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研究生：	黃玲育 Huang, Ling-Yu
論文名稱：	單細胞基因檢測分析口腔癌動物模型癌化過程 Single Cell Analysis in Different Carcinogenesis Stages of Oral Cancer Model
指導教授：	黃則達 Huang, Tze-Ta
學位類別：	碩士 Master
系所名稱：	醫學院 - 口腔醫學研究所 Institute of Oral Medicine
論文出版年：	2020
畢業學年度：	108
語文別：	中文
論文頁數：	149
中文關鍵詞：	口腔鱗狀細胞癌、4-硝基喹啉-1-氧化物、檳榔鹼、單細胞RNA定序
外文關鍵詞：	Oral squamous cell carcinoma, 4-Nitroquinoline 1-oxide, Arecoline, Single-cell RNA sequencing
相關次數：	點閱：63 下載：0
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癌症是台灣10大死因之首，每年有4萬多人因罹患癌症而死亡，不僅影響病患和家人的生活品質，造成龐大醫療費用支出，中壯年人口罹癌也影響整體經濟層面。在十大癌症死因中，口腔癌排名第五名，口腔癌每年的發生率持續上升，且主要好發於中壯年人口。造成口腔癌主要原因包括抽菸、飲酒、嚼檳榔和人類乳突瘤病毒感染所引起的慢性刺激和發炎，造成正常口腔黏膜組織轉變癌前病變並逐步演變為口腔癌。目前治療上仍以手術治療為主，其他治療包含放射線治療、化學治療、及免疫療法。然而，臨床上診斷的案例如為口腔癌晚期的病人，則治療效果有限；在早期治療癌症病患，即使手術切除加上放射療法或化學療法，病人依然有可能發生抗藥性及癌症惡化、轉移現象。腫瘤存在著高度異質性，導致每群腫瘤細胞對於治療方法產生不同反應與影響預後結果。本研究藉由以模擬香菸中之致癌物4-硝基喹啉-1-氧化物（4-Nitroquinoline 1-oxide，4-NQO）及檳榔中的致癌物檳榔鹼（Areocoline），刺激小鼠口腔鱗狀細胞癌化轉變模型，利用單細胞基因檢測分析平台，分析不同細胞群間基因表現及影響腫瘤癌化的因子，研究分別取出16週及29週對照組及實驗組小鼠舌頭正常及腫瘤細胞做單細胞分選，在所有細胞中因細胞表現特性被分成17群，從中挑選了2群細胞族群，推測這兩群細胞也許是參與細胞癌化過程的重要因子，使用基因功能富集分析，在兩群細胞族群表現最顯著所參與的調控路徑皆為MYC_targets_v1。也從這兩個細胞族群中選取了RANBP1,MCM5,EIF3B,PSMA6,NPM1與HSP90AB1基因，做後續在具有Cisplatin抗藥性的鼻咽癌細胞株中分析RNA與蛋白質表現量。本研究希望透過以單細胞分析找出適當的生物標記，應用在口腔癌前病變患者，期望找出高危險群人口，以便能及早介入。

The cancer has been the top causes of death in Taiwan. The quality of life of patients and their family were affected, the medical expenses of the society are huge, and the economic is deeply impacted while cancer incidence in middle age. Oral cancer is ranked as the fifth incidence, and the rate increased every year. Oral cancer especially onset at middle age. The causes of oral cancer include smoking, drinking, betel quid chewing, chronic stimulation and inflammation from Human Papillomavirus. Oral carcinogenesis is a sequential of normal oral mucosa, oral potentially malignant disorders, to oral canecr. Currently, surgical resection is the main treatment, and others are Radiotherapy, Chemotherapy, and Immunotherapy. However, patients who are diagnosed with the oral cancer of late stage were less effective in therapies. In the early treatment of cancer, patients also suffered from resistance of Chemotherapy, or Radiotherapy, and recurrences after surgical resection. The tumor heterogeneity is different clusters of tumor cells express different genes and different tumor behaviors. By the animal model of oral cancer with treated 4-Nitroquinoline 1-oxide and Arecoline to induce the oral cancer in mice, the main factors in carcinogenesis were distinguished in gene expression in single-cell RNA sequencing analysis. Tumor cell carcinogenesis between different tumor cell groups were analyzed. All cells in 11 samples are clustered 17 groups by Louvain algorithm in 29 weeks and 16 weeks treated groups. In the cluster 7 and 9 were analyzed by Gene Set Enrichment Analysis. The results show their genes are associated with MYC_targets_v1 pathway and are validated by cisplatin-resistant nasopharyngeal carcinoma cell lines. These biomarkers in oral cancer carcinogenesis can be applied to detect patients with oral precancerous lesions and identified the high-risk populations.

摘要	Ⅰ
Abstract	ⅡI
致謝	X
目錄	XII
圖目錄	XVI
表目錄	ⅩVIII
第一章	緒論	1
一、	口腔癌（Oral cancer）	1
二、	單細胞RNA測序（Single-cell RNA sequencing） 	4
三、	表觀基因體調控（Epigenetic regulation）	5
四、	表觀基因體調控與癌症（Epigenetic regulation and cancer）	7
五、	酪氨酸蛋白激酶6 (Protein Tyrosine Kinase 6)	9
六、	谷氨酸脫羧酶2（Glutamate Decarboxylase 2）	9
七、	焦磷酸定序驗證（Pyrosequencing） 	10
八、	研究動機	11
第二章	實驗材料與方法	12
一、	實驗動物模型建立（Establishment of experimental animal model）	12
    （1）  4-NQO and Arecoline藥物配製（4-NQO and Arecoline preparation）	12
     （2）  4-NQO and Arecoline藥物處理（4-NQO and Arecoline  
          treatment）	13
二、 舌頭細胞分離（Tongue cell preparation）	13
  （1） 酵素製備（Enzyme preparation） 	13
    （2） 組織分解（Tissue dissociation）	14
  三、10x Genomics platform 	16
（1） 微流體單細胞分選及油滴微珠包覆 (Single cell sorting used droplet-based microfluidics and GEM generation)	 17
    （2） Post GEM-RT Cleanup and cDNA Amplification 	19
    （3） 3’ Gene Expression Library Construction  	22
  四、次世代定序（Next Generation sequencing，NGS）	28
    （1） 次世代定序平台（Illumina）	28
    （2） 次世代定序數據生物資訊分析（Bioinformatic analysis of next- generation sequencing data）	29
  五、DNA 甲基化分析（DNA methylation analysis）	29   
    （1）  DNA萃取（DNA extraction）	29
   （2）  亞硫酸鹽處理（Bisulfite treatment）	31
   （3）  引子設計（Primer design） 	32
   （4）  PCR 反應增幅（PCR amplification of target region）	33
   （5）  洋菜膠體電泳分析（Agarose gel electrophoresis） 	35
   （6）  焦磷酸定序（Pyrosequencing） 	36
  六、RNA表現量分析（RNA expression assay）	38
   （1）  RNA萃取（RNA extraction）	38
   （2）  逆轉錄聚合酶鏈式反應（reverse transcription-PCR，RT-PCR）	39
   （3）  即時定量聚合酶連鎖反應（Real-time Quantitative Polymerase  
          Chain Reaction，Q-PCR）	40
  七、蛋白質表現量分析（Protein expression assay）	43
   （1）  蛋白質萃取（Protein extraction） 	43
   （2）  蛋白質濃度測定與蛋白質樣品製備（Protein assay） 	43
   （3）  十二烷基硫酸鈉聚丙烯醯胺凝膠電泳（SDS-PAGE   
         electrophoresis） 	45
（4）  西方墨點法（Western blot） 	47
八、細胞培養 (Cell culture) 	50
   (1)  細胞株 (Cell line) 	50
   (2)  細胞解凍 (Cell thawing) 	51
   (3)  細胞繼代培養 (Subculture) 	52
   (4)  細胞凍存 (Cell freezing) 	53
第三章	實驗結果	55
  一、 實驗動物模型癌化過程	55
二、	單細胞基因檢測分析對照組與實驗組小鼠	55
三、	動物模型癌化過程所參與調控路徑	58
  四、分析對照組與實驗組DNA中GAD2和PTK6基因甲基化情形	60
  五、分析對照組與實驗組GAD2和PTK6 mRNA表現量情形	61
  六、分析對照組與實驗組GAD2和PTK6蛋白質表現量情形	62
第四章	討論	63
第五章	結論	75
參考文獻	77
圖表	83
補充資料	127

                                    

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校內：2025-08-27公開
校外：2025-08-27公開

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