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系統識別號 U0026-2708201917202500
論文名稱(中文) 探討轉化生長因子β第三型接受器在口腔癌進展過程中的異常以及多能性
論文名稱(英文) The multi-faceted role of TGFBR3 deregulation in oral cancer progression
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 107
學期 2
出版年 108
研究生(中文) 方偉宇
研究生(英文) Wei-Yu Fang
學號 S58004046
學位類別 博士
語文別 英文
論文頁數 73頁
口試委員 指導教授-吳梨華
口試委員-張俊彥
口試委員-蔡森田
召集委員-陳玉玲
口試委員-王紹椿
口試委員-趙麗洋
中文關鍵字 口腔癌  TGF-β  TGFBR3  GIPC1  Angiogenin 
英文關鍵字 Oral cancer  TGF-β  TGFBR3  GIPC1  Angiogenin 
學科別分類
中文摘要 TGF-β是一個多功能的分子,能夠控制許多不同種類細胞的生長、分化、移動以及型態改變TGFBR3在TGF-β訊息傳導中扮演著很重要的角色,它是TGF-β的共同接受器。越來越多的研究發現TGFBR3在不同種類的癌症中有相反的角色,可能是腫瘤抑制基因,抑或是致癌基因。然而,有關TGFBR3在口腔癌扮演甚麼樣的角色,以及背後相關的詳細機轉仍有待釐清。在我們的研究中發現,TGFBR3表現量在口腔癌患者的組織有減少的情形,不論是利用化學免疫染色或是即時聚合酶連鎖反應。而TGFBR3啟動子的甲基化現象以及TGF-β1的表現是造成TGFBR3在口腔癌表現下降的兩個原因。我們利用大量表現或降低表現的實驗方式來探討在口腔癌細胞中TGFBR3所造成的影響。雖然TGFBR3對於口腔癌細胞的生長影響有細胞特異性的結果。但大量表現TGFBR3在口腔癌細胞不但會降低細胞移動和侵犯能力,也會降低從原位癌轉移到週邊淋巴結的能力。相反的,若是降低TGFBR3的表現,則會增加細胞的移動和侵犯能力。此外,對於TGF-β的訊息傳導來說,TGFBR3是做為一個抑制訊號傳遞的角色。我們也發現TGFBR3透過其位於膜內的蛋白質區域與GIPC1結合,來達到抑制細胞的移動以及侵犯能力。而TGFBR3大量表現的口腔癌細胞所分泌的蛋白質也同樣具有抑制腫瘤的功能,不論是在腫瘤細胞或是基質細胞中都可得到驗證。進一步分析發現Angiogenin這個蛋白質會受到TGFBR3的表現量而調控,實驗發現Angiogenin或許是TGFBR3所調控的腫瘤抑制功能的下游重要因子,且Angiogenin的表現情形與SMAD4有關。這些結果顯示TGFBR3在口腔癌癌化過程中確實是扮演腫瘤抑制基因的角色,且本研究可以促進未來利用TGFBR3的腫瘤抑制功能來達到治療口腔癌的效果。
英文摘要 TGF-β type III receptor (TGFBR3), a co-receptor for TGF-β family members, is required for the high-affinity binding of ligands to their receptors to initiate their cellular function. More and more studies showed an opposing role of TGFBR3, tumor suppressor or oncogene, in different cancer types. However, the exact role of TGFBR3 and the responsible mechanism in oral cancer remains to be characterized. By using immunohistochemical staining and real-time PCR, we found a down-regulation of TGFBR3 in oral cancer tissues when compared to their adjacent normal counterparts. Low TGFBR3 expression patients tend to have poor clinical outcome compared with high expression patients. Furthermore, promoter methylation and TGF-β1 expression were involved in the decrease of TGFBR3. To examine the role of TGFBR3 in oral cancer cells, we not only stably expressed shRNAs specific to TGFBR3 but also overexpressed TGFBR3, respectively, in oral cancer cells. TGFBR3 overexpression decreased cell migration, invasion and metastasis. Oral cancer cells with down-regulated TGFBR3 expression exhibited increased migration and invasion compared with control cells. TGFBR3 functions as a sink for TGF-β signaling. The cytoplasmic domain of TGFBR3 had a role in TGFBR3-mediated inhibition of migration and invasion through GIPC1 protein. Moreover, the conditioned medium from TGFBR3-overexpressing cancer cells also harbored tumor suppressive effects both on tumor cells and stromal cells. By using cytokine array, we found angiogenin could potentially serve as a downstream effector for TGFBR3-mediated tumor suppression. Moreover, the increased expression of angiogenin in TGFBR3-overexpressing cancer cells might depend on SMAD4. These data indicated the TGFBR3 act as a tumor suppressor in oral carcinogenesis. This study should facilitate the possibility of using TGFBR3-mediated tumor suppression for oral cancer treatment.
論文目次 INTRODUCTION 4
 Oral cancer and its genetic alterations 4
 Transforming growth factor-β (TGF-β) and TGF-β receptors 5
 Transforming growth factor-β receptor type 3 (TGFBR3) 6
 The contrasting role of TGFBR3 deregulation in cancer 7
 Tumor microenvironment (TME) 8
 Cancer-associated fibroblasts (CAFs) 8
 Endothelial cells (ECs) 9
SPECIFIC AIMS 11
MATERIALS AND METHODS 12
 Materials 12
 Patient specimens 12
 IHC staining 12
 Cell culture 13
 Isolation and cultivation of oral CAFs and NFs 13
 Human TGFBR3-expressing stable clone establishments 13
 RNA interference 14
 Quantitative RT-PCR (qRT-PCR) 14
 Nuclear and cytosol fractionation 15
 Western Blot analysis 15
 CM preparation 16
 Cell proliferation assay 16
 Wound healing assay 16
 Invasion assay 16
 Cytokine array 17
 Angiogenin ELISA assay 17
 Endothelial tube formation assay 18
 Xenograft transplantation and buccal metastasis model 18
 Promoter-driven luciferase reporter assay 18
 Statistical analysis 19
RESULTS 20
 Decreased TGFBR3 expression in oral cancer clinical specimens 20
 No alterations of TGFBR3 expression in most oral cancer cell lines 20
 The involvement of promoter methylation and TGF-β1 expression in the down-regulation of TGFBR3 21
 TGFBR3 overexpression decreased oral cancer cells motility and invasion 22
 TGFBR3 silencing increased oral cancer cells motility and invasion 22
 Ectopic TGFBR3 expression decreased lymph node metastasis while having no effect on xenograft tumorigenicity 23
 TGFBR3 inhibited TGF-β1-mediated signal transduction and migration/invasion in oral cancer cells 23
 The cytoplasmic domain of TGFBR3 had a role in TGFBR3-mediated inhibition of migration and invasion 24
 The effects of CM from TGFBR3-manipulated cancer cells on cancer cells, fibroblasts and endothelial cells 25
 Angiogenin levels were increased in TGFBR3-overexpressing OC-2 cells while decreased in TGFBR3-knockdown OC-2 cells 26
 The increase of angiogenin expression in TGFBR3-expressing cells was dependent on SMAD4 27
DISCUSSION 29
REFERENCES 34
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