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系統識別號 U0026-0302201610104000
論文名稱(中文) Rab37小GTP酶蛋白藉由胞外運送組織金屬蛋白抑制酶而阻止癌轉移
論文名稱(英文) Small GTPase Rab37 targets tissue inhibitor of metalloproteinase 1 for exocytosis and thus suppresses tumor metastasis
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 104
學期 1
出版年 105
研究生(中文) 蔡宗翰
研究生(英文) Chung-Han Tsai
學號 S58971374
學位類別 博士
語文別 英文
論文頁數 182頁
口試委員 指導教授-王憶卿
召集委員-吳梨華
口試委員-鄭宏祺
口試委員-許博翔
口試委員-游佳融
口試委員-林崇智
中文關鍵字 肺癌  Rab 小GTP酶蛋白  胞外運輸  hRAB37  TIMP1  MMP9  細胞爬行  細胞侵入  轉移  預後不良  TCGA資料庫 
英文關鍵字 Lung cancer  Rab small GTPase  exocytosis  hRAB37  TIMP1  MMP9  migration  invasion  metastasis  prognosis  TCGA 
學科別分類
中文摘要 背景介紹及研究目的:肺癌病人五年存活率大約為13%-15%,然而目前對於肺癌形成的機制以及此疾病發展過程尚未完全釐清。近年來的研究顯示在腫瘤形成的過程中,Rab 小GTP酶蛋白 (small GTPase) 控制的囊泡運輸 (vesicle traffic) 機制在腫瘤發展過程中會被改變;然而,關於Rab蛋白是否能夠抑制腫瘤細胞轉移仍未清楚。本實驗室先前研究首次證實了人類的RAB37基因 (hRAB37) 在肺癌病人中有低表達與過度甲基化的情形,且與肺癌的進程(progression) 相關。因此,本研究的主要目的是進一步證實hRAB37是否具有Rab家族調控囊泡運輸的功能,進而藉此調控癌細胞的爬行、轉移以及癌症進程的能力。
研究方法: 我們利用蛋白質體學篩選hRAB37穩定表達細胞的培養液,找出hRAB37的運送組織金屬蛋白抑制酶 (TIMP1)。我們使用共軛焦螢光顯微鏡、穿透式電子顯微鏡以及全內反射螢光顯微鏡(TIRF) 等影像技術觀察hRAB37調控TIMP1的胞外運輸。在細胞及動物模式中,我們將hRAB37穩定表達或是抑制,再藉由細胞以及裸鼠動物模型探討hRAB37運輸TIMP1以調控基質金屬蛋白酶9 (MMP9) 訊號而抑制腫瘤轉移。我們利用免疫組織化學染色以及免疫螢光染色,觀察165位肺癌病人腫瘤檢體中hRAB37以及TIMP1蛋白表現的相關性,同時分析西方族群TCGA資料庫中450位肺癌病人hRAB37與TIMP1基因表現的相關性。
研究結果:在共軛焦螢光顯微鏡實驗指出,hRAB37參與在胞外運輸(exocytosis) 的路徑且與分泌粒子 (secretory granule) 的標記蛋白相疊合;經由電子顯微鏡影像分析中發現TIMP1會存在hRAB37所屬的囊泡內;透過TIRF的活體細胞影像觀察,細胞內的hRAB37會運輸TIMP1蛋白從細胞質到細胞膜上釋放。穩定表達hRAB37在CL1-5肺癌細胞株中,其爬行以及侵入能力以及MMP9的活性皆明顯被抑制,而在H460肺癌細胞中將hRAB37的表達抑制後,H460細胞爬行以及侵入能力以及MMP9的活性皆明顯增加。特別的是,將癌細胞內的hRAB37去活化或是蛋白表達抑制後,在尾靜脈注射老鼠以及左肺到右肺轉移動物模型中皆發現會促進癌細胞轉移;有趣的是,在hRAB37穩定表現的細胞中抑制TIMP1蛋白的表現也會增加細胞爬行以及侵入的能力,同時也會活化MMP9的活性,此TIMP1抑制轉移的結果在動物模型中也獲得證實。以上研究顯示TIMP1是hRAB37所運輸以抑制腫瘤轉移的重要蛋白。臨床實驗結果顯示,在肺癌病人的臨床檢體中我們發現hRAB37蛋白的有低表達的現象,且hRAB37的低表達伴隨著TIMP1的減少 (P<0.0001),這樣的結果導致病人的轉移增加 (P=0.013) 且存活率 (P<0.001) 以及無病變存活期 (P=0.013) 明顯下降而導致病人死亡。更重要的是,我們的發現也與大型資料庫TCGA的西方族群病人比對後也有類似的結果。
研究結論:綜上所述,我們結果是第一個完整的提供了臨床、細胞以及動物資料,證實hRAB37這個小GTP酶蛋白是一個抑制癌症轉移的重要蛋白。hRAB37透過運輸TIMP1分泌到胞外去抑制癌症轉移訊號的傳遞,當hRAB37低表達的時候可能會使肺癌病人的病情更加惡化而死亡,因此hRAB37蛋白低表達可作為臨床預後的分子指標。
英文摘要 Background & Aims: The five year survival rate for lung cancer patients remains at 13-15% over the past years. However, the mechanisms involved in lung cancer progression remain unclear. Recent publications show alterations of Rab small GTPase-controlled vesicle traffic during tumorigenesis. However, whether any of the Rabs plays a metastasis suppressive role is least explored. Our previous data demonstrates for the first time that low mRNA expression and promoter hypermethyaltion of human Rab37 (hRAB37) gene correlates with lung cancer progression. Therefore, the current study aims to investigate the functions of hRAB37 to regulate vesicle trafficking and its signal pathways involved in cell migration/invasion and tumor metastasis.
Methods: We performed a proteomics screen of conditioned medium to identify one of the cargos of hRAB37, namely tissue inhibitor of metalloproteinase 1 (TIMP1). The hRAB37-mediated TIMP1 exocytosis was determined by confocal, immuno-electron microscopy (EM) and total internal reflection fluorescence imaging (TIRF). The biological effects of hRAB37 on tumor metastasis and TIMP1-metalloproteinase 9 (MMP9) signaling were detected in cultured cells and nude mice by overexpression or knockdown of hRAB37. We analyzed protein expression of hRAB37 and TIMP1 by immunohistochemistry and fluorescence-immunohistochemistry in 165 lung cancer patients and mRNA expression of hRAB37 and TIMP1 in 450 lung cancer patients derived from the The Cancer Genome Atlas (TCGA) dataset.
Results: Our confocal analysis of trafficking markers indicated that hRAB37 co-localized with secretory granule markers and involved in the exocytotic pathway. Co-localization of TIMP1 in hRAB37-containing vesicles was confirmed by immuno-EM assay. Our TIRF image analysis provided the dynamic views of hRAB37-mediated trafficking and docking of TIMP1-containing vesicles to the plasma member. Overexpression of hRAB37 resulted in loss of migration/invasion ability and MMP9 activity in CL1-5 lung cancer cells-based assays, whereas knockdown of hRAB37 in H460 lung cancer cells increased the migration/invasion ability and MMP9 activity. Notably, inactive or knockdown of hRAB37 remarkably promoted lung tumor metastasis in tail vain injection and lung-to-lung tumor metastasis animal models. Interestingly, TIMP1 knockdown increased the migration/invasion ability and MMP9 activity in hRAB37 expression cells, which were confirmed by animal metastasis assays. These data suggested that TIMP1 is essential to hRAB37-mediated metastasis suppression. Clinically, lung cancer patients with low hRAB37 showed concordantly reduced TIMP1 (P<0.0001) with distant metastasis (P=0.013) and poor overall survival (P<0.001) and poor progression-free survival (P=0.013). These clinical correlations can be observed in a large cohort of patients as part of TCGA project.
Conclusions: Our findings provided first compelling evidence from cell, animal, and clinical studies that hRAB37 is a metastasis suppressor Rab, which functions through the TIMP1-MMP9 pathway. Low expression of hRAB37 leads to poor survival of lung cancer patients, which can be used as a potential prognostic biomarker.
論文目次 CONTENTS


中文摘要 I
Abstract III
Acknowledgements V
Contents VIII
Table contents XI
Figure contents XII
Appendix contents XIV
Abbreviations XV
Introduction 1
I. Clinical significance of lung cancer
1. Clinical significance of lung cancer 1
2. Current diagnostic tools and therapeutic approaches of lung cancer 1
II. Tumor metastasis and related mechanisms
1. Tumor metastasis 2
2. Roles of MMPs in metastasis 3
3. MMPs and intergrin signal (FAK) in tumor metastasis 4
III. Rab37 in regulation of cargo secretion and cell motility
1. Rab GTPases in vesicle trafficking 5
2. The tumorigenic role of Rab proteins 6
3. The gene structure discovery of hRAB37 7
4. The protein function of hRAB37 7
5. Cargos of mRab37 8
IV. Roles of TIMP1 in cancer progression 9
STUDY BASIS AND SPECIFIC AIMs…………………………………..………..11
Materials and Methods 12
1. Cell lines, expression vectors and gene knockdown 12
2. Generation of hRAB37 antibody 13
3. VSVG transport and transferring recycling assays 13
4. CM preparation 14
5. Proteomics analysis and GO analysis 14
6. Vesicle isolation and immunoprecipitation 15
7. Confocal and EM imaging 16
8. TIRF imaging 16
9. Immunoblotting 17
10. ELISA 17
11. Gelatin-zymography assay 17
12. Migration and invasion assays 18
13. Experimental metastasis assays in vivo 18
14. Lung to lung metastasis assay in vivo 18
15. Tumor growth assay in vivo 19
16. Patient samples and clinical information 20
17. Immunohistochemistry and fluorescence immunohistochemistry 20
18. mRNA expression analysis 20
19. TCGA analysis 21
20. Statistical analysis 21
Results 22
1. hRAB37 is involved in transportation of exocytotic vesicles 22
2. TIMP1 localizes in hRAB37-containing vesicles 23
3. TIMP1 is a trafficking cargo of hRAB37 24
4. hRAB37 suppresses metastasis in a nucleotide-dependent manner 25
5. Knockdown of hRAB37 promotes metastasis in vitro and in vivo 27
6. TIMP1 is essential to hRAB37-mediated metastasis suppression 28
7. Clinical impacts of concordantly low hRAB37/TIMP1 expression 29
Discussion 31
References 38
Tables 49
Figures 52
Appendix 79

TABLE CONTENTS


Table 1. Clinicopathological parameters in lung cancer patients enrolled in this study 50
Table 2. Alteration of hRAB37 and TIMP1 protein expression levels in relation to clinicopathological parameters in 165 lung cancer patients 51



FIGURE CONTENTS

Figure 1. hRAB37 mediates trafficking of exocytotic vesicles not recycling vesicles 53
Figure 2. Functional enrichment analyses of secretomic proteins 54
Figure 3. hRAB37-mediated secretion of TIMP1 and TNF- is blocked by EXO1 treatment. 56
Figure 4. hRAB37 co-localizes with TIMP1 in the same vesicular structures 57
Figure 5. Functional hRAB37 localizes to the cytosol with vesicle binding affinity. 58
Figure 6. hRAB37 regulates TIMP1 trafficking in a nucleotide-dependent manner 59
Figure 7. Rab8a does not regulate TIMP1 trafficking in CL1-5 cells 60
Figure 8. hRAB37 suppresses lung cancer invasion and tumor metastasis in a nucleotide-dependent manner in vitro and in vivo 61
Figure 9. hRAB37 mediates TIMP1 secretion to inhibit motility in A549 and H460 lung cancer cells 63
Figure 10. hRAB37 inhibits the activity of p-FAK and RhoA in vitro and in vivo. 64
Figure 11. Knockdown of hRAB37 promotes lung cancer invasion and tumor metastasis in vitro and in vivo 65
Figure 12. Knockdown of ectopically expressed WT hRAB37 increased cell migration and invasion ability in CL1-5 cells 66
Figure 13. hRAB37 inhibits lung cancer metastasis in vitro and in vivo via TIMP1. 67
Figure 14. hRAB37 inhibits lung cancer motility in vitro via TIMP1 68
Figure 15. TIMP1 treatment abolishes lung cancer metastasis of T43N cells in vitro and in vivo. 69
Figure 16. Low hRAB37 protein coincides with low TIMP1 level and poor survival of lung cancer patients 70


Figure 17. hRAB37 correlates with TIMP1 expression in lung cancer patients 72
Figure 18. Low hRAB37 coincides with low TIMP1 level, leading to poor survival of lung cancer patients in the TCGA dataset 73
Figure 19. hRAB37 does not affect cell growth ability in vitro and in vivo. 75
Figure 20. Colon and liver cancer tissues express low level of hRAB37 mRNA. 76
Figure 21. TIMP1 is not present in hRab37-containing vesicles of RCC cells. 77
Figure 22. Low hRAB37 protein expression is associated with a poorer prognosis in early stage lung cancer patients without lymph node metastasis.. 78


APPENDIX CONTENTS

Appendix Table 1. Antibodies and their reaction conditions used in the present study. 80
Appendix Table 2. TCGA raw data of mRNA expression of hRAB37 and TIMP1 genes. 81
Appendix Table 3. TCGA data of hRAB37 mRNA expression and clinical follow-up 101
Appendix Table 4. The 185 proteins, identified with high confidence in two independent experiments (experiment 1 and 2), by proteomic analysis of CM fromcontrol and WT-hRAB37 expressing CL1-5 cells 109

Appendix Figure 1. The hRAB37 antibody developed shows high specificity 146
Appendix Figure 2. Full-length images of representative immunoblots 147

Publications 149
C-Han Tsai, H.-C. Cheng, Y.-S. Wang, P.-P. Lin, J.-J. Jen, I.-Y. Kuo, Y.-H. Chang, P.-C. Liao, R.-H. Chen, W.-C. Yuan, H.-S. Hsu, M.-H. Yang, M.-T. Hsu, C.-Y. Wu, Y.-C. Wang. Small GTPase Rab37 targets tissue inhibitor of metalloproteinase 1 for exocytosis and thus suppresses tumour metastasis. Nat. Commun.. 2014 Sep 3;5:4804. doi: 10.1038/ncomms5804.
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