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系統識別號 U0026-2707202016431500
論文名稱(中文) 探討口腔微生物相對口腔癌形成的影響
論文名稱(英文) The effect of oral microbiota on the oral carcinogenesis
校院名稱 成功大學
系所名稱(中) 口腔醫學研究所
系所名稱(英) Institute of Oral Medicine
學年度 108
學期 2
出版年 109
研究生(中文) 黃冠智
研究生(英文) Kuan-Chih Huang
學號 T46071012
學位類別 碩士
語文別 英文
論文頁數 58頁
口試委員 指導教授-陳玉玲
口試委員-洪澤民
口試委員-吳梨華
口試委員-黃振勳
中文關鍵字 口腔癌  微生物相 
英文關鍵字 oral cancer  microbiota 
學科別分類
中文摘要 口腔癌是全球第五大常見癌症,在台灣男性癌症死亡率中排名第四。人類微生物相是存在於人體組織以及體液的微生物群體。在口腔中就有25,000多種細菌,且與口腔的健康有密切的相關性。例如,目前已知Porphyromonas gingivalis 和 Aggregatibacter actinomycetemcomitans與牙周病有密切的相關性;而Streptococcus mutans 則與齲齒有關。但是口腔癌與口腔細菌之間的關係目前仍然不清楚。在本研究中,我們首先透過致癌物誘導口腔癌小鼠模型來了解抗生素的處裡對口腔癌形成的影響。結果顯示,4-硝基喹啉1-氧化物/檳榔鹼(4-NQO/arecoline)誘導的口腔上皮增生在抗生素處理的組別相較於控制組多。但有趣的是,抗生素處理的組別(0/9)則是口腔癌惡轉的比例較控制組(3/10)明顯降低。我們也收集老鼠的唾液透過次世代定序來分析其中的微生物相組成,並比較了對照組和抗生素處理組與有長腫瘤和沒長腫瘤小鼠之間口腔微生物相的變化。分析結果顯示,有長腫瘤的小鼠口腔內的微生物相豐富度較低。另外,Lactobacillus sp. 在抗生素處理組別中增加最多,而且在有長腫瘤小鼠中的減少最多。此外我們也探討人類口腔疣狀增生相關的菌株 Streptococcus anginosus 對人類口腔癌細胞株癌變相關機制的影響,我們發現Streptococcus anginosus會影響口腔癌細胞增生、遷移的信號傳導介質的表現量。增生及遷移的能力在與Streptococcus anginosus 共同培養後有受到明顯的抑制但熱抑制過後的Streptococcus anginosus則不會。我們同時也將口腔癌細胞OC2皮下注射到NOD-SCID小鼠來觀察Streptococcus anginosus是否影響口腔癌的生成,結果指出,Streptococcus anginosus的確會顯著的抑制腫瘤的生長。因此,我們認為Streptococcus anginosus在口腔癌形成的過程中扮演一個保護性的角色。釐清口腔菌相對口腔腫瘤發生的影響與機制,將有助於對口腔癌惡性轉化的預防及了解。
英文摘要 Oral cancer is the fifth most common cancer in the worldwide and ranks fourth in Taiwan for male cancer mortality. The human microbiota is the aggregate of microorganisms that resides on or within any of human tissue and biofluids. Oral cavity has more than 25,000 bacteria which are closely to the health of oral cavity. For example, Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans are associated with periodontal disease and Streptococcus mutans is associated with caries. But the relationship between oral cancer and oral microbiota is still unclear. In this study, we first evaluated the effect of antibiotics in carcinogen-induced oral cancer mouse model. The results showed that 4-nitroquinoline 1-oxide (4-NQO)/arecoline-induced oral epithelial hyperplasia are increased in antibiotic-treated group (n =9) than control mice (n = 10). But interestingly, malignant transformation rate was obviously decreased in antibiotic-treated group (0/9) compared with control group (3/10). We also analyzed the microbiota of murine saliva by next-generation sequencing (NGS) and compared the alteration of microbiota between control versus antibiotics-treated group and tumor-bearing versus no-tumor-bearing mice. The data showed that the diversity of microbiota was decreased in tumor bearing mice. Lactobacillus sp. was the most increased in the antibiotic treated group and also the most decreased in the tumor-bearing mice. Moreover, we also investigated the effect of human oral verrucous hyperplasia-associated bacteria Streptococcus anginosus on human oral cancer cells. We found that some tumor proliferation and migration mediators of oral cancer cells were suppressed by Streptococcus anginosus treatment. The proliferation and migration ability were significantly inhibited after Streptococcus anginosus co-culture but not by heat-inactivated Streptococcus anginosus. The effect of Streptococcus anginosus on oral cancer formation was investigated in xenograft mouse models by a subcutaneous injection of Streptococcus anginosus-treated OC2 cells into NOD-SCID mice. The results indicated that tumor growth of OC2 was suppressed after co-culturing Streptococcus anginosus. Therefore, we considered that Streptococcus anginosus was a preventive microbiome in oral carcinogenesis. Clarifying the effects and mechanisms of oral bacteria on the oral tumorigenesis will help prevent and understand the malignant transformation of oral cancer.
論文目次 Abstract in Chinese I
Abstract III
Acknowledgement V
Contents VI
Figure content IX
Abbreviations XI
Chapter 1. Introduction 1
I. Oral squamous cell carcinoma 1
II. Microbiota 2
III. Cancer and microbiota 2
IV. Oral disease and microbiota 3
V. Oral cancer and microbiota 3
VI. Microbiome mentioned in our study 4
VII. The carcinogens in our study. 5
VIII. The antibiotics in our study. 5
Chapter 2. Objectives of study 7
Chapter 3. Materials and Methods 8
1. Cell lines and cell culture 8
2. Bactria culture and counting 8
3. Heat inactivation of S. anginosus 9
4. Co-culture of OC2 cell and S. anginosus 9
5. Proliferation assay 10
6. In vitro wound healing assay 10
7. Mouse fecal genomic DNA (gDNA) extraction 10
8. Mouse saliva collection and genomic DNA (gDNA) extraction 10
9. Bacteria-specific 16S rDNA amplification and next generation sequencing (NGS) 11
10. Western blot assay 11
11. 4-NQO/Arecoline-induced murine oral cancer formation 12
12. Hematoxylin and Eosin (H&E) stain 13
13. Xenograft animal model 13
14. Statistical analysis. 13
Chapter 4. Results 14
I. The effects of antibiotics-induced microbiome depletion in 4-Nitroquinoline 1-oxide (4-NQO)/arecoline-induced murine oral tumorigenesis 14
II. The alteration of microbiota after antibiotics treatment. 15
III. The effects of S. anginosus on the biological functions of oral cancer cells 17
IV. S. anginosus inhibit the migration ability of OC2 cell after co-culture 17
V. Tumor progression of the OC2 cells was inhibited by S. anginosus 19
Chapter 5. Discussion 20
Chapter 6. Conclusion 24
References 26
Figures 35
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