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作者(中文):張定蓮
作者(外文):Chang, Ting Lian
論文名稱(中文):新穎醣胺多醣結合胜肽調控癌細胞移⾏的作⽤機制
論文名稱(外文):Regulatory Effects of Novel Glycosaminoglycan Binding Peptides on Cancer Cell Migration
指導教授(中文):王慧菁
指導教授(外文):Wang, Hui Ching
口試委員(中文):張大慈
張建文
口試委員(外文):Chang, Dah Tsyr
Chang, Chien Wen
學位類別:碩士
校院名稱:國立清華大學
系所名稱:分子與細胞生物研究所
學號:103080527
出版年(民國):105
畢業學年度:104
語文別:英文中文
論文頁數:77
中文關鍵詞:醣胺多醣結合胜肽細胞爬行
外文關鍵詞:Glycosaminoglycan Binding PeptideCell MigrationGBP
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癌細胞轉移是造成大部分病患死亡的主要原因,而癌症死亡原因中有約90%與癌細胞轉移有關。癌細胞本身必須具有活動力才能造成細胞轉移,因此抑制細胞移動能力成為一種治療癌症轉移的方法。本研究主要探討新穎醣胺多醣結合胜肽(GAG-binding peptide)的分子作用機制,已知GBP具有穿透細胞的能力,且能與細胞表面的硫酸乙酰肝素蛋白多醣(Heparan sulfate proteoglycan)結合,進而影響癌細胞的活動能力。為了探討GBP如何調控細胞爬行,本研究首先檢測與細胞移動有關的細胞黏著點(focal adhesion)與肌動蛋白維絲(actin filament)變化。我們發現以GBP處理細胞後,focal adhesion的數量增加、長度變長、其穩定性提升、並強化細胞附著能力,以上現象都讓細胞更緊密固著在基質並減緩細胞移動。此外,我們也發現GBP可能影響actin在細胞內的分佈並短暫增加stress fibers的表現量,但同時細胞骨架消失。GBP也誘導暫時性的磷酸化FAK以及降低paxillin的表現量。我們懷疑GBP是否與表面聚醣分子作用並減緩細胞移動速度,結果發現GBP與細胞表面聚醣蛋白syndecan-1, syndecan-4共同表現在相同位置,並促使syndecan-1往細胞內移動。綜合以上所述,本研究發現GBP可能影響focal adhesion與actin filaments的動態調控,進而導致癌細胞移行能力下降。
Metastasis is the primary cause of mortality and morbidity in most cancer patient and accounts for about 90% of cancer death. During the progression of metastasis, the cancer cell motility may determine the initiation process of metastasis. In this study, we investigate the role of a specific GAG-binding peptide (GBP), which possesses cell penetrating activity and interacts with cell surface heparan sulfate proteoglycan (HSPG), on regulating cancer cell motility. To investigate the underlying mechanism of GBP regulated cell migration, we examined focal adhesion and actin dynamics in response to GBP treatment. We found that GBP increased the focal adhesion numbers, length, and stability in A549 cells. In addition, GBP also enhanced cell adhesion, probably mediated by its intracellular function. Notably, we found that GBP changed the intracellular distribution of actin. A transient increase in stress fiber actin and a reduction of actin network was detected upon treatment with GBP. GBP also induced transient phosphorylation of FAK and down-regulation of paxillin. Next, GBP co-localized with two cell surface heparan sulfate proteoglycan, syndecan-1 (SDC-1) and syndecan-4 (SDC-4). Treatment with GBP promoted syndecan-1 internalization. Although direct targets of GBP is not identified in this study, our results indicate that GBP may interfere with dynamic regulations on focal adhesion and actin filaments, and thereby reduced cancer cell migration.
Abstract 6
中文摘要 7
1. Introduction 8
1-1. Cancer cell metastasis 8
1-2. Cell migration 8
1-3. Focal adhesion 10
1-4. GAG-binding peptide 12
1-5. Syndecan 13
1-6. Syndecan-1 regulates cell migration 17
2. Hypothesis and specific aims 18
3.Material and Method 19
4.Result 26
4-1. Intracellular stability of FITC-GBPECP in A549 cells. 26
4-2. FITC-GBPECP enriches at leading edge of A549 lung cancer cell. 26
4-3. GBPECP reduces wound-healing activity in A549 and OECM-1 26
4-4. GBPECP attenuates HB-EGF-induced cell migration. 27
4-5. GBPECP does not inhibit EGF-mediated A549 migration. 27
4-6. GBPECP enhances cell adhesion via its intracellular function. 27
4-7. GBPECP increases focal adhesion numbers and length in A549 cells. 28
4-8. GBPECP increases focal adhesion stability in A549 cells. 29
4-9. GBPECP affected the expression of focal adhesion proteins in OECM-1, but did not in A549. 29
4-10. GBPECP reduced Rho activity in A549. 30
4-11. GBPECP influences the morphology of F-actin in A549, and reduces paxillin expression in OECM-1. 30
4-12. FITC-GBPECP co-localizes with F-actin and influences the morphology of F-actin. 31
4-13. FITC-GBPECP interacts with syndecan family proteins. 31
4-14. Syndecan-1 expression in A549 cells. 32
4-15. GBPECP increases in syndecan-1 internalization in A549 cells. 32
4-16. Direct intracellular targets of GAG-binding peptide are not yet to be identified. 33
5.Discussion 35
6. Figure 41
Figure 1. Intracellular stability of GBP in A549 cells. 41
Figure 2. GBP enrich at the leading edge of A549 lung cancer cell. 42
Figure 3. GBPECP inhibits cell migration in A549 and OECM-1, but no effect in 293T. 43
Figure 4. High binding and high penetrating GBPECP attenuate HB-EGF-induced cell migration in A549 and OECM-1. 44
Figure 5. GBPECP inhibit HB-EGF-mediated A549 migration is likely dependent on the heparin-binding domain of HB-EGF. 45
Figure 6. GBPECP enhances cell adhesion in A549. 46
Figure 7. GBPECP may enhance cell adhesion via intracellular signaling pathway in A549. 47
Figure 8. GBPECP increases focal adhesion numbers and length in A549 cells. 48
Figure 9. GBPECP increases focal adhesion stability in A549 cells. 49
Figure 10. GBPECP affected the expression of focal adhesion proteins. 50
Figure 11. GBPECP reduced Rho activity in A549 cells. 51
Figure 12. GBPECP influences the morphology of F-actin. 52
Figure 13. GBPECP reduced paxillin expression in OECM-1. 53
Figure 14. FITC-GBP co-localized with F-actin and influenced the morphology of F-actin. 54
Figure 15. FITC-GBP colocalizes with endogenous syndecan-1 and syndecan-4. 55
Figure 16. Rhodamin-GBP colocalizes with GFP-SDC-1 and GFP-SDC-4. 56
Figure 17. Syndecan-1 expression in different cell lines. 57
Figure 18. GBPECP promotes in syndecan-1 internalization. 58
Figure 19. GBPECP increases in syndecan-1 internalization in A549 cells. 59
Figure 20. Compare syndecan-1 and GBP-far western blot in 1D and 2D-gel. 60
Figure 21. Identify high-molecular weight protein for MASS spectrometry analysis. 61
7. Reference 62
8. Table 68
9. Appendix 72
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