腔鱗狀細胞癌組織中的COL5α1和COL5α2之蛋白表現中位數分別為5和2、2和3以及4和2。我們也發現在頰黏膜鱗狀細胞癌中，高表現的COL1α1會有比較差的細胞分化，然而高表現的COL1α2會有比較小的腫瘤，高表現的COL5α2不會有淋巴結侵犯。在口腔鱗狀細胞癌中，高表現的COL5α1會有比較差的細胞分化 (特別是頰黏膜鱗狀細胞癌)、較晚期的腫瘤 (唇鱗狀細胞癌除外) 以及有淋巴結侵犯，然而高表現的COL5α2與比較好的細胞分化相關 (特別是頰黏膜鱗狀細胞癌)。在經過校正臨床病理因素之後發現，在舌頭鱗狀細胞癌患者中，COL5α1蛋白表現量高和較差的特定疾病存活率 (校正後存活調整風險 [AHR] 1.96, 95%信賴區間1.27-3.01, p=0.002) 以及無疾病存活率具顯著性相關 ([AHR] 1.96, 95%信賴區間1.28-3.01, p=0.002)；COL5α2蛋白表現量高則和頰黏膜鱗狀細胞癌患者較好的特定疾病存活率具顯著性相關 ([AHR] 0.49, 95%信賴區間 0.29-0.84, p=0.009)。本研究之結論顯示，COL1α1、COL1α2、COL4α1、COL5α1、COL5α2、COL6α1和COL11α1可能可作為口腔鱗狀細胞癌 (尤其是頰黏膜鱗狀細胞癌) 的腫瘤發生之生物標誌，而COL5α1和COL5α2可能是口腔鱗狀細胞癌，尤其是在頰黏膜鱗狀細胞癌和舌頭鱗狀細胞癌，的一個預後生物標誌。

Oral cancer is one of the top ten most common cancers worldwide. Oral squamous cell carcinoma (SCC) is the most common type of oral cancer. Although it can be controlled by surgical excision and radiotherapy, metastasis to the lymph nodes and distant organs, may lead to treatment failure and patient death. Recently, our next-generation sequencing assay identified 8 collagen-related genes’ expression (COL1A1, COL1A2, COL3A1, COL4A1, COL5A1, COL5A2, COL6A1, and COL11A1) involved in tumorigenesis and progression of oral SCC. The purpose of this study was to validate the association of the mRNA and protein expression of 8 collagen-related genes with the development and prognosis of oral SCC. The mRNA expression levels of 8 collagen-related proteins were assayed by real-time PCR in N-T paired tissues of 23 buccal mucosal SCC and 11 tongue SCC patients. The protein expression levels of 8 collagen-related proteins were examined by immunohistochemistry (IHC) in tissue microarray slides of 484 oral SCC patients, including 176 buccal mucosal, 246 tongue, and 62 lip patients. The mRNA and protein expression levels of 8 collagen-related proteins were significantly increased in tumor tissues as compared to the paired tumor adjacent normal tissue, except mRNA and protein expression of COL5A2 in buccal mucosal SCC. Our IHC results showed that the median expression levels of COL1α1, COL1α2, COL4α1, COL5α1, COL5α2, COL6α1, and COL11α1 were 4, 2, 2, 4, 3, 3, and 3 in 176 buccal mucosal SCC specimens, respectively. In addition, the median expression levels of COL5α1 and COL5α2 were 5 and 2, 2 and 3, as well as 4 and 2 in 246 tongue SCC specimens, 62 lip SCC specimens, and 484 oral SCC speicements, respectively. In buccal mucosal SCC, we found that a higher level of COL1α1 was correlated with higher grade of cell differentiation. However, higher level of COL1α2 was correlated with small size of tumor and higher level of COL5α2 was correlated with absence of lymph node invasion. In oral SCC, the increased expression of COL5α1 was correlated with higher grade of cell differentiation (especially for buccal mucosal SCC), late stage of disease (except for lip SCC), and involvement of lymph node (except for lip SCC). However, the increased expression of COL5α2 was correlated with lower grade of cell differentiation (especially for buccal mucosal SCC). After adjustment of clinicopathologic outcomes, tongue SCC patients with the elevated COL5α1 expression had worse disease-specific survival (adjusted hazard ratio [AHR] 1.96, 95%CI 1.27-3.01, p=0.002) and disease-free survival ([AHR] 1.96, 95%CI 1.28-3.01, p=0.002). However, buccal mucosal SCC patients with increased COL5α2 expression had better disease-specific survival ([AHR] 0.49, 95%CI 0.29-0.84, p=0.009). In conclusion, COL1α1, COL1α2, COL4α1, COL5α1, COL5α2, COL6α1, and COL11α1 could be biomarkers for tumorigenesis in oral SCC, especially for buccal mucosal SCC. Additionally, COL5α1 and COL5α2 might be prognostic biomarkers for oral SCC, especially for buccal mucosal SCC and tongue SCC.

論文審定書-----------------------------------------------------------------------------------------i
致謝--------------------------------------------------------------------------------------------------ii
Abbreviations--------------------------------------------------------------------------------------iv
Abstract in Chinese -------------------------------------------------------------------------v
Abstract in English ---------------------------------------------------------------------------- vii
Contents -------------------------------------------------------------------------------------- x
Introduction ------------------------------------------------------------------------------------- 01
1. Oral cancer--------------------------------------------------------------------------------01
2. Collagen-------------------------------------------------------------------------------- 01
3. Collagen family------------------------------------------------------------------------ 02
4. The mechanisms of Collagens on tumorigenesis or metastasis-------------------03
5. Eight collagen related proteins and cancer------------------------------------------- 05
A. Type I collagen alpha 1-----------------------------------------------------------05
B. Type I collagen alpha 2--------------------------------------------------------06
C. Type III collagen alpha 1-------------------------------------------------------06
D. Type IV collagen alpha 1-----------------------------------------------------07
E. Type V collagen alpha 1-------------------------------------------------------08
F. Type V collagen alpha 2---------------------------------------------------------09
G. Type VI collagen alpha 1-----------------------------------------------------10
H. Type XI collagen alpha 1-----------------------------------------------------11
The specific aims of this study -----------------------------------------------------------------12
Materials and Methods --------------------------------------------------------------------------13
Results ---------------------------------------------------------------------------------------------23
Section 1. Screening of 8 collagens in oral squamous cell carcinoma, including buccal mucosal squamous cell carcinoma and tongue squamous cell carcinoma
A. Transcriptome profiling of oral squamous cell carcinoma----------23
B. Validation of the mRNA expression levels of 8 collagens in the paired tissues of oral squamous cell carcinoma-----------------------23
Section 2. Seven collagens’ protein expression and buccal mucosal squamous cell carcinoma
A. Validation of the protein expression levels of 7 collagens in normal tissues, tumor adjacent normal tissues, and tumor tissues---------24
B. The demographic and clinicopathologic characteristics and their impact on survival of patients with buccal mucosal squamous cell carcinoma ----------------------------------------------------------------26
C. The association of the expression levels of 7 collagens with the clinicopathological outcomes and survival of buccal mucosal squamous cell carcinoma patients-------------------------------------27
Section 3. Type V collagen in oral squamous cell carcinoma, including buccal mucosal squamous cell carcinoma, tongue squamous cell carcinoma, and lip squamous cell carcinoma
A. The protein expression level of type V collagen in normal tissues, tumor adjacent normal tissues, and tumor tissues-------------------30
B. The demographic and clinicopathologic characteristics and their impact on survival of patients with tongue squamous cell carcinoma ---------32
C. The demographic and clinicopathologic characteristics and their impact on survival of patients with lip squamous cell carcinoma -----------33
D. The demographic and clinicopathologic characteristics and their impact on survival of patients with oral squamous cell carcinoma -----------35
E. The association of the expression levels of COL5α1 and COL5α2 with the clinicopathologic outcomes and survival of tongue squamous cell carcinoma patients-----------------------------------------------------------36
F. The association of the expression levels of COL5α1 and COL5α2 with the clinicopathologic outcomes and survival of lip SCC patients-------------------------------------------------------------------------37
G. The association of the expression levels of COL5α1 and COL5α2 with the clinicopathologic outcomes and survival of oral SCC patients---------------------------------------------------------------------38
Discussions---------------------------------------------------------------------------------------- 49
Conclusions--------------------------------------------------------------------------------------- 48
References ------------------------------------------------------------------------------------- 49
Tables ------------------------------------------------------------------------------------------- 59
Figures ---------------------------------------------------------------------------------------- 82

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