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系統識別號 U0026-0108201302042200
論文名稱(中文) TG交互因子之過度表現與上尿路上皮細胞癌預後和gemcitabine治療抗藥性相關研究
論文名稱(英文) Overexpression of TG-interacting factor is associated with worse prognosis and gemcitabine resistance in upper urinary tract urothelial carcinoma
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 101
學期 2
出版年 102
研究生(中文) 葉碧雯
研究生(英文) Bi-Wen Yeh
學號 S58941303
學位類別 博士
語文別 英文
論文頁數 117頁
口試委員 指導教授-黃暉升
口試委員-王憶卿
召集委員-吳文正
口試委員-蔡宗欣
口試委員-戴明泓
口試委員-莊正鏗
中文關鍵字 TG-交互因子(TGIF)  尿路上皮細胞癌  膀胱  上泌尿道上皮癌 ,AKT, Gemcitabine,化療藥物抗藥性 
英文關鍵字 TG-interacting factor (TGIF)  Urothelial carcinoma  Bladder  Upper urinary tract urothelial carcinoma ,AKT,Gemcitabine,Drug resistance 
學科別分類
中文摘要 預測術後的預後有利於上尿路上皮癌患者的有效治療決策。然而,至今它的預後生物標誌物沒有很好地確立。在本研究中,我們以168位人類上尿路上皮癌的手術組織標本來進行TGIF的表現研究,結果顯示,TGIF在上尿路上皮癌腫瘤組織的細胞核有過度表現的患者與較差的無進展生存期和較高的癌症相關死亡有顯著的相關。當TGIF和p21的表達同時發生改變,這些患者比那些只帶有一個標記改變或沒有標記改變的人有更壞的預後。此外,為了闡明TGIF在尿路上皮癌疾病進展過程中的作用,我們在RT4或TSGH8301細胞進行TGIF的過度表達,結果顯示,TGIF可以經由PI3K/AKT的通路而有意義的增加細胞遷移/侵犯的能力,以及基質金屬蛋白酶的表達和侵襲偽足的形成。相對的,將T24細胞株的TGIF以其特異性的shRNA來降低其活性,會造成T24細胞的細胞轉移和侵犯能力受到抑制。此外,TGIF亦可以抑制p21的表現,增加調控cyclin D1表現,磷酸化Rb,而促進G1-S週期轉變和細胞增殖。現今,gemcitabine與cisplatin(GC)的合併使用已被廣泛應用於局部晚期和轉移性尿路上皮癌,作為一個標準的化療方案。雖然末期尿路上皮癌是一種對化療敏感性的腫瘤,但使用後之化療藥物抗藥性卻是治療轉移性尿路上皮癌的一大障礙。我們在27位具侵犯與轉移性的上尿路上皮癌患者接受GC全身性化療的研究,結果發現:當TGIF以及p-AKT皆有變異時,增加這些患者的疾病進展與存活明顯有意義的減少。研究亦發現TGIF除有助於尿路上皮癌細胞增殖與侵犯性外,TGIF的表現程度會影響細胞對gemcitabine的反應。對照於原始尿路上皮癌細胞株NTUB1細胞,發現在具有對gemcitabine的抗藥性尿路上皮癌細胞(NTUB1/ G)株,其TGIF是過度表現並帶有較高侵犯能力。降低TGIF會導致NTUB1/ G細胞株的細胞生長與遷移能力下降,並增加對gemcitabine的敏感性,此過程與PI3K/AKT路徑有關。此外,在NTUB1細胞過度表達TGIF會減弱NTUB1細胞對gemcitabine的敏感性。另外,以gemcitabine治療NTUB1細胞會導致TGIF及P-AKT表現增加,但p21的表現會下降。相比之下,HDAC或PI3K/AKT路徑抑制劑治療則會導致減少TGIF,P-AKT,MMP9,但增加了p21基因的表達和抑制遷移的能力。綜上所述,本研究結果證明,TGIF有助於透過PI3K/AKT途徑造成尿路上皮癌的疾病進展。此外,TGIF的過度表現與活化AKT的磷酸化,在尿路上皮癌的腫瘤發生和gemcitabine化療抗藥發病機制占有一定的角色。基於上述研究結果,我們可以得出結論,TGIF的狀態可能是一個有用的預後指標,可依據之選擇更合適的病人去接受更理想的治療方式。
英文摘要 Prognostic outcome prediction would be useful to upper urinary tract urothelial carcinoma (UUT-UC) patients’ effective therapeutic intervention. However, its prognostic biomarkers are not well established so far. According to the analyzed results of 168 human UUT-UC specimens, patients with overexpressed TG-interacting factor (TGIF) in nuclei of tumor tissues are significantly correlated with poor progression-free survival and higher cancer-related death. When both TGIF and p21 expression are altered, these patients had an even worse prognosis than those who with one or no marker altered. Furthermore, to elucidate the role of TGIF in the progression of UC, overexpression of TGIF in RT4 or TSGH8301 cells was performed, and the results showed that TGIF could significantly increase migration/invasion ability, MMPs expression and invadopodia formation via PI3K/AKT pathway. In contrast, knockdown of TGIF with its specific shRNA inhibited the invasion ability of T24 cells. Besides, TGIF could inhibit p21WAF/CIP1 expression, up-regulate cyclin D1 expression, and phosphorylate Rb to promote G1-S transition and cellular proliferation. Currently, the combination of gemcitabine and cisplatin (GC) has been widely used as a standard chemotherapeutic regimen for locally advanced and metastatic UC. Although advanced UC is a chemo-sensitive tumor, resistance to chemotherapeutic agent is a major obstacle when treating metastatic UC. Our investigation in 27 advanced stage UUT-UC patients who received GC systemic chemotherapy treatment post-operatively has addressed the role of altered expression of both TGIF and p-AKT as independent prognostic markers, which demonstrated that when both of these were altered, an increased risk of UUT-UC disease progression and decreased patient overall survival was encountered. TGIF was found to contribute to UC cell proliferation and invasion, and expression levels of TGIF would affect the cell response to gemcitabine. Over-expressed TGIF and higher invasion ability were found in the gemcitabine-resistance
UC cells (NTUB1/G) compared with NTUB1 cells. Knockdown of TGIF in NTUB1/G cells decreased cellular growth and migration ability, and increased sensitivity to gemcitabine was associated with the PI3K/AKT pathway. Moreover, over-expression of TGIF in NTUB1 cells could attenuate its sensitivity to gemcitabine. In addition, treating the NTUB1 cells with gemcitabine resulted in increased TGIF, p-AKT but decreased p21 expression. In contrast, treating with HDAC or PI3K/AKT pathway inhibitor resulted in decreased TGIF, p-AKT, and MMP9, but increased p21 expression while inhibiting the migration ability. In summary, the present study demonstrated that TGIF contributes to the progression of UC via the PI3K/AKT pathway. In addition, TGIF overexpression and phosphorylation of AKT activates plays a role in the pathogenesis in tumorigenesis and chemo-resistance to gemcitabine in UC. Based on the above findings, we conclude that the status of TGIF might be a useful prognostic marker to allocate patients for more appropriate chemotherapy. It may serve as an attractive therapeutic or prognostic target for selected patients with UUT-UC.
論文目次 Index
Page
Abstract in Chinese I
Abstract in English III
Acknowledgements V
Contents XI
Abbreviations XIV
List of FiguresXVII
List of Tables XIX
Appendix Contents XXI
Contents
Page
Introduction 1
The epidemiology and the significance of urothelial carcinoma 1
The treatments and prognosis of UC 3
5′TG3′-interacting factor (TGIF) 5
TGIF and Cancers 7
Effects of PI3K/PTEN/AKT pathway on UC 9
Effects of HDAC inhibitors in Cancer 12
Materials and Methods 16
Patients and specimens 16
Reagents and antibodies 17
Cell culture and transfection assay 18
Cell proliferation assay 19
Colony formation assay 19
RT-PCR (reverse transcription-polymerase chain reaction) 19
Western blot 20
Gelatin zymography 21
Immunofluorescence and confocal microscopy analysis 22

Immunohistochemistry22
Cellular migration/invasion assay 23
Drug combination and synergism determination studies 24
Statistic analysis 24
Results 26
Alteration of TGIF and p21 correlated with poor prognosis of
UUT-UC patients 26
Alteration of TGIF and p-AKTSer473 expression correlated with poor
prognosis and chemo-resistance in UUT-UC patients 28
Expression of TGIF and p21 in human UC cells 31
Expression of TGIF and p-AKTSer473 in human UC cell lines 32
TGIF was involved in the promotion of migration/invasion ability and
invadopodia formation of UC cells 32
The PI3K/AKT pathway was involved in the TGIF-induced
migration/invasion phenotypes 33
Overexpression of TGIF promoted G1-S transition to increase growth
of UC cells 34

The TGIF/PI3K/AKT pathway was involved in the gemcitabine-resistant and
promotion the phenotypes formation of migration/invasion 35
Antitumor effect of TSA in advanced UC cells 36
Synergistic antitumor effect of gemcitabine and TSA in advanced UC cells 37
Discussion 39
Conclusion 48
Future Perspectives 49
References 52
Figures and legends 73
Tables 94
Appendixes 107
Publications 117
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