系統識別號 U0026-2508202019034900
論文名稱(中文) 血漿型凝溶膠蛋白作為口腔癌生物標記物及其功能性角色
論文名稱(英文) Plasma gelsolin as a biomarker of head and neck cancer and its functional roles
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 108
學期 2
出版年 109
研究生(中文) 邱貞慈
研究生(英文) Chen-Tzu Chiu
學號 S58001284
學位類別 博士
語文別 英文
論文頁數 82頁
口試委員 指導教授-謝達斌
中文關鍵字 血漿凝溶膠蛋白  細胞質凝溶膠蛋白  頭頸癌  細胞移動能力 
英文關鍵字 plasma gelsolin  cytosolic gelsolin  head and neck cancer  cell motility 
中文摘要 凝溶膠蛋白是一種多功能肌動蛋白結合蛋白,可調節細胞結構,運動性和凋亡。 凝溶膠蛋白的兩種最豐富和最著名的亞型是血漿凝溶膠蛋白和胞質凝溶膠蛋白,血漿凝溶膠蛋白與胞質凝溶膠蛋白的區別在於其分泌出細胞後N端氨基端肽仍保留在成熟蛋白中。據研究指出,胞質凝溶膠蛋白可以預測頭頸癌和其他惡性腫瘤的疾病進展,而循環中的血漿凝溶膠蛋白濃度則與感染與發炎疾病的預後密切相關。近年來,我們發現胞質凝溶膠蛋白通過常見的分子信號傳遞來調控頭頸癌的耐藥性。然而,血漿凝溶膠蛋白在癌症進展和預後中的潛在能力仍有待研究。在這項研究中,證實了在具有更高的轉移能力SCC25細胞培養基中與HONE-1細胞相比有更高血漿凝溶膠蛋白的表現。此外,我們的結果表明,透過整合蛋白(integrin)依賴性吞噬作用,經外源血漿凝溶膠蛋白誘導後,細胞內凝溶膠蛋白表現隨著外源型血漿凝溶膠蛋白濃度增加而增加。此外,內生性血漿凝溶膠蛋白的過度表達或剃除證明了血漿凝溶膠蛋白在上皮-間質轉化和遷移以及細胞侵襲中的正向作用。這些結果表明,血漿凝溶膠蛋白在頭頸癌中具有調節腫瘤活性的作用。除此之外,頭頸癌盤據台灣前十大死因排名之中,當疾病越晚期被診斷,存活率也會隨之降低。儘管晚期診斷是導致頭頸癌死亡的主要因素,但目前尚無令人滿意的生物標記物可用於早期頭頸癌檢測。血漿凝溶膠蛋白是人體循環系統中最豐富的蛋白質之一,也是發炎反應的指標,或許可做為頭頸癌的生物標記物和患者臨床預後指標。經由比對202名頭頸癌患者和45名健康對照後,我們證明頭頸癌患者血液中的血漿凝溶膠蛋白濃度顯著低於健康對照組。此外,血液中的血漿凝溶膠蛋白做為頭頸癌的獨立診斷生物標誌物,在檢測靈敏性 (82.7%)和特異性(95.6%)均優於其他候選生物標記物。同時,血漿凝溶膠蛋白和sFasL的結合,更可在早期疾病檢測中達到更高的偵測靈敏度(90.6%)。此外,血中較高的血漿凝溶膠蛋白可預測5年後較高的總生存率和無疾病進展生存率。因此,血漿凝溶膠蛋白不僅在癌症的遷移和侵襲中扮演角色,還可以獨立作為臨床預後預測因子,同時結合sFasL 可在早期頭頸癌作為新型生物標記物。
英文摘要 Gelsolin (GSN) is a multifunctional actin-binding protein that acts as a regulator of cell structure, motility and apoptosis. The two most abundant and well-known isoforms of GSN are plasma and cytosolic GSN (cGSN), plasma gelsolin (pGSN) differs from cGSN by an extended amino-terminal peptide which remains in mature protein after secretion. It has been reported that cGSN could predict disease progression in head and neck cancer (HNC) and other malignancies, while circulating pGSN levels significantly correlate with the prognosis of infectious and inflammatory diseases. In recent years, we discovered that cGSN modulates drug resistance in HNC through a common molecular signaling regulation. However, the potential roles of pGSN in cancer progression and prognosis remain elusive. In this study, the higher expression of pGSN in the medium of SCC25 was confirmed, which has a higher metastatic ability compared to HONE-1 cells. Our results showed that intracellular GSN protein levels were augmented in a dose-dependent manner upon exogenous pGSN-induction through integrin-dependent endocytosis. Furthermore, overexpression or knockdown of endogenous pGSN demonstrated the confident role of pGSN in epithelial-mesenchymal transition and migration as well as invasion of cells. These results suggested the role of pGSN in HNC to act as a tumor activity modulator. Besides, HNC ranks top ten causes of death in Taiwan, and the mortality increases considerably when the disease is diagnosed in its late stages. Despite late diagnosis being a major factor contributing to HNC mortality, no satisfactory biomarkers exist for early disease detection. As one of the most abundant proteins in circulatory system and testified indicator of inflammation modulator, the pGSN may serve as a biomarker for HNC and as the predictor of patients’ clinical outcome. After screening 202 patients with HNC and 45 healthy controls, we demonstrated that circulating pGSN levels were significantly lower in patients with HNC than in healthy controls. Moreover, circulating pGSN outperformed other candidate biomarkers as an independent diagnostic biomarker of HNC in both sensitivity (82.7%) and specificity (95.6%). Receiver operating characteristic curves indicated that combined pGSN and sFasL levels further augmented this sensitivity (90.6%) for early disease detection. Moreover, higher pGSN levels predicted improved prognosis at both 5-year overall survival and progression-free survival. We conclude that pGSN not only plays a role in cancer migration and invasion, but also could be an independent predictor of favorable clinical outcomes and a novel biomarker for the early HNC detection in combination with sFasL.
論文目次 中文摘要 I
Abstract III
誌謝 V
Table of Contents VI
List of Tables IX
List of Figures X
Introduction 1
1-1 The socioeconomic impact of head and neck cancer in Taiwan 2
1-2 Structure of gelsolin and its relation with actin dynamic regulation 2
1-3 Biological functions of gelsolins 3
1-4 Gelsolin and cancers 4
1-5 Prognostic Value of pGSN in multiple clinical conditions 6
Motivation and Rationale 7
Significance 7
Materials and Methods 9
2-1 Reagents 10
2-2 HNC cell culture 10
2-3 Transfection of pGSN plasmid DNA or siRNA 10
2-4 RNA Interference and establishment of stable clone 11
2-5 Isolation of RNA and Quantitative Real-Time RT-PCR 11
2-6 Internalization of pGSN in HONE-1 cells 12
2-7 Fluorescence conjugated with pGSN recombinant protein 12
2-8 Cellular uptake and confocal laser scanning microscopy analysis 13
2-9 Immunogold Labelling 13
2-10 Transwell assay 13
2-11 Preparation of concentrated culture medium 14
2-12 Western blot analysis 14
2-13 Ethics statement 15
2-14 Clinicopathological characteristics and collection of plasma samples 15
2-15 Immunohistochemical grading of pGSN expression 16
2-16 Circulating pGSN and SCC-Ag detection from patient’ plasma using sandwich ELISA 16
2-17 Circulating biomarker detection 17
2-18 Data analysis 18
Results 20
3-1 SCC25 presented higher pGSN expression than HONE-1 cells 21
3-2 Exogenous pGSN upregulated intracellular GSN protein levels but not mRNA levels …………………………………………………………………………….21
3-3 Exogenous pGSN augmented intracellular GSN was demonstrated by GSN knockdown stable clones 21
3-4 Exogenous pGSN entered HONE-1 cells which upregulated intracellular GSN through integrin signaling 22
3-5 Cellular uptake of exogenous pGSN into HONE-1 cells 22
3-6 Exogenous pGSN increased the motility of HONE-1 cells in vitro 23
3-7 Modulating pGSN expression confer carcinogenic phenotypes in HONE-1 cells………………………………………………… ……………… ………….23
3-8 Overexpression of pGSN correlated with the promotion of migration and invasion in HONE-1 cells 23
3-9 Knockdown of pGSN in SCC25 decreased EMT and migration as well as invasion 24
3-10 Patient characteristics 24
3-11 Expression levels of pGSN in HNC patients 25
3-12 Diagnostic value of circulating pGSN in patients with HNC 25
3-13 pGSN as a valuable diagnostic tool for early HNC stage 26
3-14 Survival analysis of circulating pGSN in validation datasets 27
3-15 Prognostic impact of circulating pGSN and its relationship with other clinicopathological parameters 28
Discussion 29
Conclusion 38
References 40
Tables 53
Figures 57
Curriculum Vitae 81
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