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系統識別號 U0026-1008202011295400
論文名稱(中文) 探討SLFN5在塑化劑導致大腸癌幹細胞特性之機轉
論文名稱(英文) Investigation the mechanisms of SLFN5 in phthalate-induced stemness colon cancer
校院名稱 成功大學
系所名稱(中) 醫學檢驗生物技術學系
系所名稱(英) Department of Medical Laboratory Science and Biotechnology
學年度 108
學期 2
出版年 109
研究生(中文) 吳芝儀
研究生(英文) Chih-Yi Wu
學號 T36071052
學位類別 碩士
語文別 英文
論文頁數 51頁
口試委員 指導教授-張權發
口試委員-王憶卿
口試委員-陳興保
中文關鍵字 大腸癌  塑化劑  Human Schlafen 5 (SLFN5)  幹細胞特性 
英文關鍵字 Colorectal cancer (CRC)  Phthalates  Human Schlafen5 (SLFN5)  cell stemness 
學科別分類
中文摘要 因為生活習慣以及飲食上的改變,使得大腸癌在世界上以及台灣的發生率及死亡率都有上升的趨勢。大腸癌在治療後的高復發率,以及化療藥物刺激後所產生抗藥性,是目前高死亡率的主要問題。我們先前的研究發現,暴露在塑化劑DEHP (di-2-ethylhexyl phthalate)或是MEHP (mono-2-ethyhexyl phthalate)之下的大腸癌細胞,其抗藥性有上升的趨勢。RNA微陣列(RNA microarray)的分析結果顯示,SLFN5 (Human Schlafen 5)是一個會在塑化劑刺激下高度表現的基因。本論文將對SLFN5在塑化劑刺激後大腸癌細胞產生幹細胞特性其機轉之探討。首先我們發現了在長期刺激塑化劑的大腸癌細胞中,SLFN5蛋白量的表現比沒有刺激塑化劑的細胞還要高。接著利用shRNA降低塑化劑長期刺激大腸癌細胞中SLFN5的表現量,發現經由塑化劑刺激下大腸癌的幹細胞特性及多重抗藥性蛋白表現(P-glycoprotein以及CD133)會因而降低。在動物實驗中,我們也發現了經由塑化劑刺激後的腫瘤細胞在小鼠體內生長的體積最大,而降低SLFN5表現之後的腫瘤細胞在小鼠體內生長的體積都較小。這些結果都證明了SLFN5會促使在塑化劑刺激下大腸癌細胞展現幹細胞以及抗藥等特性。我們發現在塑化劑的刺激下,SLFN5會有入核的現象發生。我們也觀察到SLFN5會和Sox2有交互作用,但是之間的機制尚未明確。此外,臨床統計資料統計顯示,高度表現SLFN5的大腸癌病人其癌症復發率高且病人的預後也相對不好。根據以上的研究結果,我們認為因為塑化劑刺激而被誘導出的SLFN5會影響大腸癌幹細胞的特性甚至會去影響癌症的抗藥性以及腫瘤的生成。本論文指出了SLFN5在誘發幹細胞特性所扮演的角色,相當有機會做為開發新穎大腸直腸癌的治療方法。
英文摘要 Due to the changes in the diets and habit, the incidence and mortality of colorectal cancer (CRC) have increased worldwide and in Taiwan. The high recurrence, drug-resistant-caused treatment failure and cancer metastasis are the major problems during colorectal cancer treatment. Our previous study found that phthalates (DEHP/MEHP) exposure increased drug resistance in colon cancer cells. The RNA microarray analysis showed that the SLFN5 is one of the genes upregulated in long term phthalates exposure. In this study, we tried to investigate the roles of SLFN5 in phthalates-induced stemness in CRC. First, the expression levels of SLFN5 were higher in DEHP/MEHP long-term treated HCT116 cells. Next, we established the knockdown SLFN5 cell lines by short hairpin RNA in DEHP/MEHP long-term treated HCT116 cells. We found the knockdown of SLFN5 could decrease the cell stemness and the expression levels of the drug-resistant related proteins including P-glycoprotein and CD133. The tumor size were lower in the DEHP/MEHP-treated shSLFN5 HCT116 cells in xenograft models. Then we found that SLFN5 translocated into nucleus in our cell systems by immunofluorescence image. We further demonstrated that SLFN5 could interact with Sox2 but the mechanism was still unclear. Finally, we analyzed SLFN5 expression in patients’ tissues from Oncomine web, and found that the expression of SLFN5 was higher in tumor part and were associated with poor survival rate of CRC patients. Taken together, these results suggested that SLFN5 can induce the stemness and tumorigenesis in phthalate-treated colon cancer cells. For the future works, we will investigate the detailed mechanisms about SLFN5 induce the cancer stemness and the interaction of SLFN5/Sox2 translocation. Our findings not only understand the roles of SLFN5 mediated cancer stemness, but also shed light on novel anti-cancer drug development for CRC treatment.
論文目次 摘要......II
ABSTRACT......III
Acknowledgements......IV
TABLE OF CONTENTS......V
ABBREVIATIONS......VIII
INTRODUCTION......1
Colorectal carcinoma and drug resistance......1
Phthalates and the relationship with cancer......2
The schlafen (slfn) family members......4
The function of Human schlafen family member 5 (SLFN5)......4
OBJECTIVE......6
Study objective and Specific Aim......6
Experimental Flow Chart......7
MATERIALS AND METHODS......8
Cell culture and experimental conditions......8
shRNA lentivirus production 1. shRNA lentivirus production......8
RNA extraction......9
Reverse-Transcription Polymerase Chain Reaction......9
Protein extraction and quantification......10
Cellular fractionation......10
SDS-PAGE (sodium dodecyl sulfate-polyacrylamide gel electrophoresis)......11
Immunoblotting......11
Sphere formation assay......12
Immunofluorescence......12
Immunoprecipitation......12
Statistical analysis......13
RESULTS......14
Long-term and short-term DEHP or MEHP treatment induced SLFN5 expression.......14
SLFN5 induced the cell stemness after DEHP or MEHP exposure.......14
The expressions of drug resistant-related proteins and stemness marker were induced by SLFN5.......15
SLFN5 induced the expression of Src in DEHP/MEHP exposure.......16
SLFN5 and Sox2 translocated into nucleus in DEHP/MEHP-treated HCT116 cells.......16
SLFN5 expression has correlation with poor survival in CRC patients in clinical statistics.......17
The survival rates in CRC patients with expression of SLFN5 and Sox2.......18
DISCUSSION......19
CONCLUSION......23
REFERENCE......24
FIGURE......31
Figure 1. Long-term DEHP/MEHP treatment promoted SLFN5 protein expression in HCT116 cells.......31
Figure 2. Long-term DEHP/MEHP treatment promoted SLFN5 mRNA expression in HCT116 cells.......32
Figure 3. Short-term DEHP/MEHP treatment also promoted SLFN5 expression in HCT116 cells.......33
Figure 4. SLFN5 knockdown HCT116 cells were established using short-hairpin RNAs.......34
Figure 5. Knockdown SLFN5 in DEHP/MEHP-treated HCT116 cells reduced the stemness.......35
Figure 6. SLFN5 enhanced tumor growth in DEHP/MEHP-exposed HCT116 cells in vivo........36
Figure 7. SLFN5 induced stemness and drug resistance in DEHP/MEHP exposure; while knockdown of SLFN5 reduced stemness and drug resistance in DEHP/MEHP exposure.......37
Figure 8. Knockdown SLFN5 reduced Src expression and activation after DEHP/MEHP exposure.......38
Figure 9. The interaction in SLFN5 and Sox2 after DEHP/MEHP exposure.......39
Figure 10. SLFN5 translocated into the nuclear due to the DEHP/MEHP exposure.......40
Figure 11. SLFN5 protein translocated into the nuclear due to the DEHP/MEHP exposure.......41
Figure 12. Sox2 translocated into the nuclear due to the DEHP stimulation.......42
Figure 13. Sox2 translocated into the nuclear due to the MEHP stimulation.......43
Figure 14. The expression of SLFN5 was higher in colon cancer patients compared to normal people.......44
Figure 15. High expression level of SLFN5 correlated with lower survival rate.......45
Figure 16. High expression level of SLFN5/Sox2 correlated with lower survival rate.......46
Figure 17. The schematic diagram of phthalates-induced stemness and drug resistance in colon cancer.......47
SUPPLEMENTAL FIGURE......48
Supplemental Figure 1. SLFN5 was upregulated in DEHP/MEHP treatment.......48
Supplemental Figure 2. DEHP/MEHP treatment upregulated the stemness-related proteins in HCT116 cells.......49
Supplemental Figure 3. Sox2-interacted proteins identified in human brain cancer by MudPIT analysis.......50
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