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研究生：	吳妮虹 Wu, Ni-Hung
論文名稱：	建立體外及體內模型以研究具核梭桿菌在結腸癌和口腔癌所扮演的角色 Establishing in vitro and in vivo models to study the role of Fusobacterium nucleatum in colon and oral cancer
指導教授：	陳振暐 Chen, Jenn-Wei
學位類別：	碩士 Master
系所名稱：	醫學院 - 微生物及免疫學研究所 Department of Microbiology & Immunology
論文出版年：	2021
畢業學年度：	109
語文別：	英文
論文頁數：	53
中文關鍵詞：	具核梭桿菌、大腸癌動物模型、口腔鱗狀細胞癌
外文關鍵詞：	F. nucleatum, colorectal animal model, oral squamous cell carcinoma
相關次數：	點閱：220 下載：0
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大腸直腸癌是全球第三常見癌症的死亡原因。年齡、遺傳和環境因子等因素會促進大腸直腸癌的進展。近年來，大量研究證實腸道微生物群在大腸直腸癌進展中發揮了重要的作用。在先前的研究中提到，大腸直腸癌患者的16S定序結果顯示口腔病原體具核梭桿菌的豐度增加。具核梭桿菌是一種革蘭氏陰性厭氧桿菌，通常存在於口腔內已知會引起牙周炎等疾病。多項研究表明，FadA和Fap2這兩種在具核梭桿菌表面的蛋白與腫瘤增殖有關。除了這兩種表面蛋白之外，目前對其他具核梭桿菌的毒力因子能否有促進大腸直腸癌的能力並不清楚。在我們的實驗室先前為具核梭桿菌建立了一個隨機轉座子突變文庫。為了便於鑑定新的具核梭桿菌毒力因子，建立了氧化偶氮甲烷/葡聚醣硫酸鈉所誘導的大腸直腸癌小鼠模型。此外，我們將具核梭桿菌和中間普雷沃氏菌兩種菌給予到該動物模型中，以評估這些病原菌對在大腸直腸癌的作用。在我們的結果中，結合氧化偶氮甲烷/葡聚醣硫酸鈉和病原菌共同處理的遠端結腸顯著增加了腫瘤數量，且氧化偶氮甲烷/葡聚醣硫酸鈉與具核梭桿菌共同處理會使腸道上皮細胞的組織病理學檢查分數增加。此外，當病原菌存在時，小鼠會產生抗體並增加細胞因子的表達。為了研究具核梭桿菌的體外作用，我們開始了與細胞增殖、細胞遷移、細胞侵襲相關的實驗。我們建立了具核梭菌感染大腸直腸癌的動物模型，證明具核梭菌促進了大腸直腸癌的發展。我們也建立了口腔細胞相關的細胞實驗，並證實了具核梭桿菌的代謝物可以增加細胞遷移和侵襲的能力。

Colorectal cancer (CRC) is the third most common cancer cause of death worldwide. Multiple factors such as age, genetic, and environmental effects contribute to the progression of CRC. In recent years, numerous studies have confirmed that gut microbiota play an important role in CRC progression. Previously, 16S sequencing of CRC patients revealed an increase in abundance of the oral pathogen Fusobacterium nucleatum (F. nucleatum). F. nucleatum is a gram-negative anaerobic bacillus usually found within in the oral cavity and is known to cause periodontitis. Several studies have demonstrated that FadA and Fap2; two surface proteins found on the surface of F. nucleatum, is involved in tumor proliferation. Aside from these two surface proteins, nothing is currently known about any other F. nucleatum proteins that would aid in its ability to promote CRC. Previously in our lab, a random transposon mutant library was constructed for F. nucleatum. In order to facilitate the identification of novel F. nucleatum virulence factors, the azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colon cancer mice model was established. Moreover, we inoculated F. nucleatum and P. intermedia to this animal model for evaluating the contribution of these pathogens to CRC. To investigate the effects of F. nucleatum in OSCC cell, we started the experiment related to cell proliferation, cell migration, cell invasion. In our results, morphology of the distal colon from combining AOM/DSS and pathogens treatment significantly increased tumor numbers. In addition, mice produced antibodies and increased the expression of cytokines when pathogens existed. In cell experiments, we found wild type F. nucleatum can promote the migration and invasion ability of oral cells. In summary, we established the animal model of F. nucleatum infected CRC and proved F. nucleatum promote the development of CRC. We also set up the oral cell-related experiments and confirmed F. nucleatum could increase the ability of cell migration and invasion.

中文摘要 I
ABSTRACT II
致謝 III
CONTENTS IV
ABBREVIATION VIII
CHAPTER I 1
INTRODUCTION 1
1.1 Colorectal cancer 1
1.2 Risk factors of colorectal cancer 1
1.3 F. nucleatum 2
1.4 Virulence mechanism of F. nucleatum in colorectal cancer 3
1.5 CRC animal model 4
1.6 Oral squamous cell carcinoma with F. nucleatum 5
1.7 Rationale 6
CHAPTER II 7
MATERIALS AND METHODS 7
2.1 Bacterial strains and cell lines 7
2.2 Bacterial culture conditions 7
2.2.1 Fusobacterium spp. 7
2.2.2 Prevotella intermedia 8
2.3 Cell culture conditions 8
2.3.1 SG 8
2.3.2 SCC15 9
2.4 Pathogens effects in AOM/DSS mouse model 9
2.4.1 Establishment of AOM/DSS mouse model 9
2.4.2 Establishment of AOM/DSS mouse model with bacterial infection 10
2.4.3 Fecal and tissue DNA extraction and PCR 10
2.4.4 Cytokine enzyme linked immunosorbent assays (ELISA) measurement 11
2.4.5 Whole bacteria cell-coating ELISA measurement 12
2.4.6 RNA extraction and Real-time reverse transcription PCR 13
2.5 Cell proliferation assay 14
2.5.1 Seeding 14
2.5.2 Bacterial conditioned medium preparation 14
2.5.3 Co-culture of cell and conditioned medium 14
2.6 Wound-Healing Assay 15
2.7 Transwell Invasion Assay 15
2.8 Statistical analysis 15
CHAPTER III 17
RESULTS 17
3.1 Establishment of CRC animal model combine F. nucleatum and P.intermedia treatment 17
3.1.1 Combining F. nucleatum and P. intermedia to AOM/DSS model aggravates tumor severity 17
3.1.2 F. nucleatum ATCC 23726 promoted severity of histopathology in AOM/DSS model 18
3.1.3 F. nucleatum and P. intermedia could not be amplified by PCR 19
3.1.4 The cytokine protein and mRNA expression in AOM/DSS model 20
3.1.5 F. nucleatum infection could increase F. nucleatum antibody expression 20
3.2 Establishment of OSCC-related cell experiment with F. nucleatum infection 21
3.2.1 The conditioned medium of F. nucleatum ATCC 23726 was able to accelerate migration ability of oral epithelial cell 21
3.2.2 The conditioned medium of F. nucleatum ATCC 23726 and ATCC 25586 could enhance invasion ability of oral epithelial cell 22
3.2.3 The conditioned medium of wild type F. nucleatum was unable to promote oral epithelial cell proliferation 22
CHAPTER IV 24
DISCUSSION 24
REFERENCES 29
TABLES 38
Table 1. Oligonucleotide primers used in this study 38
FIGURES 39
Figure 1. Establishment of AOM/DSS mouse model procedures. 39
Figure 2. AOM and DSS treatment induced tumor formation in mice. 40
Figure 3. Histopathological stain of the dysplasia in distal colon of AOM/DSS model. 41
Figure 4. F. nucleatum and P. intermedia infection enhanced the tumor formation in AOM/DSS model. 42
Figure 5. Histopathological examination of the dysplasia in distal colon of AOM/DSS model with infection. 43
Figure 6. PCR detection of F. nucleatum and P. intermedia both fecal and tissue. 45
Figure 7. Cytokine protein and mRNA expression in AOM/DSS with infection. 46
Figure 8. The conditioned medium of wild type F. nucleatum ATCC 23726 accelerated cell migration ability. 48
Figure 9. The conditioned medium of wild type F. nucleatum ATCC 23726 facilitated cell invasion capacity. 49
Figure 10. The ability of different concentrated conditioned medium with different strain F. nucleatum promote cell proliferation. 52
SUPPLEMENTARY FIGURES 53
Supplementary Figure 1. Detection of F. nucleatum specific antibody in the serum of infected mice. 53
                                    

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