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系統識別號 U0026-0510201513342300
論文名稱(中文) Sp1藉由IRES調控其表現量以及在癌症形成與轉移中所扮演的角色
論文名稱(英文) The role of Specificity protein (Sp1) expression regulated by internal ribosomal entry site (IRES) in tumorigenesis and metastasis
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 104
學期 1
出版年 104
研究生(中文) 洪家揚
研究生(英文) Chia-Yang Hung
學號 S58994097
學位類別 博士
語文別 英文
論文頁數 103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-蔣輯武
口試委員-曾大千
口試委員-陳青周
口試委員-譚婉玉
中文關鍵字 Sp1  nucleolin  nm23  hnRNPA2/B1  internal ribosomal entry site (IRES)  肺癌 
英文關鍵字 Sp1  nucleolin  nm23  hnRNPA2/B1  internal ribosomal entry site (IRES)  lung cancer 
學科別分類
中文摘要 轉錄因子特異性蛋白質(Sp1),表現在哺乳類細胞中且參與許多細胞的生理作用。此外Sp1會大量累積及表現在人類的癌症組織中,並且Sp1的表現量與腫瘤的惡性程度相關;我們先前的研究指出在缺氧的狀況下,Sp1會藉由IRES的機制大量表現在細胞當中,此研究提供在外在壓力與病理的狀況下,可以透過IRES的機制使Sp1大量表現於細胞當中。本研究的目的是在探討Sp1藉由IRES機制調控其表現量於腫瘤形成及轉移。首先,我們發現Sp1蛋白質會大量表現在肺癌病患的肺組織中,並且透過轉譯調控的方式來增加其表現量。進一步我們利用RNA-免疫沉澱法分析,發現nucleolin能夠藉由GAR domain結合在Sp1 5端非轉譯區並且促使Sp1 IRES活化以增加Sp1的表現量。使用gefitinib, LY294002和MK2206等抑制劑,可以顯著抑制Sp1 IRES的活化,證實EGFR下游的訊息傳遞能夠透過Akt的活化並調控Sp1的表現量。我們也證實在肺癌的病程中,癌細胞能藉由EGFR下游的訊息傳遞磷酸化nucleolin上蘇胺酸641/707的位置,使nucleolin活化並且作為ITAF結合在Sp1 5端非轉譯區,藉此增加Sp1的表現量;最近的研究也指出癌組織中Sp1的表現量下降有利於腫瘤的惡化;本研究中我們也釐清,癌細胞能透過IRES的機制導致Sp1的表現量下降以利於腫瘤的惡化。我們利用Sp1 5端非轉譯區的序列在試管內合成RNA探針,並用質譜分析的方式找到nm23與hnRNPA2/B1可以結合在Sp1 5端非轉譯區。nm23能夠透過磷酸化Sp1上蘇胺酸739的位置以增加Sp1蛋白質的穩定性,並與hnRNPA2/B1形成複合體結合在Sp1 5端非轉譯區。利用基因默化(silence)降低nm23與hnRNPA2/B1的蛋白質表現量可以抑制Sp1 IRES的活化並增加肺癌細胞移動的能力。進一步我們也分析了肺癌病人的肺組織,發現Sp1與nm23低表現量的病人有較差的癒後及活存率。此外,我們也發現降低nm23蛋白質表現量,可以減少hnRNPA2/B1的蛋白質穩定性以抑制Sp1 IRES的活化及Sp1的表現。綜合以上實驗的結果,我們證實並釐清nucleolin, nm23及hnRNPA2/B1如何調控Sp1在肺癌細胞中的表現量,以利於肺癌的進程成及惡化。
英文摘要 The transcription factor, Specificity protein-1 (Sp1) is expressed in mammalian cells and involved in many cellular processes. Sp1 was accumulated in several cancer types and the Sp1 levels correlated with tumor stages. Our previous study indicated that Sp1 is accumulated during hypoxia in an internal ribosomal entry site (IRES)-dependent manner. This study provided evidences that Sp1 accumulation is IRES-mediated manner in stressful or pathological conditions. The overall objective of this study is to investigate the regulation of Sp1 levels through IRES-dependent manner in tumorigenesis and metastasis. First, we found that the Sp1 was induced strongly at the protein level, but not in the mRNA level, in lung tumor tissue, indicating that translational regulation might contribute to the Sp1 accumulation during tumorigenesis. A further study showed that the translation of Sp1 was dramatically induced through an IRES-dependent pathway. RNA immuniprecipitation analysis of proteins bound to the 5-untranslated region (5-UTR) of Sp1 identified interacting protein-nucleolin. We found nucleolin positively facilitates Sp1 IRES activation. Further analysis of the interaction between nucleolin and the 5-UTR of Sp1 mRNA revealed that the GAR domain was important for IRES-mediated translation of Sp1. Moreover, gefitinib, LY294002 and MK2206 compounds inhibited IRES-mediated Sp1 translation, implying that activation of the epithelial growth factor receptor (EGFR) pathway via Akt activation triggers the IRES pathway. EGFR activation-mediated nucleolin phosphorylated at Thr641 and Thr707 was recruited to the 5-UTR of Sp1 as an IRES trans-acting factor (ITAF) to modulate Sp1 translation during lung cancer formation. Furthermore, recent studies have indicated that a decrease in Sp1 level is beneficial to the lung cancer malignancy. We also clarified the decrease of Sp1 levels was regulated through IRES-dependent manner in cancer malignancy. Herein, we used in vitro transcript 5-UTR of Sp1 as probe and analyzed interacting proteins by LC/MS/MS. We found nm23 and hnRNPA2/B1 as interacting proteins in Sp1 5-UTR. We demonstrated that nm23 not only increased the phosphorylation of Sp1 at Thr739 to enhance the protein stability of Sp1 but also formed a complex with hnRNPA2/B1 that was recruited to the 5'-UTR of Sp1 mRNA. Knocking down nm23 or hnRNPA2/B1 decreased Sp1 expression in a cap-independent manner, suggesting that nm23 and hnRNPA2/B1 contributed to the IRES-mediated translational activity of Sp1. Knocking down nm23 or hnRNPA2/B1 also increased the migratory activity of lung cancer cell lines. Furthermore, patients with lung cancer with poor prognosis had low levels of Sp1 and nm23, suggesting an association between nm23/Sp1 levels and survival rate. Studies performed to elucidate the mechanism underlying this relationship indicated that a decrease in nm23 levels in the lung cancer cells with more malignant activity inhibited hnRNPA2/B1 protein stability, and thus subsequently decreased the recruitment of hnRNPA2/B1 to the 5'-UTR of Sp1 mRNA, repressing Sp1 expression through inhibition of the cap-independent transcriptional activity. Taken together, these results suggest that understanding the relationship between nucleolin, nm23, hnRNPA2/B1, and Sp1 in regulating lung cancer tumorigenesis and malignancy will be beneficial of lung cancer.
論文目次 中文摘要 I
Abstract II
Acknowledgements IV
Contents VII
Abbreviations XI
Introduction 1
I. Specificity protein-1 (Sp1) 1
1. The overview of Sp1 1
2. Post-translational modifications of Sp1 1
3. Regulation of Sp1 in tumorigenesis and metastasis 2
II. Protein synthesis 4
1. Cap-dependent translation 4
2. Cap-independent translation 4
III. Nucleolin 6
1. Basic concept of nucleolin 6
2. The role of nucleolin in cancer formation 7
IV. Non-metastatic gene-23 (Nm23) 7
V. Heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2/B1) 8
VI. Research aims 9
Material and methods 10
Results 21
1. Cap-independent translational activity contributes to Sp1 accumulation during tumorigenesis 21
2. Nucleolin is involved in cap-independent translation of Sp1 22
3. GAR domain of nucleolin is important for the interaction with Sp1 IRES elements 24
4. Phosphorylation of nucleolin at Thr641/707 facilitates Sp1 IRES activity 25
5. Epidermal growth factor (EGF) signaling enhances Sp1 IRES activation 26
6. Depletion of nm23 enhances invasive phenotype and downregulates Sp1 expression in cancer cells 27
7. Low expression levels of Sp1 and nm23 are correlated with poor prognosis in patients with lung cancer 28
8. Nm23-mediated Sp1 expression is involved in EMT of lung cancer cells. 29
9. Sp1 is critical for nm23-mediated lung cancer progression 30
10. Nm23-stabilized hnRNPA2/B1 positively regulates Sp1 expression through a cap-independent translation pathway 30
11. Knockdown of hnRNPA2/B1 decreases Sp1 expression to enhance cancer cell migration 31
Discussion 33
Conclusions 40
References 41
Figure 1. Sp1 is accumulated in tumorigenesis. 53
Figure 2. Sp1 5'-UTR contains internal ribosomal entry site (IRES) element. 55
Figure 3. Nucleolin is involved in IRES-mediated translation of Sp1. 56
Figure 4. Nucleolin increases Sp1 expression through enhancing ribosome recruitment. 58
Figure 5. Nucleolin does not affect the Sp1 protein stability. 60
Figure 6. GAR-domain of nucleolin interacts with 5-UTR of Sp1 mRNA. 62
Figure 7. Overexpression of nucleolin increase cap-independent translation. 63
Figure 8. Phosphorylation at Thr641/Thr707 residues of nucleolin is critical for IRES-mediated translation of Sp1. 64
Figure 9. EGF enhances Sp1 IRES-mediated translation. 65
Figure 10. Akt activation involves in nucleolin phosphorylation at Thr641/707. 67
Figure 11. Nucleolin induces Sp1 expression and increases cell proliferation. 69
Figure 12. The role of nm23 in Sp1 expression. 71
Figure 13. The relevance between Sp1/nm23 levels and the prognosis of lung cancer patients. 72
Figure 14. The role of nm23-mediated Sp1 expression in epithelial and mesenchymal transition of lung cancer cells. 74
Figure 15. The role of nm23-mediated Sp1 expression on lung cancer malignancy. 76
Figure 16. The effect of nm23 interacted with hnRNPA2/B1 on the Sp1 expression. 78
Figure 17.The effect of hnRNPA2/B1 on cancer cell invasive phenotype and migration ability. 80
Figure 18. The correlation between nm23, hnRNPA2/B1 and Sp1 on the different lung cancer stage. 83
Table 1. Characteristics of lung cancer patients which are involved in determining Sp1 and Nm23 expression by Immunohistochemistry staining 84
Appendix 1 85
Appendix 2 86
Appendix 3 87
Appendix 4 88
Appendix 5 89
Appendix 6 90
Curriculum vitae 91
Published thesis (First author)………………………………………………92
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