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研究生:詹郁恬
研究生(外文):Yu-Tien Chan
論文名稱:STAT3在瀰漫性大型B淋巴瘤促進變形運動的產生
論文名稱(外文):STAT3 facilitates amoeboid movement in diffuse large B-cell lymphoma
指導教授:楊慕華楊慕華引用關係
指導教授(外文):Muh-Hwa Yang
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:臨床醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2017
畢業學年度:105
語文別:英文
論文頁數:68
外文關鍵詞:STAT3amoeboid movementDLBCLERM
相關次數:
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瀰漫性大型B細胞淋巴瘤(diffuse large B-cell lymphoma; DLBCL)是發生於淋巴組織中B細胞的惡性腫瘤,是成人最主要的惡性淋巴瘤之一。DLBCL的擴散在臨床上最主要的特徵是具有不連續性的特色,並且擴散的方式與實體固態瘤轉移所遵循的步驟有非常大的不同。然而,目前對DLBCL移動及擴散機制之了解非常有限。在我們的研究中,DLBCL在三度空間培養系統下,是以變形運動(amoeboid movement)為主要的運動模式,這種模式一開始是發現在白血球在發炎時,前往發炎組織在生物體內移動之方式,它是一種速度快且與蛋白溶解活性無關之移動方式,恰好可以解釋DLBCL在人體內擴散之特性。在我們的研究中發現轉錄因子STAT3的活化可以誘發白細胞介素10 (Interleukin 10;IL-10)的產生,進而在DLBCL形成正向回饋的路徑。STAT3的活化可以抑制微小管(microtubule)的聚合,並且釋放ARHGEF2而活化RhoA,進而導致變形運動的發生。此外,我們還發現ezrin/radixin/moesin (ERM)蛋白在DLBCL變形運動之角色。STAT3所調控微小管的聚合,可以影響ERM蛋白與ICAM家族蛋白的交互作用。在我們的動物實驗中,利用臨床上JAK的抑制劑ruxolitinib以及微小管穩定劑taxol都能夠抑制DLBDL在小鼠體內的轉移。最後我們在臨床上病人的樣本中,驗證了STAT3誘導的變形運動對於病人第一期到第二期的轉型是非常重要。本篇研究闡明了DLBCL的擴散機制,在臨床上,我們提供了針對晚期擴散性淋巴瘤採取JAK/STAT抑制劑與微小管穩定劑合併治療的可能性。
Diffuse large B-cell lymphoma (DLBCL) is an aggressive B-cell malignancy and it is one of the most common types of lymphoma in adults. A major clinical character of DLBCL is that the dissemination of DLBCL occurs early in the disease course and skip metastasis is frequently observed in DLBCL, which is distinct from the process of solid tumor metastasis. However, the mechanism that drives the unique movement mode of DLBCL remains elusive. Here we show that the major movement mode of DLBCL in a 3D culture system is amoeboid-type movement, which is originally noted in leukocytes migration. The speed of amoeboid movement is fast and it is proteolysis independent, which explains the unique dissemination character of DLBCL. Here, we find that STAT3 activation induces IL-10 expression to constitute a positive feedback loop in DLBCL. Activated STAT3 regulates microtubule dynamics and releases ARHGEF2 to activate RhoA. In addition, we also demonstrate the involvement of ezrin/radixin/moesin (ERM) proteins in amoeboid movement of DLBCL. Furthermore, STAT3-mediated microtubule dynamics also regulates the interaction between ICAM-2 and ERM proteins leading to DLBCL migration. Both the pan-JAK inhibitor ruxolitinib and the microtubule-stabilizing agent taxol effectively suppress DLBCL dissemination in vivo. Analysis of clinical samples reveals that STAT3-driven amoeboid movement is particularly important for the stage I-to-II transition. This study elucidates the mechanism of DLBCL dissemination and also indicates a potential strategy for treating disseminated DLBCL.
Contents i
Abstract iv
摘要 v
I. Introduction 1
1-1 Lymphoma 1
1-2 Diffuse large-B-cell lymphoma 3
1-3 STAT3 in diffuse large-B-cell lymphoma 6
1-4 Treatment of diffuse large-B-cell lymphoma 7
1-5 Amoeboid movement 8
1-6 The important of ERM in amoeboid movement 8
II. Project aim 11
III. Materials and Methods 12
3-1 Mouse experiments 12
3-2 Patient samples and immunohistochemistry 13
3-3 Cell lines, plasmids and reagents 13
3-4 Virus production and infection 14
3-5 Trajectory tracking of DLBCL migration 15
3-6 Transendothelial migration assay 15
3-7 Gene Set Enrichment Analysis 16
3-8 cDNA microarray analysis 16
3-9 Accession number 17
3-10 Immunoblotting and immunoprecipitation 17
3-11 Small GTPase activity assay 17
3-12 Statistics 18
IV. Result 19
4.1 Amoeboid movement is critical for the early dissemination of DLBCL. 19
4.2 JAK-STAT3 signaling is the major pathway mediating amoeboid movement in DLBCL. 20
4.3 The IL10-JAK-STAT3 positive feedback loop contributes to the dissemination of DLBCL. 21
4.4 STAT3 suppresses tubulin acetylation to activate RhoA. 22
4.5 STAT3 facilitates the interaction between ICAM-2 and ERM proteins to increase amoeboid movement. 24
4.6 Disruption of the JAK/STAT3-microtubule-RhoA axis attenuates DLBCL dissemination and progression. 25
V. Discussion 27
VI. Conclusion 30
VII. References 31
VIII. Figures 41
Figure 1. Amoeboid movement involved in the early dissemination of DLBCL. 42
Figure 2. Amoeboid movement is detected in DLBCL in vivo and in vitro. 45
Figure 3. JAK-STAT3 signaling is the major pathway mediating amoeboid movement in DLBCL. 48
Figure 4. The IL10-JAK-STAT3 positive feedback loop contributes to DLBCL motility in vitro and in vivo. 51
Figure 5. STAT3 activate RhoA through suppresses tubulin acetylation. 54
Figure 6. STAT3-regulated microtubule dynamics facilitates the interaction of ICAM2 and ERM proteins to promote amoeboid movement. 57
Figure 7. Validation of the JAK/STAT3-micrtotubule-RhoA axis in DLBCL in vivo and clinical samples. 59
Figure 8. A schema for showing the molecular mechanism guiding amoeboid movement in disseminated-stage DLBCL. 61
IX. Tables 62
Table 1. Baseline characteristics of patients with diffuse large B-cell lymphoma. 62
Table 2. Information for the working concentration of the inhibitors used in this study. 63
Table 3. Information of reagents, shRNA sequences and PCR primers used in this study. 64
Table 4. Information of gene signatures used in this study. 67
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