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系統識別號 U0026-2408201717014200
論文名稱(中文) Rab37經由胞外運輸sST2進而抑制腫瘤微環境中巨噬細胞的極化
論文名稱(英文) Rab37 mediates exocytosis of soluble ST2 to inhibit macrophage polarization in tumor microenvironment
校院名稱 成功大學
系所名稱(中) 藥理學研究所
系所名稱(英) Department of Pharmacology
學年度 105
學期 2
出版年 106
研究生(中文) 蘇靖欽
研究生(英文) Ching-Chin Su
學號 S26041046
學位類別 碩士
語文別 英文
論文頁數 78頁
口試委員 指導教授-王憶卿
口試委員-徐欣伶
口試委員-呂增宏
口試委員-洪建中
中文關鍵字 Rab37  巨噬細胞  類介白素1受體1  癌症進程 
英文關鍵字 Rab37  macrophages  soluble interleukin 1 receptor like 1  tumor progression 
學科別分類
中文摘要 研究背景: 腫瘤細胞在生長過程中會釋放出細胞激素 (cytokines) 以及趨化激素 (chemokines),以其和周圍環境中不同種類的細胞溝通,並與之構成腫瘤微環境。微環境中的細胞受到腫瘤細胞釋出的物質所吸引,並被其教育成為具有促進腫瘤細胞生長能力的族群,其中間質細胞 (stromal cells) 中的巨噬細胞 (macrophages) 在微環境中扮演重要的角色,透過調控腫瘤細胞與其他間質細胞的功能,進而導致腫瘤生長加速和遠端轉移。本實驗室在先前的研究中發現到一種小G蛋白 (small GTPase) Rab37調控細胞內物質的胞吐作用 (exocytosis),釋出的物質中包含組織金屬蛋白抑制酶,其功能為抑制腫瘤本身移動能力,進而達到抑制遠端轉移的效果。而Rab37所調控的胞吐作用對於腫瘤微環境之形成與巨噬細胞的調控目前仍未被充分了解。
研究目的: 本研究探討Rab37所調控的胞吐作用與腫瘤微環境之關聯性,並以巨噬細胞為目標,研究Rab37如何透過調控巨噬細胞的功能,以影響腫瘤微環境。
研究結果: 體外培養腫瘤細胞實驗發現,腫瘤細胞增生速度並不會因為Rab37的表現量高低而有所差異;但若將這兩類細胞分別以皮下注射的方式植入裸鼠體內,則觀察到腫瘤形成的大小與Rab37的表現量呈反比,而將腫瘤組織切下並且進行免疫組織染色後,發現Rab37高表現的組別中,巨噬細胞的族群偏向抑制腫瘤生長的一類 (M1 type);反之在Rab37低表現的組別裡,多數的巨噬細胞屬於促進腫瘤生長的一群 (M2 type)。而在細胞實驗中我們也觀察到Rab37高表現的腫瘤細胞,其上清液 (conditioned medium) 能夠促進巨噬細胞極化成抑制腫瘤生長的M1型態,反之受到Rab37低表現細胞的上清液所培養的巨噬細胞,發展成能夠促進腫瘤生長的M2型態。接著我們利用細胞激素/趨化激素陣列 (cytokines/chemokines array) 分析,篩選出在上清液中蛋白質變化量與Rab37的表現量呈現正相關的目標,在比對中挑出類介白素1受體1 (IL1RL1,又稱為ST2),以西方墨點法確認ST2在腫瘤細胞上清液中的表現量與腫瘤細胞中Rab37的表現量呈正相關,且透過免疫螢光染色與全反射倒立螢光顯像證實Rab37調控ST2運輸到細胞外的過程。後續的細胞重組實驗也顯示,在Rab37高表現的細胞中降低ST2之表現量,其上清液則不具有促進M1巨噬細胞極化的作用,而在動物重組實驗中利用也觀察到Rab37抑制腫瘤生長的效果,會因為ST2的低表現而被反轉。另外於肺癌病人癌組織切片染色中也觀察到腫瘤細胞為Rab37低表現且ST2低釋出者,較易促進M2巨噬細胞極化,其癌症進程較惡化,且預後較差。
研究結論: 本研究指出Rab37藉由調控ST2之分泌,抑制腫瘤微環境中巨噬細胞的M2型態,進而導致此類族群的巨噬細胞無法有效促進腫瘤細胞生長,使癌症進程被延緩。未來將在肺癌病人癌組織切片染色確定Rab37促進ST2的釋放,進而促使巨噬細胞極化成M1型態,抑制腫瘤生長、轉移及存活率相關性。
英文摘要 Background: Tumor cells release cytokines/chemokines and other substances to create a tumor microenvironment to recruit stromal cells and educate them to have pro-tumoral functions. Stromal cells such as macrophages, play important roles in modulating tumor growth and metastasis. Our lab previously identified Rab37 small GTPase, which mediates the exocytosis of tissue inhibitor of metalloproteinases 1 to suppress tumor metastasis in lung cancer. However, the role of Rab37 in modulating tumor microenvironmental cells such as macrophages is not well understood.
Purpose: Our aims are to investigate whether Rab37-mediated tumor suppressive functions are through inhibition of macrophages polarization in tumor microenvironment and to identify what secreted factors are involved.
Results: Our in vitro and in vivo cancer cell growth results showed that cancer cells with Rab37 silencing significantly promoted tumor growth in mice, but had similar proliferation rate in cell culture system compared with control group, suggesting that factors in tumor microenvironment of Rab37 silencing xenograft play roles in promoting tumor growth in vivo. Notably, conditioned medium (CM) derived from Rab37 overexpressing lung cancer cells promoted M1 type macrophage polarization, while CM from Rab37 knockdown cancer cells skewed macrophages polarization towards M2 phenotypes, which were known to enhance the motility of cancer cells. Moreover, educated M2 macrophages by CM derived from Rab37 knockdown cancer cells promoted both primary tumor growth and lung metastasis in by co-injection of CM-educated macrophages and cancer cells subcutaneously. We then collected CM from cancer cells with Rab37 manipulation to identify the Rab37-mediated secretory factor(s) that regulated macrophage polarization by human cytokine array. The results showed that soluble interleukin 1 receptor like 1 (ST2) was the potential exocytic cargo mediated by Rab37. Immunofluorescence images and total internal reflection fluorescence images confirmed that Rab37 mediated ST2 secretion in tumor cells in a GTPase nucleotide-dependent manner. Reconstitution experiments by knocking down of ST2 in cancer cells expressing wild-type Rab37 demonstrated that ST2 was important for promoting M1 type macrophage polarization by the in vitro CM culture system and for inhibiting tumor growth in vivo. Clinically, lung cancer patients with Rab37 expression showed concordant expression of ST2 and high M1 over M2 macrophages ratio (M1/M2 ratio). The patients with Rab37low-ST2low-M1/M2 ratiolow had worst clinical outcome.
Conclusion: These results provide new evidence of interplay between cancer cells and stromal macrophages via Rab37-mediated ST2 secretion in tumor microenvironment. The Rab37-ST2 axis in regulating macrophage polarization possesses clinically significance.
論文目次 Introduction 1
I. Clinical significance of lung cancer 1
(a) Epidemiology of lung cancer 1
(b) Therapeutic strategies in lung cancer 1
II. Tumor microenvironment 3
(a) Role of stromal cells in tumor microenvironment 3
(b) Regulation of tumor progression by tumor-associated macrophages 4
(c) Signaling transduction between macrophages and tumor cells 5
III. Soluble interleukin 1 receptor like 1 (ST2) signaling in regulating tumor-associated macrophages 5
IV. Rab GTPases in vesicle trafficking and tumor progression 6
(a) Role of Rab GTPases in vesicle trafficking 6
(b) Oncogenic and tumor suppressor-like Rab GTPases 7
(c) Our previous findings on Rab37 8
Study basis and specific aims 10
Materials and methods 12
I. Cell lines and culture condition 12
II. Plasmids, RNAi and transfection 12
III. Conditioned medium (CM) preparation 13
IV. Macrophage education 14
V. RNA extraction and quantitative reverse transcriptase polymerase chain reaction (RT-qPCR) assay 14
VI. Vesicles isolation and immunoprecipitation 14
VII. Cytokines/chemokines array 15
VIII. Western blot analysis 15
IX. Confocal microscopy 16
X. Total internal reflection fluorescence (TIRF) microscopy 16
XI. Animal studies 17
XII. Immunohistochemistry assay (IHC) 17
XIII. Statistical analysis 18
Results 19
1. Overexpression of Rab37 in lung cancer cells attenuated tumor growth in vivo and recruited M1 polarized macrophages. 19
2. Knockdown of Rab37 in lung cancer cells accelerated tumor growth in vivo and recruited M2 polarized macrophages. 20
3. CM derived from cancer cells expressing wild-type Rab37 inhibited M2 macrophage polarization and consequently reduced the motility of cancer cells and in vivo tumor growth. 20
4. Identification and validation of soluble ST2 (sST2) as a cargo protein secreted by Rab37 mediated exocytosis. 22
5. Rab37-mediated sST2 secretion suppressed M2 macrophage polarization in vitro and primary tumor growth in vivo. 24
6. Correlation among expression of Rab37 and sST2 in tumor tissues in clinical lung cancer patients. 25
7. Patients with low Rab37 and low sST2 were associated with progressive tumor stages and poor prognosis. 26
Discussion 28
References 33
Figures 40
Tables 67
Appendix 75

FIGURE CONTENTS
Figure 1. Overexpression of Rab37 inhibited in vivo tumor growth. 41
Figure 2. Overexpression of Rab37 inhibited macrophage infiltration and M2 polarization in xenograft. 42
Figure 3. Knockdown of Rab37 promoted in vivo tumor growth. 44
Figure 4. Knockdown of Rab37 promoted macrophage infiltration and M2 polarization in xenograft. 45
Figure 5. Conditioned medium derived from Rab37-manipulated cancer cells promoted M1 macrophage polarization. 47
Figure 6. Conditioned medium-educated M1 macrophages reduced the motility of cancer cells. 49
Figure 7. Conditioned medium-educated M2 macrophages promoted malignant tumor growth in vivo. 51
Figure 8. Identification and validation of Rab37-mediated cargo protein candidates. 53
Figure 9. sST2 was secreted by Rab37 at the GTPase nucleotide-dependent manner. 55
Figure 10. Reconstitution of ST2 in Rab37-manipulated cancer cells modulated macrophage polarization. 58
Figure 11. Rab37-mediated ST2 educated macrophages to regulate cancer cell migration in vitro. 59
Figure 12 Knockdown of ST2 in Rab37 expressing cancer cells promoted primary tumor growth and M2 macrophage infiltration in vivo. 61
Figure 13 Correlation between Rab37 and ST2 expression in lung cancer patients. 62
Figure 14 Patients with low Rab37 and low ST2 expression correlated with poor overall survival and disease-free survival. 63
Figure 15 Patients with low Rab37, low ST2 expression and low M1/M2 ratio correlated with poor overall survival and disease-free survival. 65
Figure 16 Rab37 mediates the exocytosis of sST2 to inhibit M2-specific macrophage polarization in tumor microenvironment. 66


TABLE CONTENTS
Table 1. The plasmids and their characteristics used in the current study. 68
Table 2. The primers used in the current study. 69
Table 3. Antibodies and their reaction conditions used in the current study. 70
Table 4. The correlation between Rab37 and ST2 protein expression along with M1/M2 ratio in tumor tissue of 122 lung cancer patients 71
Table 5 Alteration of Rab37 and ST2 protein expression in relation to clinicopathological parameters in 122 lung cancer patients 72
Table 6. Cox regression analysis of risk factors for cancer-related death in lung cancer patients 74



APPENDIX CONTENTS
Appendix Figure 1. Polarization of tumor-associated macrophages. 76
Appendix Figure 2. IL-33 is processed and secreted into extracellular region. 77
Appendix Figure 3. Regulation of Rab proteins 78
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