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系統識別號 U0026-1908201915041700
論文名稱(中文) Rab37介導IL-6分泌活化STAT3訊息傳遞使巨噬細胞極化成為M2進而促進肺癌進程
論文名稱(英文) Rab37-mediated exocytosis of IL-6 skews M2 polarization and activates STAT3 signaling in macrophages to promote lung cancer progression
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 107
學期 2
出版年 108
研究生(中文) 楊侑恩
研究生(英文) You-En Yang
學號 S26064052
學位類別 碩士
語文別 英文
論文頁數 79頁
口試委員 指導教授-王憶卿
口試委員-阮雪芬
口試委員-蘇五洲
口試委員-張志鵬
中文關鍵字 肺癌  腫瘤微環境  巨噬細胞  Rab37  白血球介素6  第一型干擾素 
英文關鍵字 Lung cancer  Tumor microenvironment  Macrophages  Rab37  IL-6  Type I IFN 
學科別分類
中文摘要 研究背景:腫瘤微環境中的癌細胞與免疫細胞交互作用參與癌症的進程。我們初步的研究結果顯示,相較於野生型 (wild-type, WT) 老鼠,Rab37全身剃除 (knockout, KO) 老鼠有明顯的抑制皮下腫瘤生長的現象;有趣的是,我們進一步發現在Rab37 KO 老鼠皮下腫瘤中,促進腫瘤生長的M2型態巨噬細胞浸潤的數量明顯的少於WT老鼠的皮下腫瘤,這些結果也暗示Rab37在腫瘤微環境中,擁有促腫瘤生長的潛力。然而,Rab37在巨噬細胞中所扮演的角色仍然尚未清楚。
研究目的: 由於Rab37在上皮細胞已知調控胞吐作用 (exocytosis),本研究想探討Rab37趨化巨噬細胞走向M2型態極化的胞吐作用及機制。
研究結果: 根據即時逆轉錄聚合酶連鎖反應 (RT-qPCR) 和流式細胞儀 (flow cytometry) 實驗結果顯示,Rab37 KO 老鼠之骨髓源性巨噬細胞 (bone marrow-derived macrophages,BMDMs) 較易極化為M1巨噬細胞。為了探討此極化現象是否與Rab37所調控的分泌蛋白有關,我們分別從WT和Rab37 KO的老鼠中取出BMDMs 進行細胞激素/趨化激素陣列分析 (cytokines and chemokines array),結果顯示白血球介素6 (interleukin 6, IL-6) 的分泌與Rab37的表現呈現正相關;我們也在老鼠巨噬細胞株RAW264.7 cells之囊泡分離 (vesicle isolation) 的實驗中,證實IL-6的確存在於Rab37所調控的囊泡中;進一步我們藉由酵素結合免疫吸附分析法 (enzyme-linked immunosorbent assay, ELISA) 和免疫螢光染色 (immunofluorescence, IF) 驗證Rab37以鳥苷核苷酸依賴性的方式 (GTP-dependent manner) 調控IL-6的分泌。另外,我們在DNA微陣列分析中發現第一型干擾素 (type I interferon, type I IFN) 的訊息傳遞路徑,在肺癌細胞的培養液處理下,Rab37缺失的BMDMs基因圖譜中有上調的現象。利用RT-qPCR驗證基因富集分析 (Gene Set Enrichment Analysis, GSEA) 和信息路徑分析 (pathway analysis),篩選出的IFNα/β與信號轉導及轉錄激活蛋白1 (Signal transducer and activator of transcription 1, STAT1) 下游的干擾入誘導基因 (interferon stimulated genes, ISGs),的確在Rab37缺失的BMDMs有上調的情形;相反的,在巨噬細胞中過表現Rab37時,能抑制這些基因的表現和IFNβ的分泌,同時增加M2巨噬細胞的基因表達。我們進一步以西方墨點法 (Western blotting) 與免疫螢光染色證實,Rab37會藉由調控IL-6分泌,活化下游的STAT3促進M2巨噬細胞極化,同時抑制STAT1與其下游的第一型IFN相關基因表現。
結論: 我們的結果揭露了Rab37介導IL-6分泌,抑制第一型IFN訊號路徑的新機制,進而趨化巨噬細胞走向M2型態。這可能有助於未來開發,以腫瘤微環境的巨噬細胞中Rab37/IL-6樞紐為標靶的治療策略。
英文摘要 Background: Recent studies have revealed that bidirectional interactions between tumor cells and immune cells in the tumor microenvironment contribute to tumor progression. Our preliminary data showed that mice systemically lacking Rab37 (Rab37 KO) suppressed tumor growth of subcutaneously injected with Lewis lung carcinoma (LLC) cells. Interestingly, Rab37 KO mice displayed low infiltration of pro-tumor M2 macrophages in LLC allografts, suggesting that Rab37 possesses pro-tumor functions in tumor microenvironment. However, the role of Rab37 small GTPase-mediated exocytosis in stromal macrophages remains unknown.
Purpose: This study aims to investigate whether Rab37-mediated exocytosis skews macrophages toward M2 polarization and explore the mechanism involved.
Results: Our quantitative RT-PCR (qRT-PCR) and flow cytometry data showed that bone marrow derived macrophages (BMDMs) from Rab37 KO mice suppressed M2 macrophages polarization. Next, we performed the cytokine/chemokine arrays to reveal Rab37-mediated cytokines using conditioned media of BMDMs derived from wild-type (WT) or Rab37 KO mice. Interestingly, among the differential cytokines/chemokines, the secreted level of interleukin-6 (IL-6) correlated with Rab37 expression in BMDMs. Vesicle isolation revealed that IL-6 enriched in Rab37-specific vesicles in RAW264.7 macrophage cell line. ELISA and immunofluorescence (IF) images confirmed that Rab37 mediated IL-6 secretion in RAW264.7 cell in a GTPase nucleotide-dependent manner, i.e., IL6 secretion was upregulated in RAW264.7 cells expressing Rab37WT and GTP-bound Rab37Q89L. In addition, our cDNA microarray data showed that BMDMs from Rab37 KO mice displayed increased IFN-I signaling pathways compared to those from WT BMDMs after LLC conditional medium treatment. Gene Set Enrichment Analysis (GSEA) and pathway analysis demonstrated that IFNα/β genes and STAT1 downstream interferon stimulated genes (ISGs) were upregulated in Rab37 KO BMDMs. qRT-PCR assays confirmed the increased expression of IFNβ and ISGs genes, including IFIT3, IRF7 and Mx1 in BMDMs from Rab37 KO mice. In contrast, expression of these genes was decreased in Rab37 overexpressing RAW264.7 cells, which led to increased expression of M2 marker genes Arg1 and Ym1. Indeed, ELISA data showed that the level of IFN-β was decreased in Rab37WT and Rab37Q89L RAW264.7 cells. Among type I IFN upstream transcription factors, we validated that STAT3 inhibited STAT1/IRF3 nuclear translocalization and suppressed type I IFN-associated genes expression through Rab37 mediated IL-6 secretion by immunoblotting and IF image.
Conclusions: Our results uncover a novel role of Rab37-mediated IL-6 secretion in regulating type I IFN signaling to skew macrophage polarization toward M2. Therapeutic strategies targeting Rab37/IL-6 axis in stromal macrophages in tumor microenvironment is a testable approach in the future.
論文目次 Introduction 1
I. Lung cancer 1
(A). Epidemiology of lung cancer 1
(B). Therapeutic strategies in lung cancer 1
II. Tumor microenvironment (TME) 3
(A). Population of stromal cells in tumor microenvironment 3
(B). The Role of tumor-associated macrophages
in tumor progression 3
III. Interleukin 6 (IL-6) and signal transducer and activator of transcription (STAT) signaling pathways 5
(A). The roles of IL-6 in macrophages polarization 5
(B). The roles of IL-6/STAT3 signaling in tumor progression and
macrophage polarization 5
(C). Therapeutic targeting the IL-6/STAT3 signaling in cancer 6
IV. Interferons (IFNs) 7
(A). Classification of IFNs 7
(B). Immunomodulatory and anti-tumor effects of type I IFNs 8
V. The Rab small GTPase family in vesicle trafficking 9
(A). Role of Rab GTPases in vesicle trafficking 9
(B). Oncogenic and tumor suppressor-like Rab GTPases 10
(C). The roles of Rab37 in cancer and immune cells 12
Study basis and specific aims 13
Materials and methods 15
I. Cell lines and culture conditions 15
II. Lewis lung carcinoma subcutaneous models 15
III. Bone-marrow-derived macrophages (BMDMs) isolation
and culture conditions 15
IV. Preparation of L929-conditioned medium (CM) 16
V. Immortalized bone-marrow-derived macrophages establishment 16
VI. Lewis lung carcinoma (LLC)-derived conditional medium
collection 17
VII. Flow cytometry analysis 17
VIII. Plasmids, shRNA and transfection 18
IX. Cytokine and chemokine array 18
X. Enzyme-linked immunosorbent assay 19
XI. Protein extraction and Western blot 20
XII. Rab37 specific vesicle isolation 20
XIII. Immunofluorescence-immunohistochemistry assay and confocal microscopy 20
XIV. cDNA microarray 21
XV. Pathway analysis 22
XVI. RNA extraction and quantitative reverse transcriptase-polymerase
chain reaction assays 23
XVII. Statistical analysis 23
Results 24
I. Rab37 deficiency displayed anti-tumor TME 24
(A). Rab37 knockout suppressed tumor growth 24
(B). Lack of Rab37 attenuated M2 macrophage polarization 25
II. Rab37 mediated IL-6 secretion in macrophage 26
(A). Cytokine and chemokine array of BMDMs from Rab37
wild-type (WT) and knockout (KO) mice identified cargo
candidates of Rab37 26
(B). Validation of IL-6 as a cargo of Rab37-mediated exocytosis
in a GTP-dependent manner 26
III. BMDMs from Rab37 deficiency mouse possessed an anti-tumor mRNA expression profile 27
(A). cDNA microarray and pathway analyses of BMDMs from
WT and Rab37-KO mice revealed high IFN-α/β expression profile in Rab37 KO macrophages 27
(B). Rab37-mediated IL-6 secretion regulated M2 macrophage polarization via STAT3 and thus inhibited STAT1 activation and downregulated expression of type I IFN genes in TME 29
Discussion 31
I. Exocytosis of IL-6 as well as other potential cargos were regulated by Rab37 in macrophages 31
II. Rab37 deficiency displayed anti-tumor profiling in macrophages 33
III. The two faces of IL-6 in the tumor microenvironment 33
IV. Conclusion and perspectives 35
References 37
Tables 57
Figures 62
Appendix Tables and Figures 76

TABLE CONTENTS
Table 1. The plasmids and their characteristics used
in the current study 58
Table 2. The antibodies and their reaction conditions used
in the current study 59
Table 3. The primers used in the current study 60
Table 4. The proteins selected from cytokine and chemokine arrays------- 61

FIGURE CONTENTS
Figure 1. Rab37 deficiency suppressed tumor growth of syngeneic
LLC model in vivo 63
Figure 2. Rab37 promoted macrophages toward M2 polarization 64
Figure 3. Cytokine/chemokine array identified IL-6 as a potential
cytokine cargo in CM derived from BMDM of WT and
Rab37 KO mice macrophages 66
Figure 4. Rab37 expression positively correlated with IL-6 secretion
in ex vivo cultured BMDMs and macrophage cell lines in a GTP-dependent manner 67
Figure 5. cDNA microarray and pathway analyses revealed
upregulation of type I IFN genes in Rab37 KO BMDMs 70
Figure 6. Validation of increased expression of type I IFN
genes in Rab37 KO BMDMs and macrophage cell lines 72
Figure 7. Rab37 mediated IL-6 secretion to promote M2 macrophage polarization via STAT3 activation and STAT1/IRF3 down-regulation. 73
Figure 8. Neutralization of IL-6 attenuated M2 macrophage polarization and activated STAT1 functions. 74


Figure 9. The schematic model of Rab37/IL-6/Stat3 axis skews M2 macrophages to promote tumor growth of lung cancer. 75

APPENDIX CONTENTS
Appendix Figure 1. IL6 downstream signaling promotes polarization
of M2 macrophages. 77
Appendix Figure 2. Type I interferon pathway. 78
Appendix Table 1. FDA-approved drugs whose treatment-
induced transcriptional changes were similar
to those associated with Rab37 KO
in responseto the CM derived from LLC. 79
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