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研究生:陳威昌
研究生(外文):CHEN, WEI-CHUNG
論文名稱:探索提高食道癌生存率的潛在因素:喝茶、PD-L1免疫療法和Elafin蛋白分布的角色
論文名稱(外文):Investigating Potential Factors for Improving Survival Rates in Esophageal Cancer: The Role of Tea Consumption, PD-L1 Immunotherapy, and Elafin Protein Distribution
指導教授:吳宜珍吳宜珍引用關係
指導教授(外文):WU, I-CHEN
口試委員:陳立宗白禮源王文倫張維倫
口試委員(外文):CHEN, LI-TZONGBAI, LI-YUANWANG, WEN-LUNCHANG, WEI-LUN
口試日期:2023-10-13
學位類別:博士
校院名稱:高雄醫學大學
系所名稱:環境職業醫學博士學位學程
學門:醫藥衛生學門
學類:公共衛生學類
論文種類:學術論文
論文出版年:2023
畢業學年度:112
語文別:英文
論文頁數:157
中文關鍵詞:食道鱗狀上皮癌喝茶預後
外文關鍵詞:esophageal squamous cell carcinomateaprognosisPD-L1Elafin
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食道癌是一種侵略性極強的癌症,治療晚期/不可切除食道癌的方法非常有限。即使進行完整的化療和放療(CRT)以及最佳的支持治療,晚期食道鱗狀細胞癌(ESCC)患者的五年生存率仍低於20%。ESCC的發病風險因素與酒精消費、吸煙和嚼檳榔高度相關,這些也是台灣藍領工人的常見習慣。我們發現,喝茶的習慣可以減少頭頸部鱗狀細胞癌患者同步食道腫瘤的風險,特別是在那些具有三種風險因素的患者中。綠茶中含量豐富的表兒茶素-3-没食子酸酯(EGCG)也可以通過AKT和ERK1/2通路以與活性氧無關的方式減少檳榔鹼誘導的癌細胞增殖和集落形成。為了探索提高ESCC患者生存率的可能性,我們評估了抗程序性死亡配體1(PD-L1)免疫治療的可能性,並在同步CRT之前和之後檢查了ESCC組織中的PD-L1和CD8蛋白質表達量。在總共64名患者中,PD-L1陽性率為54.7%,在23名配對患者中為52.2%。64名患者的腫瘤中PD-L1 H分數較高與預後不良有關(校正危險比= 2.81;p = 0.02),23名配對患者也得出了相同的結果(校正危險比= 3.46;p = 0.03)。在23名配對患者中,接受同步CRT後PD-L1表達呈下降趨勢,CD8陽性信號增加。在第三項研究中,我們發現了一種名為elafin的分泌蛋白,它通過調節上皮-間質轉換可促進侵襲和遷移。通過三維組織影像掃描,我們發現,elafin的分布呈現出一種交織狀的纖維結構,在具有高elafin血清水平和預後不佳的患者的組織基質中散布,而在血清elafin水平較低且預後較好的患者中,elafin的分布則局限於腫瘤巢內或周圍。總之,我們的研究結果表明,飲用茶類減少同步食道腫瘤的風險可能來自EGCG的作用,CRT的治療過程可能導致ESCC腫瘤上PD-L1表達呈下降趨勢,而ESCC組織內elafin蛋白的分布狀態可作為預後指標。
Esophageal cancer is one of aggressive cancers that had limited courses to treat advanced/unresectable esophageal cancer. Even with full course of chemoradiotherapy (CRT) and the best supportive treatment, the 5-year survival rate is still below 20% on advanced esophageal squamous cell carcinoma (ESCC) patients. The risk factors of ESCC occurrence are highly related with alcohol consumption, cigarette smoking and betel nut chewing, which also correlated with the hobbies of blue-collar worker in Taiwan. We had found tea consumption could reduce the risk of synchronous esophageal neoplasm in head and neck squamous-cell carcinoma patients, especially in those with three risk factors. The epigallocatechin-3-gallate (EGCG), which is abundant in green tea, also decreased arecoline induced cancer cell proliferation and colony formation via AKT and ERK1/2 cascade with reactive oxygen species-independent manner. To explore possibility for increasing the survival rate of ESCC, we had evaluated the possibility of anti- programmed death ligand 1 (PD-L1) immunotherapy, the second study we had examined the PD-L1 and CD8 expression in ESCC tissues before and after concurrent CRT. The prevalence of PD-L1 positivity was 54.7% in total 64 patients and 52.2% in paired 23 patients. High pre-CCRT PD-L1 H-score in tumors from 64 patients was related to poor prognosis (adjusted hazard ratio = 2.81; p = 0.02), and same result obtained from 23 paired patients (adjusted hazard ratio = 3.46; p = 0.03). In 23 paired patients, a trend of decreased PD-L1 expression and increased CD8 positive signal after receiving concurrent CRT. The third study we discovered a secretory protein named elafin which showed invasion and migration promoting ability though regulated epithelial-to-mesenchymal plasticity. Under three-dimensional tissue scanning, the distribution of elfin scattered as an interweaved-like fibrous structure in the stroma of tissue obtained from patients with high serum levels of elafin and poor prognoses, whereas confined inside or around the tumor nest in patients who had lower serum levels and better survival. In conclusion, our findings suggested the reduced risk of synchronous esophageal neoplasm from tea consumption may come from EGCG, the treatment course of CRT may cause decreasing trend of PD-L1 expression on ESCC tumor, and the distribution of elafin protein inside ESCC tissue may serve as prognosis indicator.
中文摘要 ii
Abstract iv
致謝 vi
目次 vii
List of Figures xi
List of Tables xiii
Chapter I Background 1
1.1 Introduction of esophageal cancer and esophageal squamous cell carcinoma in Taiwan 1
1.2 Second cancer of head and neck squamous-cell carcinoma (HNSCC) 3
1.3 Immune checkpoint inhibitor on ESCC 5
1.4 Introduction of elafin 8
Chapter II Material and Methods 10
2.1 The material and method used in “Influence of tea consumption on the development of second esophageal neoplasm in patients with head and neck cancer” 10
2.1.1 The study population of esophageal squamous cell neoplasm 10
2.1.2. Substance Use and Demographic Data Collection 11
2.1.3. Esophageal Cancer Cell Lines and Chemicals 11
2.1.4. Cell viability and proliferation assay 12
2.1.5 DCFH-DA Cellular ROS Assay 12
2.1.6. Colony formation assay 13
2.1.7. Western Blot 14
2.1.8. Statistical Analysis 15
2.2 The material and methods used in “Change in PD-L1 and CD8 expression after chemoradiotherapy for esophageal squamous cell carcinoma” 15
2.2.1 Patients and Specimens 16
2.2.2 Immunohistochemistry Staining for PD-L1 and CD8 16
2.2.3. Quality Control for PD-L1 of E1L3N Clone 18
2.2.4. Evaluation of PD-L1 and CD8 18
2.2.5. Statistical Analysis 19
2.3 The material and methods used in “Three-dimensional optical images and mechanisms of elafin expression underlying locoregional esophageal squamous cell carcinoma aggressiveness” 20
2.3.1 Selection of ESCC patients to provide sample for 3-D imaging 20
2.3.2 Sample preparation for 3-D imaging and confocal imaging acquisition 21
2.3.3 Processing of 3-D tissue images 23
2.3.4 3-D tissue rendering and modeling 24
2.3.5 Elafin expression in tissue arrays of resected ESCC specimens 25
2.3.6 Elafin mRNA expression in TCGA dataset 26
2.3.7 Cell lines and cell culture 27
2.3.8 Plasmids, short hairpin RNAs, and lentivirus production 28
2.3.9 Immunoblot analysis 30
2.3.10 Cell proliferation assay 31
2.3.11 Cell motility and invasion assays 31
2.3.12 Statistical Analysis 32
Chapter III Results 35
3.1 Influence of tea consumption on the development of second esophageal neoplasm in patients with head and neck cancer 35
3.1.1 Factors Associated with the Development of Synchronous Esophageal Neoplasm in HNSCC Patients 35
3.1.2 EGCG Suppressed Low-Concentration Arecoline-Induced Proliferation and Colony Formation of ESCC Cells 36
3.1.3 EGCG Suppressed Arecoline-Induced Akt and ERK1/2 Phosphorylation Through An ROS-Independent Pathway 38
3.1.4 Inhibition of Akt Phosphorylation Suppressed Arecoline-Induced ESCC Cell Proliferation and Colony Formation. 39
3.2 Change in PD-L1 and CD8 expression after chemoradiotherapy for esophageal squamous cell carcinoma 40
3.2.1 Study Subjects 40
3.2.2 Down Regulation of PD-L1 in ESCC after CCRT Treatment 41
3.2.3 Prognostic Relevance of Tumor PD-L1 Expression in ESCC Patients 41
3.2.4 CD8 Positive Cells in Tumor Specimens before and after CCRT 43
3.3 Three-dimensional optical images and mechanisms of elafin expression underlying locoregional esophageal squamous cell carcinoma aggressiveness 44
3.3.1 Selection of locoregional ESCC patients for 3-D tissue imaging 44
3.3.2 The distinct 3-D spatial distribution of elafin expression in ESCC patients with different prognoses 44
3.3.3 Overexpression of elafin protein in tissue arrays of resected ESCC specimens 46
3.3.4 Elafin increased proliferation, migration and invasion of the ESCC cell lines 47
3.3.5 Elafin induced epithelial-to-mesenchymal transition 47
Chapter IV Discussion 50
4.1 Discussion of “Influence of tea consumption on the development of second esophageal neoplasm in patients with head and neck cancer” 50
4.2 Discussion of “Change in PD-L1 and CD8 expression after chemoradiotherapy for esophageal squamous cell carcinoma” 56
4.3 Discussion of “Three-dimensional optical images and mechanisms of elafin expression underlying locoregional esophageal squamous cell carcinoma aggressiveness” 61
Chapter V Future Perspectives 66
5.1 Future Research Directions 66
5.2 Application and Implementation 66
5.3 Challenges and Opportunities 67
5.4 Emerging Trends 67
Chapter VI Summary 68
6.1 Key Findings 68
6.2 Implications 68
6.3 Future Research Directions 69
Chapter VII References 70
Chapter VIII Figure and Tables 85
Chapter IX Appendix 143


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