以去氧羥四環素調控神經幹細胞對惡性C6神經膠腫瘤細胞進行分化及自殺基因的複合療法

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研究生：	朱映瑞 Chu, Inn-Ray
論文名稱：	以去氧羥四環素調控神經幹細胞對惡性C6神經膠腫瘤細胞進行分化及自殺基因的複合療法 A Doxycycline-Inducible Neural Stem Cell-Based Combination of Differentiation and Suicide Gene Therapy for Tumorigenic C6 Glioma Cells
指導教授：	潘榮隆 Pan, Rong-Long 吳立真 Wu, Li-Chen 楊重熙 Yang, Chung-Shi
口試委員:	張壯榮 Chang, Chuang Rung 曾淑芬 Tzeng, Shun-Fen
學位類別：	博士 Doctor
系所名稱：	生命科學暨醫學院 - 生物資訊與結構生物研究所 Institute of Bioinformatics and Structural Biology
論文出版年：	2021
畢業學年度：	109
語文別：	英文
論文頁數：	103
中文關鍵詞：	癌幹細胞、分化療法、介白素-6 、膠質纖維酸性蛋白、游離介白素-6 受體、腫瘤壞死因子-α 、神經幹細胞、自殺基因療法、連接蛋白-43
外文關鍵詞：	cancer stem cell, differentiation therapy, interleukin-6, glial fibrillary acidic protein, soluble interleukin-6 receptor, tumor necrosis factor-α, neural stem cell, suicide gene therapy, connexin-43
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癌幹細胞由於具有治療抗性，且可造成腫瘤的發生、復發和轉移，因而被認為是癌症治療上的一個障礙。分化療法是運用來治療癌幹細胞的其中一種方式，可藉由誘導癌幹細胞進入分化的程序以降低其致瘤性。介白素-6被發現可提高膠質纖維酸性蛋白在C6神經膠腫瘤細胞的表現量，這說明了介白素-6可誘導此細胞分化的可能性。此外，C6神經膠腫瘤細胞株被證實含有高比例的癌幹細胞，這些觀察促使我們假設介白素-6可引發惡性C6神經膠腫瘤細胞分化。然而當我們以介白素-6處理此細胞時，發現並無法有效地誘導其進行分化。因此，不同強度的介白素-6訊息傳遞誘發物被運用來檢視其誘導分化的效果，包括介白素-6、介白素-6/游離介白素-6受體和腫瘤壞死因子-α/介白素-6/游離介白素-6受體。實驗的結果顯示較強的介白素-6訊息傳遞誘發物可有效地誘導惡性C6神經膠腫瘤細胞分化。近年來利用神經幹細胞的癌細胞趨性來進行基因療法，已成治療腦癌的一個有效手段。但此一策略面臨到兩個重要的挑戰，即是要避免神經幹細胞在到達腫瘤病灶處前被本身所攜帶之治療基因的產物所影響，以及清除治療後所遺留下來的外源性神經幹細胞。為此，我們建立的一個可被去氧羥四環素誘導的逆病毒質體pTRE3G-sIL6R-TNFα- IL6-IRES-TKGFP，讓攜帶有此質體或是轉導由此質體製造出的逆病毒之幹細胞，進行分化療法搭配自殺基因療法的複合式治療。腫瘤壞死因子-α/介白素-6/游離介白素-6受體可有效地誘導惡性C6神經膠腫瘤細胞進行分化，降低其細胞的增生速度和致瘤性，並增加細胞分化指標的表現，例如連接蛋白-43。間隙連接被證實可增強自殺基因療法的旁觀者效應。實驗結果顯示，運用攜帶有逆病毒質體之神經幹細胞進行分化療法搭配自殺基因療法來處理惡性C6神經膠腫瘤細胞的效果比起只使用自殺基因療法的好。此篇研究為利用神經幹細胞進行分化療法搭配TK/GCV自殺基因系統治療神經膠腫瘤細胞的首例。

Cancer stem cells (CSCs) are obstacles to cancer therapy due to their therapeutic resistance, ability to initiate neoplasia, and roles in tumor relapse and metastasis. Efforts have been made to cure CSCs, such as the use of differentiation therapy, which induces cancer stem-like cells to undergo differentiation and decrease their tumorigenicity. Interleukin 6 (IL-6) upregulates the expression of glial fibrillary acidic protein (GFAP) in C6 glioma cells, indicating that it is able to induce the differentiation of these cells. The C6 glioma cell line forms a high percentage of cancer stem-like cells, leading us to speculate whether IL-6 signaling could modulate the differentiation of tumorigenic C6 glioma cells. However, we observed that IL-6 alone could not efficiently induce the differentiation of these cells. Therefore, different IL-6 signaling elicitors, including IL-6 alone, a combination of IL-6 and soluble IL-6 receptor (IL-6/sIL-6R), and tumor necrosis factor-α (TNF-α) plus IL-6/sIL-6R (TNF-α/IL-6/sIL-6R) were evaluated for their potential use in differentiation therapy. Our results indicated that enhanced IL-6 signaling could effectively induce tumorigenic C6 glioma cell differentiation. Neural stem cell (NSC)-based gene therapies have been recently developed as effective strategies for treating brain tumors through inherent tumor tropism. However, there are two considerable challenges for this methodology: preventing NSCs from dying from the therapeutic agents encoded by their equipped genes before reaching tumor sites and the clearance of exogenous NSCs after therapeutic treatments. For these purposes, we established a novel doxycycline-inducible retroviral plasmid, pTRE3G-sIL6R-TNFα-IL6- IRES-TKGFP, for stem cell-based combination gene therapy. We verified that TNF-α/IL-6/sIL-6R could efficiently induce tumorigenic C6 glioma cell differentiation, resulted in down-regulating the cell proliferation rate and the tumorigenicity of glioma cells and up-regulating the production of differentiation markers, such as connexin-43. Furthermore, gap junctions could enhance the bystander effect in suicide gene therapy. Consequently, we found that the retroviral plasmid transfected NSCs exerted stronger remedial effects on tumorigenic C6 glioma cells through the combination of differentiation and suicide gene therapy than by suicide gene therapy alone. This study is also the first case applying NSCs to conduct the combination of differentiation and herpes simplex type 1 thymidine kinase (TK)/ ganciclovir (GCV) based-suicide gene therapy on glioma cells.

Contents
致謝 (i)
Abstract (ii)
中文摘要 (iv)
Abbreviations (vi)
Contents (x)
Chapter 1 Introduction (1)
1.1 Brain cancer (1)
1.2 Cancer stem cell therapy (1)
1.3 Enhanced IL-6 signaling for differentiation of tumorigenic C6 glioma cells (2)
1.4 Stem cell-based gene therapy (5)
Chapter 2 Materials and Methods (9)
2.1 Cell cultures and restriction enzymes (9)
2.2 RNA extraction and RT-PCR (9)
2.3 Western blot analysis (10)
2.4 Dye coupling assay (12)
2.5 Cell proliferation assay (12)
2.6 Apoptosis and necrosis detection (13)
2.7 Soft agar assay (14)
2.8 Sphere formation assay (14)
2.9 Construction of doxycycline-inducible retroviral plasmid (15)
2.10 Retroviral system (18)
2.11 Cytotoxicity assay (19)
2.12 Cell sorting (19)
2.13 Functional analysis of PTRE3G (20)
2.14 Puromycin selection (20)
2.15 Combination of differentiation and suicide gene therapy (21)
2.16 Statistical Analysis (22)
Chapter 3 Results (23)
Part I: Differentiation of tumorigenic C6 glioma cells induced by enhanced IL-6 signaling (23)
3.1 The expression of IL-6 efficiently triggered by TNF-α/IL6/sIL-6R (23)
3.2 Differentiation of C6 glioma cells induced by TNF-α/IL-6/sIL-6R as evidenced by changes in biomarker levels (23)
3.3 Decrease of the proliferation rate in C6 glioma cells by TNF-α/IL-6/sIL-6R (24)
3.4 Downregulation of the tumorigenicity in C6 glioma cells by TNF-α/IL-6/sIL-6R (25)
3.5 Part I summary: Differentiation of tumorigenic C6 glioma cells induced by enhanced IL-6 signaling (27)
Results Part II: Neural stem cell-based combination of differentiation and suicide gene therapy for tumorigenic C6 glioma cells (27)
3.6 Construction and functional analysis of pQcXIX-TKGFP (27)
3.7 Construction and functional analysis of pTRE3G-TKGFP (29)
3.8 Construction of pTRE3G-sIL6R-TNFα-IL6-IRES-TKGFP (30)
3.9 Tumorigenic C6 glioma cells treated with combined differentiation and suicide gene therapy by C17.2 NSCs (30)
3.10 Part II summary: Neural stem cell-based combination of differentiation and suicide gene therapy for tumorigenic C6 glioma cells (32)
Chapter 4 Discussion (33)
4.1 Differentiation of Tumorigenic C6 Glioma Cells induced by Enhanced IL-6 signaling (33)
4.2 Neural stem cell-based combination of differentiation and suicide gene therapy for tumorigenic C6 glioma cells (37)
Chapter 5 Figures and Tables (42)
Figure 1. Upregulation of IL-6 in C6 glioma cells (42)
Figure 2. The differentiation state of C6 glioma cells determined according to biomarkers (43)
Figure 3. Upregulation of gap junction in C6 glioma cells (44)
Figure 4. The proliferation rate of C6 glioma cells reduced by TNF-α/IL-6/sIL-6R (45)
Figure 5. Downregulation of the tumorigenicity in C6 glioma cells evidenced by the soft agar assay (46)
Figure 6. Downregulation of the tumorigenicity in C6 glioma cells evidenced by the sphere formation assay (47)
Figure 7. The size distribution of spheres (48)
Figure 8. Construction of TK-GFP fusion protein (49)
Figure 9. Functional analysis of TK in TK-GFP fusion protein (50)
Figure 10. Functional analysis of GFP in TK-GFP fusion protein (51)
Figure 11. Construction of pTRE3G-TKGFP (52)
Figure 12. Functional analysis of PTRE3G in pTRE3G-TKGFP (53)
Figure 13. Construction of three cytokine genes for differentiation therapy into pTRE3G-TKGFP (54)
Figure 14. Cytotoxicity effect exerted by C17.2 NSCs through differentiation therapy combined with suicide gene therapy (55)
Figure 15. Participation of connexin-43 in the astrocytic differentiation of tumorigenic C6 glioma cells (56)
Figure 16. Combined differentiation and suicide gene therapy performed by C17.2 NSCs against tumorigenic C6 glioma (57)
Table 1. PCR primers specific for Il-6 and Gapdh (58)
Table 2. PCR primers for construction of doxycycline-inducible retroviral plasmid (59)
Table 3.  PCR primers specific for Tet-On 3G transactivator (60)
Supplemental information (61)
Supplemental information 1. pHSV1tk-AcGFP vector sequence (61)
Supplemental information 2. pQcXIX-TKGFP vector sequence (67)
Supplemental information 3. pTRE3G-TKGFP vector sequence (75)
Supplemental information 4. pTRE3G-sIL6R-TNFα-IL6-IRES-TKGFP vector sequence (83)
Appendixes (93)
Appendix I. The remedial strategies for CSCs (93)
Appendix II: Classic- and trans-signaling of IL-6 (94)
Appendix III: Process of suicide gene therapy (95)
References (96)

                                

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