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系統識別號 U0026-0506201209262600
論文名稱(中文) Sp1在肺癌發展中扮演的角色
論文名稱(英文) The Role of Sp1 in Lung Cancer Progression
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 100
學期 2
出版年 101
研究生(中文) 徐宗溢
研究生(英文) Tsung-I Hsu
電子信箱 dabiemhsu@gmail.com
學號 s58961345
學位類別 博士
語文別 英文
論文頁數 153頁
口試委員 指導教授-張文昌
共同指導教授-洪建中
召集委員-蔡少正
口試委員-蔣輯武
口試委員-呂佩融
口試委員-洪文俊
口試委員-吳國瑞
口試委員-陳怡榮
中文關鍵字 肺癌  Sp1  Kras  轉移  mithramycin A  betulinic acid  cyclin A2 
英文關鍵字 lung cancer  Sp1  metastasis  mithramycin A  betulinic acid  cyclin A2 
學科別分類
中文摘要 在台灣,肺癌的死亡率高於其他類型的癌症,罹患肺癌的病人預後情況相當不理想,五年存活率僅15%,甚至早期發現並接受手術切除的病人,五年存活率僅70%,找出造成肺癌的分子機制有助於針對細胞訊息傳遞發展新的標靶治療,例如,在肺癌細胞中突變的Ras蛋白質會持續活化與細胞存活增生相關的訊息傳遞,進而幫助腫瘤生長與惡化,因此發展出針對Ras蛋白質的標靶治療。此外,過去的研究也發現許多人類癌症組織會過度表現特異性蛋白質 (Sp1),而Sp1也跟腫瘤的惡性程度與不良的預後情形有關,此研究目的是探討Sp1在肺腫瘤發展中扮演的功能性角色,在此研究的第一個部分,我們首先建立可被四環黴素 (doxycycline) 激活KrasG12D並誘發肺腫瘤的基因轉殖鼠,探討Sp1在此動物模式中對肺部腫瘤生長與基因表現的影響,我們發現Sp1表現量在肺腫瘤有大量上升,同時在有注射Sp1抑制劑mithramycin A (MMA)的組別發現肺腫瘤有明顯的變小,伴隨著Sp1明顯的下降。接著我們釐清Sp1表現量在肺癌病人的臨床意義:相較於正常細胞與肺組織,我們發現Sp1在侵略性較差的肺癌細胞與第一期肺癌病人的檢體有顯著的增加;相較於肺癌早期,在高侵略性的肺癌細胞以及第四期肺癌病人的檢體,Sp1則有顯著的下降,但仍然比正常組織高。我們進一步地證明Sp1負向調控肺癌細胞的侵略性、移動能力與體內轉移的能力,在不同侵略性的肺癌細胞Sp1的表現量會有如此變化,是因為Sp1蛋白質的穩定性不同:在侵略性差的細胞,Sp1蛋白質比較穩定,不容易被降解,此外,在侵略性高的肺癌細胞,過度表現Sp1可誘發轉移抑制蛋白質,E-cadherin,的表現進而將-catenin固定在細胞膜附近,避免其入核而幫助癌細胞更惡化,綜合以上的證據,Sp1在肺癌早期會大量累積,在晚期則有下降的現象,這樣的現象分別幫助肺癌細胞在早期的增生以及在晚期的轉移。在第二部分我們探討會影響Sp1蛋白質穩定度的藥物樺木酸(betulinic acid)對肺腫瘤生長的影響,發現樺木酸藉由降低細胞內SENP1的表現量,造成Sp1的類泛素化(sumoylation) ,類泛素化的Sp1與RNF4產生交互作用,造成Sp1泛素化(ubiquitination)依賴性的蛋白質降解,此外,在KrasG12D誘發的肺癌轉殖鼠中,樺木酸與MMA皆明顯的抑制腫瘤生長,經由比較有無接受Sp1抑制劑的肺癌轉殖老鼠中帶有腫瘤的肺部基因表現,有542個基因在Sp1被抑制後受到影響,其中,鑑於cyclin A2與細胞增生與癌化相關,我們對其做進一步探討,不論是造成Sp1蛋白質降解的樺木酸,或是抑制Sp1結合到DNA能力的MMA,都顯著的降低cyclin A2的表現量,樺木酸的抗癌效果也進一步的在異種移植的小鼠模式被證實,而cyclin A2的減少降低了下游Rb蛋白質的磷酸化,最後造成細胞週期停滯在G2/M期,令人驚訝的是,Sp1基因默化(silence)的細胞對樺木酸產生明顯的抗藥性,這些發現釐清了樺木酸對Sp1的影響機制,以及證實了Sp1的存在對樺木酸的抗癌效果極為重要。
英文摘要 Lung cancer is the leading cause of cancer mortality and the prognosis for lung carcinoma patients is generally poor (5-yr survival rate < 15%) in Taiwan, even if diagnosed and treated successfully, patients with early stage of lung carcinoma have a 5-year survival rate of only 70% after surgical resection. Understanding of the molecular attributes of lung tumors provides clues to develop the therapy targeting defective cellular pathways for lung cancer, such as Ras proteins which activates Ras/Raf-1/mitogen-activated protein kinase pathway. The transcription factor, specificity protein (Sp) 1 was found to be overexpressed in several human cancers and the Sp1 levels correlated with tumor grade/stage and poor prognosis. The overall objective of this study is to identify the functional role and potential contribution of Sp1 in lung tumorigenesis. In the first section, we showed that the Sp1 level was highly increased and required for lung tumor growth in transgenic mice bearing KrasG12D-induced lung tumors under the control of doxycycline. Furthermore, the Sp1 level was highly upreguated in lung adenocarcinoma cells with low invasiveness and in patients with stage I lung cancer. We also demonstrated that Sp1 was downregulated in lung adenocarcinoma cells with high invasiveness and in patients with stage IV lung adenocarcinoma. In particular, Sp1 expression in highly invasive lung adenocarcinoma cells is still significantly higher than that in normal lung fibroblast. Moreover, Sp1 inversely regulated migration, invasion and metastasis of lung adenocarcinoma cells in vivo. In addition, a decrease in the Sp1 level in highly invasive lung adenocarcinoma cells resulted from instability of the Sp1 protein. Furthermore, overexpression of Sp1 in highly invasive lung adenocarcinoma cells increased expression of E-cadherin, a suppressor of metastasis, and attenuated the translocation of -catenin into the cellular nucleus which leads to tumor malignancy. Taken together, Sp1 level accumulates strongly in early stage and then declines in late stage, which are important for lung cancer cell proliferation and metastasis, respectively, during tumorigenesis. In the second section, we evaluated the effect of an anti-tumor drug, betulinic acid (BA), targeting Sp1 on lung cancer in vitro and in vivo. Herein, we found that BA treatment increased the sumoylation of Sp1 by inhibiting SENP1 expression and the recruitment of E3 ligase, RNF4, followed by resulting in ubiquitination-mediated degradation in a 26S proteosome-dependent pathway. In addition, both of BA and mithramycin A (MMA) treatment inhibited lung tumor growth, and downregulated Sp1 protein expression in KrasG12D-induced lung cancers of bitransgenic mice. In the study of gene expression profiles of KrasG12D-induced lung cancers of bitransgenic mice with and without Sp1 inhibition, 542 of genes were affected by repressing Sp1 expression. One of these important genes, cyclin A2 (CCNA2), was addressed deeply to indicate that CCNA2 expression was attenuated by BA and MMA treatments through decreasing Sp1 protein stability and DNA binding affinity, respectively. Downregulation of CCNA2 led to decrease in Rb phosphorylation and to causing cell cycle G2/M-arrest. BA-mediated cellular Sp1 degradation and antitumor effect were also further confirmed in xenograft mouse model by using H1299 cells. Knock down of Sp1 in lung cancer cells attenuated the anti-cell growth effect of BA. Taken together, this study clarified the mechanism of BA-mediated Sp1 degradation, and identified that Sp1 level plays a pivotal role in BA-induced repression of lung cancer growth.
論文目次 中文摘要 I
Abstract III
Acknowledgements V
Contents VI
Abbreviations XII
Introduction
I. Lung cancer
A. Epidemiology and histological classification 1
B. Pathogenesis 1
C. Metastasis 3
D. Common genetic abnormalities in lung cancer 3
E. Kras mutation in lung cancer 5
F. Transcription factors in lung cancer 6
II. Specificity protein (Sp) 1
A. Basic concept of Sp1 8
B. Target genes for cellular functions 8
C. Post translational modifications of Sp1 9
D. Sp1 in human disease 10
E. The possible role of Sp1 in lung cancer 11
III. Anti-tumor drugs targeting Sp1
A. Overview 12
B. Mithramycin A (MMA) 13
C. Betulinic acid (BA) 13
IV. Research aims and significance of this study 14
Materials and Methods
Materials 16
Methods 22
Results
Chapter 1: Sp1 is involved in lung tumor growth, but represses lung tumor metastasis
Rationale 31
Experimental results
1. The role of Sp1 in lung tumor growth 32
2. The clinical significance of Sp1 in lung cancer patients 33
3. The role of Sp1 in metastasis of lung tumor cells 35
4. The mechanism underlying the alteration of the Sp1 level in lung adenocarcinoma cells with different invasiveness 37
5. The mechanism of Sp1-mediated repression in metastasis 38
6. Effect of MMA on CL1-0 cells 40
7. Summary I 40
Figures and Table
Figure 1. Kras inhibition by FTI-276 decreases the protein level of Sp1 in
A549 cells. 42
Figure 2. The model of Kras4bG12D induced lung tumorigenesis under the control of doxycycline. 43
Figure 3. MMA prevents doxycycline-induced pathological changes in the lungs of bitransgenic mice. 44
Figure 4. Constitutively activated Kras triggered by doxycycline induces lung tumor formation, and MMA attenuates this phenomenon. 46
Figure 5. H-score for the signals of Kras, pErk, PCNA and CCSP. 47
Figure 6. Sp1 expression is negatively correlated with survival of lung adenocarcinoma patients. 48
Figure 7. Sp1 negatively regulates invasive and migratory abilities of lung cancer cells. 50
Figure 8. Sp1 overexpression promotes proliferation of CL1-5, not 1-0
and 1-1 cells. 52
Figure 9. Sp1 knockdown enhances invasive and migratory abilities of
CL1-0 cells. 53
Figure 10. Sp1 suppresses lung adenocarcinoma cell metastasis in vivo. 55
Figure 11. Downregulation of Sp1 expression in highly invasive lung adenocarcinoma cells is caused by instability of Sp1 protein. 57
Figure 12. Sp1 positively regulates E-cadherin expression and attenuates the translocation of -catenin into the cell nucleus. 59
Figure 13. Effect of MMA on CL1-0 cells. 62
Figure 14. The illustration explaining that Sp1 expression regulates lung tumor progression. 63
Table 1. Characteristic of 118 patients with lung adenocarcinoma analyzed by immunohistochemical staining. 65
Chapter 2: Betulinic acid inhibits lung tumor growth through inducing sumoylation- and ubiquitination-dependent Sp1 degradation
Rationale 66
Experimental results
8. Effect of BA on the Sp1 level in cancer cells 67
9. Effect of BA on lung tumor growth in vitro and in vivo 68
10. The role of Sp1 in BA-induced apoptosis in lung cancer cells 69
11. Identification of possible Sp1-regulated genes in lung tumorigenesis 70
12. Effect of BA on the expression of Sp1 target gene, cyclin A2 (CCNA2) 71
13. The consequence of BA-suppressed Sp1-regulated CCNA2 expression 71
14. Summary II 72
Figures and Table
Figure 15. Effects of BA on Sp1 protein degradation and SENP1 expression. 74
Figure 16. Effect of BA on the protein level of SENP1 in A549 cells. 76
Figure 17. Effect of BA on cellular proliferation and Sp1 expression in lung adenocarcinoma cells. 77
Figure 18. Effect of BA and MMA on lung tumor growth in vivo. 78
Figure 19. Effect of Sp1 knockdown on BA-mediated antitumor effect in lung adenocarcinoma cells. 80
Figure 20. Identification of Sp1-regulated gene expression related to proliferation in KrasG12D-driven lung tumorigenesis. 82
Figure 21. Heatmap of microarray data show that 542 genes are possibly regulated by Sp1 in the growth of lung tumor. 84
Figure 22. Effect of BA on Sp1-regulated CCNA2 expression in lung adenocarcinomas. 85
Figure 23. Effects of BA on RB phosphorylation and cell cycle progression in lung adenocarcinomas. 87
Figure 24. The proposed model illustrates that BA induces proteasome-dependent degradation of Sp1. 89
Table 2. Characteristics of 36 patients with lung adenocarcinomas analyzed by immunohistochemical staining. 90
Table 3. Microarray analysis reveals that 40 of well-known genes related to proliferation are regulated by Sp1 in lung tumor growth. 91
Discussion
1. The possible role of Sp1 in metastasis 96
2. Whether MMA-mediated Sp1 downregulation affects metastasis ? 96
3. Drugs targeting Sp1 may only benefit patients with early stage of lung cancer. 97
4. Post translational modification modulates Sp1 protein stability in lung cancer cells with different invasiveness. 97
5. Sp1 may regulate metastasis through controlling E-cadherin expression. 98
6. Different outcomes of Sp1 overexpression in highly invasive lung adenocarcinoma cells. 98
7. Sp1 attenuates -catenin translocation into cell nucleus for tumor malignancy. 99
8. Why is the decrease of the Sp1 level required for BA-induced cellular
apoptosis ? 99
9. The possible mechanism of BA-induced Sp1 degradation in a proteasome-dependent manner. 100
10. Sp1-regulated target genes expressions are important for lung tumor growth. 100
Conclusions 102
Figure 25. Sp1 promotes lung tumor growth through cyclin A2/Rb cascade, and inversely regulates metastasis through inducing E-cadherin expression. 103
References 104
Appendixes
Appendix 1 131
Appendix 2 132
Appendix 3 133
Appendix 4 134
Appendix 5 135
Appendix 5 (Continue) 136
Curriculum vitae 137
Published thesis (First author) 138
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