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研究生：	古德翰 D.V.N.Goutham
論文名稱：	探討肝腫瘤相關巨噬細胞中由細胞自噬調節之半乳糖凝集素1的分泌與角色 Autophagy-dependent secretion of galectin-1 by tumor-associated macrophages and its role in hepatocellular carcinoma
指導教授：	張志鵬 Chang, Chih-Peng
學位類別：	博士 Doctor
系所名稱：	醫學院 - 基礎醫學研究所 Institute of Basic Medical Sciences
論文出版年：	2021
畢業學年度：	109
語文別：	英文
論文頁數：	141
中文關鍵詞：	肝細胞癌、腫瘤相關巨噬細胞、自噬、半乳糖凝集素 1 、高遷移率群盒蛋白 1
外文關鍵詞：	Hepatocellular carcinoma, Tumor-associated macrophages, Autophagy, Galectin-1, High-mobility group box protein 1
相關次數：	點閱：78 下載：2
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摘要
肝細胞癌 (HCC) 是台灣最常見的癌症之一，在癌症相關死亡人數中排名第二。腫瘤相關巨噬細胞 (TAM) 在腫瘤微環境 (TME) 中發揮重要作用，促進 HCC 腫瘤發生。自噬作用是維持細胞穩定型態所必需的溶酶體途徑。選擇性自噬作用保護細胞免受病原體入侵與損傷，但其在調節腫瘤發展所必需的 TAM 分泌因子中作用尚不清楚。 Galectin-1 是一種分泌型凝集素，具有促生物體活性，已知與巨噬細胞密切相關。其在調節免疫抑制和腫瘤發生方面有潛在作用，但是galectin-1 的來源和分泌途徑仍然未知。使用巨噬細胞分化模型，我們發現骨髓來源的巨噬細胞 (BMDM) 在存在肝癌條件培養基 (CM) 的情況下會分化為 M2 表現型，並主動分泌 galectin-1。這種分泌的 galectin-1 在促進 SCID 小鼠 HCC 的腫瘤發生中扮演重要角色。此外，galectin-1 抑製劑的治療消除了 TAM 對蕾莎瓦誘導的細胞死亡的保護活性。自噬作用的抑制阻止了肝癌刺激的巨噬細胞 (HSM) 分泌 galectin-1。獨特的 TLR2 依賴性活性氧 (ROS) 產生被激活以誘導自噬並調節 HSM 中的 galectin-1 分泌。此外，對一些HCC 患者的分析表明，自噬作用與 TAM 中的 galectin-1 成負相關，這進一步與 HCC 患者的總體生存率較差相關。 HCC 衍生或使用重組的高遷移率族框蛋白 (HMGB1) 能夠觸發這種 TLR2 介導的 galectin-1 分泌。此外，通過分析HCC患者樣本的血清，我們發現HMGB1與galectin-1成正相關。我們的研究結果提供了一條通過 TLR2 介導的 HMGB1 信號選擇性自噬分泌 galectin-1 的新途徑。此外，我們的研究將提供一種新的生物標誌物來預測 HCC 結果和提高化療療效的新治療策略
關鍵詞。肝細胞癌、腫瘤相關巨噬細胞、自噬、半乳糖凝集素 1、高遷移率群盒蛋白 1

Hepatocellular carcinoma (HCC) is one of the most common cancers in Taiwan and the second in cancer-related deaths. Tumor-associated macrophages (TAMs) play an essential role in tumor microenvironment (TME) to promote HCC tumorigenesis. Autophagy is a lysosomal pathway essential to maintain cellular homeostasis. Selective autophagy protects the cells from pathogen invasion and stress damage, but its role in regulating the secreting factors in TAMs essential for tumor progression is not clear. Galectin-1 is a secretory lectin with protumeric activities and known to be associated strongly with macrophages. Acknowledging its potential effect in regulating the immunosuppression and tumorigenesis, the source and secretory pathways of galectin-1 is still unknown. Using a macrophage cell differentiation model, we found that bone marrow derived macrophages (BMDM) will differentiate into a M2 like phenotype in presence of hepatoma condition medium (CM) and actively secretes galectin-1. This secreted galectin-1 was found to play an essential role in promoting the tumorigenesis of HCC in SCID mice. In addition, treatment of a galectin-1 inhibitor abolished the protective activity of TAMs to sorafenib-induced cell death. Inhibition of autophagy blocked the secretion of galectin-1 from hepatoma stimulated macrophages (HSMs). A unique TLR2-dependent reactive oxygen species (ROS) production was activated to induce autophagy and regulate galectin-1 secretion in HSMs. Furthermore, analysis of the limited HCC patients showed that autophagy is negatively correlated with galectin-1 in TAMs which further correlated with the poor overall survival rate of HCC patients. HCC-derived or recombinant high mobility group box protein (HMGB1) is able to trigger this TLR2-mediated galectin-1 secretion. Moreover, by analyzing the serum of HCC patient samples, we found that HMGB1 is positively correlated with galectin-1. Our findings provide a novel pathway of galectin-1 secretion by TLR2-mediated selective autophagy signaled from HMGB1. Moreover, our study will provide a novel biomarker to predict the HCC outcome and new therapeutic strategies to increase the efficacy of the chemotherapy
Keywords. Hepatocellular carcinoma, Tumor-associated macrophages, Autophagy, Galectin-1, High-mobility group box protein 1

Contents

Abstract                                                                                                                      I
Acknowledgement                                                                                                     II
Contents                                                                                                                      III
List of figures                                                                                                              XI
Abbreviation index                                                                                                    XIII                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
1. Introduction                                                                                                              
   1.1 Hepatocellular carcinoma                                                                                1
     1-1.1 Epidemology of HCC and staging                                                                 1
     1-1.2 Risk factors or causes                                                                                    2
     1-1.3 Biomarkers                                                                                                     3
     1-1.4 Treatment                                                                                                       5
  1.2 Tumor microenvironment                                                                                 7
     1-2.1 Cancer-associated fibroblasts                                                                        8
     1-2.2 Tumor-associated endothelial cells                                                                8
     1-2.3 Extracellular matrix                                                                                        9
     1-2.4 Hepatic stellate cells                                                                                       9
     1-2.5 Immune and inflammatory cells                                                                    10
         1-2.5.1 Tumor-associated neutrophils                                                                 10 
         1-2.5.2 Tumor infiltering Tregs                                                                          11
         1-2.5.3 Marrow derived suppressor cells                                                            11
1-2.5.4	Tumor-associated macrophages                                                              12
  1-3 TAM derived factors in HCC                                                                            13
     1-3.1 IL-6                                                                                                                 14
     1-3.2 TNF-α                                                                                                             14
     1-3.3 IL-10                                                                                                               14
     1-3.4 IL-17                                                                                                              14
     1-3.5 Chemokines                                                                                                   15
     1-3.6 TAM-derived growth factors                                                                         15
         1-3.6.1 TGF-β                                                                                                      15
         1-3.6.2 VEGF                                                                                                      15
         1-3.6.3 Other TAM-derived factors                                                                     16
  1-4 Galectin-1 and its inflammatory responses                                                     16
     1-4.1 Galectin-1 in tumor microenvironment                                                         17
     1-4.2 Galectin-1 in fibroblast activation                                                                 18
     1-4.3 Galectin-1 in tumor endothelial cells                                                             19
     1-4.4 Galectin-1 in macrophages and other immune cells                                      20
  1-5 Autophagy and HCC tumorigenesis                                                                 22
     1-5.1 Autophagy in HCC targeted therapy                                                             23
  1-6 Secretory autophagy                                                                                          24
  1-7 HMGB1                                                                                                               24
2. Specific aims                                                                                                            26
3. Materials and methods                                                                                           27
   3-1 Materials                                                                                                            27
      3-1.1 Cells and media	                                                                                            27
      3-1.2 Antibodies                                                                                                     27
      3-1.3 Plasmid                                                                                                          31
      3-1.4 siRNA                                                                                                           32
      3-1.5 Inhibitors                                                                                                       32
      3-1.6 Recombinant proteins                                                                                   33
      3-1.7 Reagents                                                                                                        33
      3-1.8 Consumables and devices                                                                              39
   3-2 Methods
      3-2.1 Culture of bone marrow-derived macrophages                                            40                                           
      3-2.2 Human monocyte isolation                                                                           41
      3-2.3 Immunostaining                                                                                            41
      3-2.4 Total internal reflection microscopy (TIRF) imaging                                  42
      3-2.5 RNA extraction and quantitative reverse transcriptase polymerase chain reaction                (qRT-PCR) assay                                                                                                          42
       3-2.6 Western blot                                                                                                 43 
      3-2.7 Immuno-electron microscopy                                                                  43
      3-2.8 Lentivirus-mediated shRNA transfection                                                44
      3-2.9 siRNA-based gene silence                                                                       45
      3-2.10 Lactate dehydrogenase assay                                                                 45
      3-2.11 ELISA                                                                                                    45
      3-2.12 Measurement of intracellular ROS                                                         46
      3-2.13 Tumor supernatant preparation                                                              46
      3-2.14 Antibody-neutralizing experiment                                                         46
      3-2.15 Patients and specimens                                                                          46
      3-2.16 Dual immunofluorescence                                                                     47
      3-2.17 Autophagosome extraction                                                                    48
      3-2.18 Mice and murine insitu hepatoma model                                              48
      3-2.19 Gsea analysis                                                                                         49
      3-2.20 Statistical analysis                                                                                 49
4 Results
   4.1 Galectin-1 secretion by TAMs associated with poor prognosis of HCC      50
      4.1.1 Macrophages in HCC patients showed enhanced expression 
               of galectin-1                                                                                                   50
      4.1.2 Tumor cell CM induced the expression and secretion of galectin-1 
               from BMDMs                                                                                                51
      4.1.3 Loss of galectin-1 in macrophages inhibited the HCC progression 
               in murine model                                                                                           52
   4.2 Mechanisms and signaling of galectin-1 secretion in BMDMs                     52
      4.2.1 Activated autophagy correlated with the increased secretion 
               of galectin-1 in HSMs                                                                                  52
      4.2.2 p62, MVB, Rab11 and VAMP7 are required for autophagosomes 
               to transport galectin-1                                                                                  54
      4.2.3 TLR2 dependent reactive oxygen species production regulates 
               the secretion of galectin-1 in HSMs                                                             55    
      4.2.4 HCC patients showed altered expression of autophagy
               in macrophages                                                                                              56
      4.2.5 High autophagy activity was associated with low galectin-1 expression 
      in tumor-associated macrophages of HCC tumor tissues and cooccurrence 
      of these two events correlated with poor overall survival rate of HCC 
      patients                                                                                                                  56
   4.3 Tumor factors secretes galectin-1
      4-3.1 Hepatoma derived HMGB1 promotes the secretion of galectin-1             58
4-3.2	Hepatoma derived HMGB1-dependent galectin-1 secretion 
            contribute to the poor prognosis of HCC                                                      58                                                  
5. Discussion
   5-1 Galectin-1 as a target in tumor microenvironment
      5-1.1 TME-associated-galectin-1 pathogenic roles in HCC                                60 
      5-1.2 Galectin-1 expression and secretion is enhanced in 
               TAMs                                                                                                          61
      5-1.3 Galectin-1 secretion contributes to promote HCC 
               Tumorienesis                                                                                                 62
5-2 Mechanisms involved in secretion of galectin
       5-2.1 Autophagy mediates the secretion of galectin-1                                         63
       5-2.2 Mechanisms of autophagy-mediated galectin-1 secretion and 
               its signaling                                                                                                   64
      5-2.3 LC3 cargos galectin-1 in autophagosomes                                                   65                                                    
      5-2.4 MVBs are associated with galectin-1 secretion                                            66
      5-2.5 HSMs secretes galectin-1 via Rab-11-mediated amphisomes                      67
      5-2.6 VAMP7 facilitates the secretion of galectin-1 from TAMs                          69
      5-2.7 p62 enhances the secretion of galectin-1                                                       70
      5-2.8 ROS is required to induce galectin-1 secretion by 
               inducing autophagy                                                                                       71
      5-2.9 TLR signaling mechanisms behind the secretion 
               of galectin-1                                                                                                   72
     5-2.10 5.10 Secretion of galectin-1 through exosomes                                           73                                                                                              
   5-3 TAMs-associated galectin-1 as biomarker
      5-3.1 Protective role of TAMs-associated galectin-1 in HCC                               74
      5.3.2 Galectin-1 as a potential therapy target                                                         75
   5-4 HMGB1 as a biomarker of HCC
      5-4.1 HMGB1 enhances the secretion of galectin-1 in HCC                                75
      5-4.2 HMGB1 in clinical applications                                                                   77
6. Conclusion                                                                                                               78                  
7. References                                                                                                               79
8.Tables                                                                                                                       93
                                    

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校內：2023-08-09公開
校外：2023-08-09公開

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