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系統識別號 U0026-0602201510192800
論文名稱(中文) 第四型膠原蛋白/整合素所活化之訊息傳遞在調控腫瘤細胞軟硬度及基質纖維母細胞浸潤的新穎機制
論文名稱(英文) A novel mechanism regulates the tumor cell rigidity and cancer-associated fibroblast infiltration through the collagen IV/integrin-initiated signaling pathway
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 103
學期 1
出版年 104
研究生(中文) 陳勝義
研究生(英文) Sheng-Yi Chen
電子信箱 wilson1211983@gmail.com
學號 S58971251
學位類別 博士
語文別 英文
論文頁數 83頁
口試委員 指導教授-楊倍昌
召集委員-江美治
口試委員-凌斌
口試委員-王仰高
口試委員-許秉寧
口試委員-戴明泓
中文關鍵字 第四型膠原蛋白  纖維母細胞  A型血小板衍生生長因子  細胞硬度  細胞爬行 
英文關鍵字 type IV collagen  cancer-associated fibroblast  PDGF-A  cell stiffness  cell migration 
學科別分類
中文摘要 細胞外基質及腫瘤微環境在腫瘤的進程中扮演重要的角色。第四型膠原蛋白過度堆積在腫瘤微環境中,可影響腫瘤細胞的侵襲能力、基質細胞的行為及組織張力的平衡。為了了解其中的分子機制,我們利用慢病毒攜帶干擾核糖核酸 (shRNA),抑制了腫瘤細胞中第四型膠原蛋白alpha 1基因的表現。這些細胞株命名為shCol細胞。雖然shCol-B16F10細胞在體外的生長速率沒有改變,它在C57BL/6小鼠皮下所長成的腫瘤明顯變小,而且alpha平滑肌肌動蛋白陽性纖維母細胞在腫瘤的浸潤明顯較少。當第四型膠原蛋白基因表現受抑制,或者利用抗體阻斷膠原蛋白與整合素之間的結合,皆可以降低纖維母細胞的趨化因子:「A型血小板衍生生長因子」的表現。此外,促進整合素的聚合可提升小鼠B16F10細胞、人類U118MG和Huh7細胞表現A型血小板衍生生長因子。透過A型血小板衍生生長因子專一的shRNA及中和性抗體,皆能抑制纖維母細胞的穿透爬行。在shCol細胞培養液中加入A型血小板衍生生長因子,可恢復其吸引纖維母細胞穿透移動的能力。以上的證據支持A型血小板衍生生長因子是本研究中,腫瘤吸引纖維母細胞的主要趨化因子。整合素活化而表現A型血小板衍生生長因子需要透過Src及ERK激酶的活化。由觀察肝癌及腦瘤病人的病理組織染色切片,也發現第四型膠原蛋白與A型血小板衍生生長因子的表現,位於同一細胞區塊上。因此,透過膠原蛋白與整合素結合而活化Src及ERK激酶的訊息傳遞路徑,將導致A型血小板衍生生長因子的表現。而這是造成腫瘤組織中,纖維母細胞浸潤關鍵的主要原因。
在另一方面,我們也進一步分析第四型膠原蛋白如何影響細胞軟硬度及爬行能力。雖然生長速率無差異,在細胞的型態上,shCol細胞比控制組細胞較為攤平。而且,shCol細胞的細胞硬度較高、爬行較慢。利用β1或α2β1整合素阻斷型抗體,或利用PP1與U0126抑制Src及ERK激酶,皆能有效地降低細胞的爬行能力、增加細胞硬度。如前所述,在shCol細胞中,Src及ERK激酶的活化程度下降。大量表現β1整合素不只刺激Src及ERK激酶的磷酸化,而且會降低細胞的鋼性、增加細胞的爬行能力。在C57BL/6小鼠的實驗性肺轉移動物模式中, B16F10-shCol細胞所產生的肺部腫瘤較少、也較小。因此,膠原蛋白也會促進腫瘤轉移。
綜合本研究的結果:在腫瘤微環境中,第四型膠原蛋白的堆積可刺激腫瘤細胞之整合素訊息活化及產生A型血小板衍生生長因子,吸引纖維母細胞浸潤。另外,它也會改變細胞的硬度,增加腫瘤轉移的能力。
英文摘要 It has been recognized that stromal cells and tumor microenvironment play pivotal roles in tumor progression. Collagen IV deposition in tumor microenvironment can influence cancer cells invasive capacity, stromal cell behaviors, and tissue tension homeostasis. To gain a better understanding of the underlying molecular mechanism, we knocked-down the type IV collagen alpha 1 gene (Col4A) of cells by the lentiviral-mediated RNA interference strategy, designated as shCol cells. Although there was no obvious effect on cell growth in vitro, silencing the Col4A gene decreased the tumorigenicity of B16F10 in C57BL/6 mice, which was accompanied by a reduction in the stromal infiltration of alpha-smooth muscle actin-positive (-SMA+) fibroblasts. Silencing Col4-Agene or disrupting integrin engagement by blocking antibody reduced the expression of platelet-derived growth factor A (PDGF-A), a potent chemotactic factor for fibroblasts. Furthermore, ectopic expression of the autoclustering integrin mutant significantly stimulated PDGF-A expression in murine B16F10, human U118MG, and Huh7 cells. PDGF-A-specific sh-RNA and neutralizing anti-PDGF-A antibody effectively inhibited the transwell migration of fibroblasts. Adding recombinant PDGF-A back to shCol cells-conditioned media restored the fibroblast-attraction ability, supporting the notion that PDGF-A is a major chemotactic factor for fibroblasts in the current model. The integrin-associated PDGF-A production correlated with the activation of Src and ERK. High type IV collagen staining intensity colocalized with elevated PDGF-A expression was observed in tumor tissues obtained from hepatoma and glioma patients. The integrin signal pathway was activated by collagen engagement through Src and ERK, leading to enhanced PDGF-A production, which serves as a key regulator of fibroblast recruitment.
Further to understand how type IV collagen affects mechanical rigidity and migration. Although having similar growth rates, shCol cells featured a flatter morphology compared to that of the corresponding controls. Notably, knocking-down the Col4A1gene endowed the cells with higher levels of elasticity and lower motility. Exposure to blocking antibodies against human β1integrin, α2β1integrin or the pharmacological inhibition of Src and ERK activity by PP1 and U0126, respectively, effectively reduced cell motility and raised cell stiffness. Reduced Src and ERK activities in shCol cells indicate the involvement of a collagen IV/integrin signaling pathway. The forced expression of β1 integrin significantly stimulated Src and ERK phosphorylation, reduced cell stiffness, and accelerated cell motility. In an experimental metastasis assay using C57BL/6 mice, B16F10 shCol cells formed significantly fewer and smaller lung nodules, confirming the contribution of collagen to metastasis.
In summary, the integrin signaling pathway activated in a tumor environment with collagen deposition appears to be responsible for cancer-associated fibroblast recruitment, low cell elasticity and high metastatic ability.
論文目次 Table of Contents
中文摘要 I
Abstract (English) III
Acknowledgement V
Table of Contents VII
List of table and figures X
List of abbreviations XII
1. Introduction 1
1.1 The relationship between type IV collagen and cancer-associated fibroblast infiltration 1
Extracellular matrix 1
Basement membrane 1
Type IV collagen 2
Integrin and non-integrin receptors of collagen IV 3
Collagen IV deposition in tumors 4
Cancer-associated fibroblast 5
Collagen and PDGF expression 6
1.2 The association of type IV collagen in cellular stiffness and migration ability 6
Cell movement regulated through ECM substrate rigidity 7
Type IV collagen promotes tumor metastatic ability 7
Higher cell stiffness with lower metastatic potential 8
Integrin signaling regulates cell stiffness 9
2. Rationale and Specific Aims 10
3. Materials and Methods 11
3.1 Materials 11
Chemicals and Reagents 11
Antibodies 13
Commercial Kits 14
Materials of Cell Culture 14
Materials for Western Blotting 15
Materials for Bacteria Culture 15
Machinery 16
Cell Lines 17
Media and Buffers 17
3.2 Methods 24
Cell culture 24
Bacterial strain store 24
Plasmid DNA Extraction 25
Lentivirus production 25
Quantitative real-time PCR 26
Reverse-Transcription Polymerase Chain Reaction (RT-PCR) 27
Western blot analysis 27
Single cell motility assay 28
Polarized cell migration assay 28
In vitro chemo-attractive invasion assay 29
Cell stiffness measurement 29
Immunofluorescence staining 29
In vivo experimental pulmonary metastasis assay 30
In vivo tumor formation 31
Statistical analysis 31
4. Results 32
Impaired tumorigenesis of B16F10 cells and reduced myofibroblast infiltration by knocking-down Col4A1 gene 32
Correlation of type IV collagen with PDGF-A expression 32
Contribution of integrin signaling to collagen-associated PDGF-A expression 33
Effect of kinase inhibitors on PDGF-A expression 34
Knocking-down Col4A1 gene-altered cell morphology, but not in vitro proliferation 35
Increase in cell stiffness after knocking-down Col4A1 gene 35
Modulation of cell stiffness by collagen IV/integrin downstream signaling through Src and ERK 36
Association of Col4A1 gene with cell migration 37
Association of Col4A1 gene with metastasis in vivo 38
5. Discussion 39
5.1 The relationship of type IV collagen and cancer-associated fibroblast infiltration 39
Collagen IV-related signaling modulates the expression of PDGF-related factors, and may also contribute to fibroblast recruitment 39
Tissue rigidity and receptor activation may be altered by knock-down of the collagen IV gene 40
β1 integrin receptor is the candidate for PDGF production by engagement of collagen IV 41
Over-expression of β1 integrin is responsible for Src and ERK activation and PDGF-A expression 41
5.2 The association of type IV collagen in cellular stiffness and migration ability 42
Consistency with prior evidence of shCol cells that elevated cell stiffness correlates with flatter morphology 42
Cell rigidity may be directly regulated by β1integrin receptor engagement with collagen IV 43
Upregulated cell stiffness but reduced cell migration through Col4A1 gene knock-down 44
6. Conclusion 45
7. References 46
8. Tables and Figures 56


List of table and figures
Table 1. Quantitative real-time PCR oligonucleotide primers used in this study 56
Table 2. RT-PCR oligonucleotide primers used in this study 57
Figure 1. Knocking-down of type IV-α1 chain collagen. 58
Figure 2. Reduced tumor growth and fibroblast infiltration of B16F10-derived shCol cells. 60
Figure 3. Reduction of fibroblast recruitment ability and PDGF-A expression of B16F10-derived shCol cells. 61
Figure 4. Impaired fibroblast recruitment by knock-down PDGF-A expression. 63
Figure 6. Contribution of integrin signaling to collagen-associated PDGF-A expression. 68
Figure 7. Suppression of PDGF-A expression by ERK and Src inhibitors. 69
Figure 8. Alteration of PDGF genes by knocking-down type IV-α1 collagen. 70
Figure 9. Reduced expression of PDGF genes by ERK inhibitor. 71
Figure 10. Proposed model for tumor fibroblast infiltration mediated by PDGF production through type IV collagen-β1 integrin-Src-ERK signaling pathway. 72
Figure 11. Alteration of cell morphology but not in vitro proliferation by knocking-down Col4A1 gene. 73
Figure 12. Increase in cell stiffness after knocking-down Col4A1 gene. 74
Figure 14. Over-expression of β1 integrin decreased cell stiffness. 77
Figure 15. Reduced integrin signal stabilizes F-actin structure. 79
Figure 16. Knocking-down Col4A1 gene decreased cell migration. 80
Figure 17. Knocking-down the Col4A1 gene of B16F10 cells decreased lung metastasis. 82
Figure 18. Proposed model for cell stiffness and cell migration ability mediated by type IV collagen-β1 integrin-Src-ERK signaling pathway. 83
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