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博碩士論文 etd-0029116-230311 詳細資訊
Title page for etd-0029116-230311
論文名稱
Title
GBP5,GBP6和DDX60蛋白表現與口腔癌的發展和預後之相關性
The association of GBP5, GBP6, and DDX60 expressions with the development and prognosis of oral cancer
系所名稱
Department
畢業學年期
Year, semester
語文別
Language
學位類別
Degree
頁數
Number of pages
87
研究生
Author
指導教授
Advisor
召集委員
Convenor
口試委員
Advisory Committee
口試日期
Date of Exam
2016-01-19
繳交日期
Date of Submission
2016-01-29
關鍵字
Keywords
腫瘤發展、預後、口腔鱗狀上皮細胞癌、鳥苷酸結合蛋白6、(天門冬氨酸-谷氨酸-丙氨酸-天門冬氨酸)盒多肽六十、鳥苷酸結合蛋白5
GBP5, oral squamous cell carcinoma, prognosis, tumor development, DDX60, GBP6
統計
Statistics
本論文已被瀏覽 5667 次,被下載 48
The thesis/dissertation has been browsed 5667 times, has been downloaded 48 times.
中文摘要
背景:口腔癌是全球最常見的癌症之一,且在台灣男性癌症死亡原因排行第4名。干擾素(IFNs)包括第一型干擾素(IFN-α/β)和第Ⅱ型干擾素(IFNs-γ)是宿主防禦病毒和微生物致病菌感染眾所皆知強而有力的細胞激素。然而,最近它們已被證明參與癌症發展。鳥苷酸結合蛋白(GBPs),GBP5和GBP6,屬於在癌細胞轉型上扮演重要角色的鳥苷三磷酸酶超家族。鳥苷三磷酸酶在細胞增殖、分化、訊息傳遞、細胞內蛋白運輸有發揮重要的作用。此外,GBPs的表現會被第Ⅱ型干擾素(IFN-γ)誘導。另外,(天門冬氨酸-谷氨酸-丙氨酸-天門冬氨酸)盒多肽六十(DDX60),一種DEXD / H盒解旋酶,是病毒感染時產生RIG-I或MDA5依賴性的第I型干擾素所必需的。DDX60也屬於涉及癌症發展中大多數重要細胞過程的核糖核酸解旋酶。然而,到目前為止,GBP5、GBP6和DDX60在腫瘤中的作用尚未被確定,尤其是在口腔鱗狀上皮細胞癌。本研究旨在探討口腔鱗狀上皮細胞癌患者的GBP5、GBP6和DDX60表現含量與臨床病理參數和預後之間的相關性。
方法:我們從次世代定序分析的初步數據得知,在兩對口腔鱗狀上皮細胞癌組織與相應的癌旁正常組織的配對組織中,GBP5和DDX60在口腔鱗狀上皮細胞癌組織中的表現量顯著高於相應的癌旁正常組織,GBP6在口腔鱗狀上皮細胞癌組織中的表現量顯著低於相應的癌旁正常組織。我們使用定量即時聚合酶連鎖反應評估GBP5、GBP6和DDX60分別於23對口腔頰黏膜鱗狀上皮細胞癌患者及14對舌頭鱗狀上皮細胞癌患者其配對組織(腫瘤比正常)中訊息核糖核酸的表現量;再利用免疫組織化學染色法,分析494例口腔鱗狀上皮細胞癌患者包括180例口腔頰黏膜鱗狀上皮細胞癌、241例舌頭鱗狀上皮細胞癌和73例唇鱗狀細胞癌患者組織微陣列晶片上GBP5、GBP6和DDX60蛋白質的表現量。
結果:最後統計分析結果發現免疫組織化學染色法與次世代定序分析和定量即時聚合酶連鎖反應的結果是一致的。腫瘤組織與相應的癌旁正常組織相較之下,GBP5和DDX60的表達量顯著增加(p值均小於0.005),而GBP6的表達量顯著減少(p值小於0.001)。在494例口腔鱗狀上皮細胞癌患者組織中,GBP5高表現量與年齡超過50歲(p值等於0.019)和腫瘤高分化程度(p值等於0.036)有關,而GBP6低表現量與腫瘤較差分化程度(p值小於0.001)有關。在180例頰黏膜鱗狀上皮細胞癌患者組織中,GBP5高表現量與年齡超過50歲(p值等於0.021)有關,而GBP6低表現量則與腫瘤較差分化程度(p值等於0.039)有關。在241例舌頭鱗狀上皮細胞癌患者組織中,GBP6低表現量與腫瘤較差分化程度(p值小於0.001)和淋巴結轉移(N1- N1,p值等於0.047)有關。此外,GBP6低表現量口腔鱗狀上皮細胞癌患者具有較差的疾病特異性存活率相關,尤其是對舌頭鱗狀上皮細胞癌患者。
在口腔鱗狀上皮細胞癌中,DDX60高表現量與男性(p值等於0.002)、腫瘤高分化程度相關(p值等於0.004)、病理分期晚期(Ⅲ-Ⅳ期,p值等於0.023)和較大的腫瘤 (T3-T4,p值等於0.001)有關。在頰黏膜鱗狀上皮細胞癌中,DDX60高表現量與病理分期晚期(Ⅲ-Ⅳ期,p值等於0.042)和較大的腫瘤(T3-T4,p值等於0.032)有關。在舌頭鱗狀上皮細胞癌中,DDX60高表現量與男性(p值等於0.023)、腫瘤高分化程度(p值小於0.001)和較大的腫瘤 (T3-T4,p值等於0.017)有關。此外,DDX60高表現量與唇鱗狀細胞癌患者較差的疾病特異性存活率及口腔鱗狀上皮細胞癌患者的復發率有關,尤其是舌頭鱗狀細胞癌患者。
結論:GBP5可能是腫瘤發展的生物標誌物,但不是口腔鱗狀上皮細胞癌的預測因子。GBP6可能是口腔鱗狀上皮細胞癌尤其是舌頭鱗狀細胞癌一個較好預後的預測因子。DDX60可能是口腔鱗狀上皮細胞癌腫瘤發展及預後的生物標誌物,特別是唇鱗狀細胞癌生存率和舌頭鱗狀細胞癌患者復發的預測因子。
Abstract
Backgrounds: Oral cancer is one of the most common cancers worldwide and the fourth leading cause of cancer death among males in Taiwan. Interferons (IFNs) including Type I IFNs (IFN-α/β) and type II IFNs (IFN-γ) are well-known potent cytokine in host defenses against infection with viral and microbial pathogens. However, they have been proven in malignant transformation of tumor cells. Guanylate binding protein (GBP) 5 and GBP6 belong to the guanosine triphosphatase (GTPase) superfamily, which plays an important role in cell proliferation, differentiation, signal transduction, and intracellular protein transportation. In addition, GBP expression is mostly induced by IFN-γ. On the other hand, DDX60, a subtype of DEXD/H Box Helicase, is required for RIG-I- or MDA5-dependent type I interferon production. DDX60 belongs to a DEAD box RNA helicase involving in most cellular processes, such as essential for cancer development. However, roles of GBP5, GBP6 and DDX60 in cancer especially for oral squamous cell carcinoma (OSCC) were not identified so far. The purpose of this study was to investigate the association of the expression levels of GBP5, GBP6 and DDX60 with tumorigenesis, clinicopathologic outcomes, and survival of patients with OSCC and three primary subsites.
Methods: Our preliminary data from next generation sequencing (NGS) indicated that in two pairs of OSCC and corresponding tumor adjacent normal (CTAN) tissues, the gene expressions of GBP5 and DDX60 in OSCC tissue were significant higher than that in CTAN tissue but the GBP6 gene expression in OSCC tissue was significant decreased than that in CTAN tissue. Gene expressions of GBP5, GBP6 and DDX60 were further confirmed by real-time polymerase chain reaction (RT-PCR) using 23 pairs of mucosa squamous cell carcinoma (BMSCC) and CTAN tissues as well as 14 pairs of tongue squamous cell carcinoma (TSCC) and CTAN tissues. In the study, expression levels of GBP5, GBP6 and DDX60 were examined by immunohistochemistry with tissue microarray slides of 494 OSCC patients including 180 buccal mucosal SCC (BMSCC), 241 tongues SCC (TSCC), and 73 lip SCC (LSCC) patients.
Results: The expression results of GBP5, GBP6 and DDX60 assayed by NGS, RT-PCR and immunohistochemical staining were quite consistent. GBP5 and DDX60 expressions (all p <0.05) significantly increased, whereas GBP6 (p <0.001) expression decreased in tumor tissues compared to that in CTAN tissues, indicating that GBP5 and DDX60 might be oncoproteins, but GBP6 was a tumor suppressor. Among OSCC tissues of 494 patients, the higher GBP5 expression was associated with older age over 50 yrs. (>50 yrs.; p=0.019) and well differentiation (p=0.036), whereas decreased GBP6 expression was associated with poor differentiation (p<0.001). Among BMSCC tissues of 180 patients, the GBP5 expression was positively associated with older age (>50 yrs.; p=0.021), although GBP6 expression was negatively associated with poor differentiation (p=0.039). Among TSCC tissues of 241 patients, the loss of GBP6 expression was associated with poor differentiation (p<0.001) and lymph node metastasis (N1- N2, p=0.047). Moreover, the decreased GBP6 expression was correlated with the poor disease-specific survival (DSS) for only TSCC patients. Increased DDX60 expression was associated with males (p=0.002), well differentiation (p=0.004), advanced pathological stage (III-IV, p=0.023), and large tumor size (T3-T4, p=0.001) in OSCC. Higher DDX60 expression was associated with advanced pathological stage (III-IV, p=0.042) and larger tumor size (T3-T4, p=0.032) in BMSCC. Higher DDX60 expression was positively associated with males (p=0.023), well differentiation (p<0.001), and large tumor size (T3-T4, p=0.017) in TSCC. Moreover, the elevated DDX60 expression was correlated with the poor DSS in LSCC patients, and the poor disease-free survival (DFS) in OSCC, especially in TSCC patients.
Conclusion: GBP5 may be the biomarkers for tumor development but not for prognosis in OSCC. GBP6 may be a predictor of better prognosis in TSCC. DDX60 may be the biomarkers for tumor development and prognosis of OSCC, particularly for survival of LSCC and recurrence of TSCC.
目次 Table of Contents
Chinese Abstract------------------------------------------------------------------------------------------i
English Abstract-----------------------------------------------------------------------------------------iii
Contents----------------------------------------------------------------------------------------------------vi
Abbreviation------------------------------------------------------------------------------------------------x
Chapter I: Introduction --------------------------------------------------------------------------------1
1.1 Oral Cancer -----------------------------------------------------------------------------------------1
1.2 Tumor Microenvironment & Chronic Inflammation -----------------------------------2
1.3 Guanylate Binding Proteins (GBPs) -------------------------------------------------------3
1.4 DExD/H-box RNA Helicase Family --------------------------------------------------------4
Chapter II: Specific Aims ---------------------------------------------------------------------------6
Chapter III: Materials & Methods-----------------------------------------------------------------7
3.1 Patients and Tissue Specimens -----------------------------------------------------------7
3.2 Collection of Target Cells by Laser Capture Microdissection (LCM) from Frozen
Sections ---------------------------------------------------------------------------------------------8
3.3 Hematoxylin and Eosin Stain ---------------------------------------------------------------9
3.4 Extraction of RNA from LCM Captured Cells for Next Generation Sequencing (NGS)-------9
3.5 NGS --------------------------------------------------------------------------------------------------9
3.6 RNA Extraction----------------------------------------------------------------------------------10
3.7 Quantitative Real-Time PCR Analysis -------------------------------------------------10
3.8 Tissue Microarray (TMA) Construction ------------------------------------------------12
3.9 Immunohistochemistry (IHC) --------------------------------------------------------------12
3.10 IHC Analysis and Score -------------------------------------------------------------------13
3.11 Statistical Analysis --------------------------------------------------------------------------14
Chapter IV: Results----------------------------------------------------------------------------------16
4.1 Section 1. Screening of GBP5, GBP6 and DDX60 in OSCC ------------------16
4.1.1Transcriptome profiling of OSCC, including BMSCC ----------------------------16
4.1.2 Analyze of gene expression levels of GBP5, GBP6 and DDX60 in paired tissues
of OSCC -----------------------------------------------------------------------------------------16
4.2 Section 2. Investigating the correlation of expressions levels of GBP5 and GBP6
with OSCC -------------------------------------------------------------------------17
4.2.1 Expression levels of GBP5 and GBP6 in normal tissue, CTAN tissue and tumor
tissue ---------------------------------------------------------------------------------------------17
4.2.2 Relation of GBP5 and GBP6 expressions to the demographic and clinicopathologic
outcomes in patients with BMSCC ---------------------------------------------------19
4.2.3 Relation of GBP5 and GBP6 expressions to the demographic and clinicopathologic
outcomes in patients with TSCC -------------------------------------------------------20
4.2.4 Relation of GBP5 and GBP6 expressions to the demographic and clinicopathologic
outcomes in patients with LSCC --------------------------------------------------------21
4.2.5 Relation of GBP5 and GBP6 expressions to the demographic and clinicopathologic
outcomes in patients with OSCC -------------------------------------------------------21
4.2.6 The association of expression levels of GBP5 and GBP6 with the survival of
OSCC patients --------------------------------------------------------------------------------23
4.3 Section 3. Investigating the correlation of expression levels of DDX60 with OSCC
-------------------------------------------------------------------------------------------24
4.3.1 The expression level of DDX60 in normal tissue, CTAN tissue and tumor tissue
-------------------------------------------------------------------------------------------------------24
4.3.2 Relation of DDX60 expression to the demographic and clinicopathologic outcomes
in patients with BMSCC -------------------------------------------------------------------25
4.3.3 Relation of DDX60 expression to the demographic and clinicopathologic outcomes
in patients with TSCC ----------------------------------------------------------------------26
4.3.4 Relation of DDX60 expression to the demographic and clinicopathologic outcomes
in patients with LSCC ----------------------------------------------------------------------27
4.3.5 Relation of DDX60 expressions to the demographic and clinicopathologic outcomes
in patients with OSCC ---------------------------------------------------------------------28
4.3.6 The association of the expression levels of DDX60 with the survival of OSCC
patients ----------------------------------------------------------------------------------------29
Chapter V: Discussion &Conclusion---------------------------------------------------------31
References--------------------------------------------------------------------------------------------39
Tables--------------------------------------------------------------------------------------------------47
Figures-------------------------------------------------------------------------------------------------59
Indexes------------------------------------------------------------------------------------------------74
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