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研究生：	蒲詩雯 Pu, Shih-Wen
論文名稱：	食道鱗狀細胞癌中hRAB37的低表達及其與癌症轉移的機制探討 Downregulation of hRAB37 and Its Roles in Cancer Metastasis of Esophageal Squamous Cell Carcinoma
指導教授：	王憶卿 Wang, Yi-Ching
學位類別：	碩士 Master
系所名稱：	醫學院 - 藥理學研究所 Department of Pharmacology
論文出版年：	2012
畢業學年度：	100
語文別：	英文
論文頁數：	80
中文關鍵詞：	hRAB37 、胞吐作用、食道癌、轉移
外文關鍵詞：	hRAB37, exocytosis, esophageal squamous cell carcinoma, metastasis
相關次數：	點閱：52 下載：2
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研究背景: 根據衛生署統計結果顯示，食道癌為國人男性癌症死因的第六名，超過50%的病人有癌症轉移的現象。食道癌主要分為兩種類型：鱗狀細胞癌 (squamous cell carcinoma, SCC) 及腺癌 (adenocarcinoma)。在亞洲及台灣主要盛行的是鱗狀細胞癌。因此，在食道鱗狀細胞癌中尋找和癌症轉移相關基因為當務之急。我們實驗室先前以cDNA二端定序法 (random amplification of cDNA ends RACE) 首次定義出人類RAB37 (hRAB37) 基因序列，並發現hRAB37轉譯出一種small GTPase，在肺癌中扮演癌症轉移抑癌基因角色。同源型老鼠Rab37最早是在骨髓巨大細胞中被發現，位於細胞的分泌顆粒(granule)上，暗示Rab37可能會幫助細胞進行胞吐作用(exocytosis)，而詳細的機制仍待闡明。
研究目的: 本研究旨在透過臨床、細胞及動物實驗層次探討hRAB37在食道鱗狀細胞癌 (esophageal squamous cell carcinoma, ESCC) 的轉移機制中所扮演的角色。
研究結果: 利用免疫組織染色的實驗，我們在ESCC病人中檢測hRAB37蛋白的表現程度，共有23.9% (26/109) 的病人為hRAB37低表達的情形；而透過quantitative reverse-transcriptase-PCR，發現21.9% (25/114)的病人有mRNA低表達的情形，並與不良預後有顯著關係，顯示hRAB37可為有潛力的食道鱗狀細胞癌預後指標。接著我們檢測了三株台灣食道癌細胞株 (CE48T, CE81T, CE146T) 中hRAB37 mRNA和蛋白的表現程度，發現hRAB37表現程度與其細胞爬行(migration) 能力有負相關的情形。更進一步建立了CE48T及CE81T持續表達hRAB37的細胞株，透過wound healing assay 及transwell invasion assay，顯示過度表達hRAB37會抑制ESCC細胞的爬行及invasion能力。由於hRAB37可能參與調控細胞的胞吐作用，我們蒐集CE48T及CE81T持續表達hRAB37細胞的conditioned medium (CM) 處理原始的 (parental) CE48T及CE81T細胞，發現其會抑制parental CE48T及CE81T細胞的爬行能力，暗示hRAB37可能是透過運送可抑制細胞爬行的物質到細胞外。因此，根據secretomics分析，我們鑑定出一個可能為hRAB37所調控運送的蛋白，thrombospondin-1 (TSP-1)；在CE81T持續表達hRAB37細胞的CM中，TSP-1確實有大量表現的情形；而將hRAB37進行knockdown實驗後，TSP-1在CM中的表現情形有下降的現象。利用共軛焦顯微鏡的觀察，證實hRAB37和TSP-1在trans-Golgi apparatus 有colocalization的情形。由於TSP-1已知會抑制metaloproteinase (MMP) 活性，經由gelatin zymography實驗，hRAB37抑制MMP-2及MMP-9的活性；而knockdown hRAB37後，MMP-2及MMP-9的活性有回復的情形。經由Western blot檢測，說明了hRAB37可能是透過分泌TSP-1進而抑制p-FAK, p-Paxillin, p-ERK這條與癌症轉移相關的路徑而抑制了細胞的爬行及invasion；在動物實驗模式中，觀察到持續表達hRAB37抑制肺轉移的情形。
研究結論：總結以上，hRAB37在ESCC中可能透過分泌TSP-1，進而降低MMP/FAK/ERK路徑而抑制癌轉移，hRAB37低表現並可作為ESCC病人的不良預後指標。

Background: The predominant type of esophageal cancer in Asia countries including Taiwan is esophageal squamous cell carcinoma (ESCC). Prognosis of ESCC patients is poor and patients often have metastatic diseases. Therefore, identification and characterization of metastasis-related genes in ESCC is urgent. Our lab previously cloned the human RAB37 (hRAB37) small GTPase and demonstrated that hRAB37 acts as a metastasis suppressor in lung cancer patients. The mouse homolog Rab37 has been reported to be involved in regulating exocytic events. However, the function and etiological role of hRAB37 in ESCC remains undefined.
Purpose: The aim of this study is to elucidate the roles and underlying mechanisms of hRAB37 in metastasis of ESCC from clinical, cell and animal models.
Results: We found that absent hRAB37 protein expression in 23.9% (26/109) of ESCC patients by immunohistochemistry. Using quantitative reverse-transcriptase-PCR assay, hRAB37 mRNA was found to be low expression in 21.9% (25/114) ESCC patients. Both low mRNA and absent protein expressions of hRAB37 correlated with poor prognosis of ESCC patients in overall survival analysis. In addition, the mRNA and protein level of hRAB37 was lower in CE48T and CE81T Taiwanese ESCC cell lines, which showed high migration ability as compared with another Taiwanese ESCC cell line CE146T, which showed relatively low migration ability by wound healing assay. Note that overexpression of hRAB37 suppressed migration and invasion ability of CE81T cells. Due to the exocytic role of hRAB37, we therefore tested the effects of cells cultured under the conditioned medium (CM) from stably hRAB37 overexpressed CE48T and CE81T cells. The migration ability of parental CE48T and CE81T cells which cultured with CM from stably hRAB37-overexpressed CE48T and CE81T cells was suppressed as compared to cultured with CM from control cells. Through secretomic analysis, we identified a hRAB37 trafficking cargo protein candidate, thrombospodin-1 (TSP-1), which was reported to inhibit metaloproteinase (MMP) activity. Furthermore, CM from hRAB37-overexpressed cells suppressed MMP-2 and MMP-9 activities by gelatin zymography assay, whereas the activities of MMP-2 and MMP-9 were restored by CM from si-hRAB37. Furthermore, hRAB37 overexpression suppressed metastasis related proteins, such as p-FAK, p-Paxillin and p-ERK. CM from hRAB37-overexpressed cells had increased amount of TSP-1 expression. On the contrary, CM from si-hRAB37 cells had decreased amount of TSP-1 expression. In addition, hRAB37 colocalized with TSP-1 in trans-Golgi apparatus in ESCC cells using confocal microscopy. In animal metastasis model, we further confirmed that hRAB37 overexpression suppressed tumor metastasis of CE81T xenograft.
Conclusion: Our cell, animal, and clinical results suggested that hRAB37 is a metastasis suppressor and a potential prognosis biomarker for ESCC via secretion of TSP-1 to inhibit MMP/FAK/ERK signal in ESCC.

Introduction----------------------------------------------------------	1
I.	Clinical significance of esophageal squamous cell carcinoma   (ESCC)	1
(a)	Esophageal cancer in Taiwan, Asia and worldwide	1
(b)	Known life style and environmental factors of
	esophageal cancer--	1
(c)	 Known molecular alterations of esophageal squamous cell
	carcinoma	2
(d) 	Genetic and epigenetic alterations in esophageal cancer	4
II.	Human RAB37 (hRAB37) in previous study	5
(a)	Rab GTPases in vesicle trafficking	5
(b)	Gene locus and protein motif of hRAB37	6
(c)	Roles of murine Rab37 (mRab37) and human RAB37 (hRAB37)	7
III.	hRAB37 in regulation of exocytosis	9
(a)	Effectors and interacting proteins of Rab37	9
(b)	Cargo proteins of mRab37 and hRAB37	10
Study basis and specific aims	11
Materials and methods	13
I.	Clinical samples of ESCC patients	13
II.	Cell lines and culture	13
III.	Plasmid, RNAi and transfection	14
IV.	RNA extraction and quantitative reverse-transcriptase PCR
	(qRT-PCR) assays	15
V.	Immunohistochemistry (IHC) assay	15
VI.	Genomic DNA extraction and sodium bisulfate conversion	16
VII.	Pyrosequencing assay	16
VIII.	5’-Aza-2’-deoxycitidine (5’-Aza-dC) treatment	17
IX.	DNA dosage and qPCR assay	17
X.	Western blot analysis	17
XI.	Wound healing assay	18
XII.	Trans-well migration and invasion assays	18
XIII.	Conditioned medium preparation	19
XIV.	Gelatin zymography assay	19
XV.	Immunocytochemistry (ICC) assay	19
XVI.	Immunoprecipitation (IP) assay	20
XVII.	Animal metastasis assay	20
XVIII.	Statistical analysis	21
Results	22
I.	In clinical model:
(a)	hRAB37 protein expression is downregulated in ESCC patients
and have a significant association with poorer survival.	22
(b)	hRAB37 mRNA expression is downregulated in ESCC patients
and have a significant association with poorer survival.	22
(c)	hRAB37 exon 1 methylation level in ESCC patients.	23
(d)	hRAB37 DNA dosage level in ESCC patients.	23
II.	In cell model:
(a)	hRAB37 promoter and exon 1 region are hypermethylated in
ESCC cell lines and can be demethylated by 5’-Aza-dC treatment.	24
(b)	DNA dosage loss of hRAB37 was observed in ESCC cell lines.	24
(c)	Lower expression of hRAB37 exhibits higher cell migration
	ability.	25
(d)	Ectopically overexpression of hRAB37 inhibits cell migration 
	and invasion abilities.	25
(e)	hRAB37-mediated secreted proteins such as thrombospondin-1
inhibit ESCC cells migration.	25
(f)	hRAB37 colocalizes with TSP-1 in trans-Golgi apparatus of 
ESCC cells.	26
(g)	hRAB37 and TSP-1 are in the same protein complex.	26
(h)	hRAB37 inhibits MMP/FAK/Paxillin pathways in vitro.	27
III.	 In animal model:
(a)	hRAB37 inhibits ESCC metastasis in vivo.	27
(b)	hRAB37-mediated migration signaling proteins are validated in
	xenograft tissues.	28
Discussion	29
References	35
Tables	40
Figures	50
Appendix	72

 
TABLE CONTENTS

Table 1	The primers used in the current study.	41
Table 2	The antibodies and their reaction conditions used in the     current study.	42
Table 3	The cell lines and their characteristics used in the current
	study.	43
Table 4		siRNA sequences used in the current study.	45
Table 5	Alteration of hRAB37 protein expression level in relation to
	clinicopathological parameters in 109 ESCC patients.	46
Table 6	Alteration of hRAB37 mRNA expression level in relation to
	clinicopathological parameters in 114 ESCC patients.	47
Table 7	DNA copy dosage and methylation alterations of hRAB37    gene in 21 ESCC patients.	48

 
FIGURE CONTENTS

Figure 1	hRAB37 protein is downregulated in ESCC patients and
	shows a significant association with poorer survival.	51
Figure 2	hRAB37 mRNA is downregulated in ESCC patients and
	shows a significant association with poorer survival.	53
Figure 3	The dot plot analysis of DNA methylation of hRAB37 gene of paired normal and tumor tissues from 41 ESCC patients and correlation of DNA methylation with mRNA expression of hRAB37.	54
Figure 4	The DNA dosage analyses of ESCC patients and cell lines.	55
Figure 5	DNA elements of methylation analysis and methylation status   of hRAB37 gene using pyrosequencing in ESCC cell lines.	57
Figure 6 	Restoration of hRAB37 expression by treatment with demethylation reagent 5’-Aza-dC.	59
Figure 7	The migration potential in Taiwanese ESCC cell lines.	60
Figure 8	Overexpression of hRAB37 inhibits ESCC cells migration     and invasion abilities.	61
Figure 9	hRAB37 mediated secreted proteins such as thrombospondin-1 (TSP-1) to inhibit ESCC cells migration.	63
Figure 10	hRAB37 colocalizes with thrombospondin-1 (TSP-1) in trans-Golgi apparatus of ESCC cells.	65
Figure 11	hRAB37 and TSP-1 are in the same protein complex in     ESCC cells.	66
Figure 12 hRAB37 inhibits FAK/Paxillin/MMP pathways in vitro.	67
Figure 13	hRAB37 inhibits ESCC cells metastasis in vivo.	68
Figure 14 hRAB37 suppresses p-FAK and p-Paxillin in vivo.	70
 
APPENDIX

Figure 1		Geographical distribution of cumulative rates,               age (0–74 years), for esophageal carcinomas.	73
Figure 2	Risk factors affecting the development of esophageal  malignancies.	74
Figure 3	Localization and function of Rab GTPases.	75
Figure 4	The Rab switch and its circuitry.	76
Figure 5 	Rab functions in vesicle trafficking of cargos via
	effector-mediated processes.	77
Figure 6 	hRAB37 amino acid sequences, alignment of hRAB37        and to other RAB proteins, and mRNA level of hRAB37         in various tissues.	78
Figure 7	mRNA expression and promoter/exon1 hypermethylation       of hRAB37 gene in lung cancer patients.	79
Figure 8	Predicted hRAB37 interacting proteins.	80

                                    

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