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研究生:侯沛琪
研究生(外文):Hou, Pei-Chi
論文名稱:雙特異性去磷酸酶-2對於腫瘤幹細胞特性及上皮細胞的上皮-間質轉化之角色探討
論文名稱(外文):The functional role of dual-specificity phosphatase 2 (DUSP2) in cancer-stemness and epithelial-mesenchymal transition (EMT).
指導教授:蔡少正
指導教授(外文):Tsai, Shaw-Jenq
口試委員:陳玉玲沈延盛林秋烽鄭宏祺呂昱瑋
口試委員(外文):Yuh-Ling ChenYan-Shen ShanChiou-Feng LinHung-Chi ChengYu-Wei Leu
口試日期:2017-05-26
學位類別:博士
校院名稱:國立成功大學
系所名稱:基礎醫學研究所
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:104
中文關鍵詞:癌幹細胞性上皮-間質轉化轉移雙特異性去磷酸酶-2缺氧
外文關鍵詞:Cancer stemnessMetastasisDual specificity protein phosphatase 2 (DUSP2)Hypoxia
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大量文獻指出,癌腫瘤的復發以及遠端轉移的發生與癌症幹細胞的存在有關。然而,癌症幹細胞的產生機制,仍有待更進一步的釐清。當癌組織生長超過一毫米立方,缺氧會使癌細胞為了克服生存,進而發展出一套機制,以利細胞於缺氧的壓力下生存。癌症幹細胞具有是一群具有緩慢增生、自我更新/補充的多能性次要族群。這些特性,使得細胞於缺氧環境下得以存活下來。本團隊先前的研究指出,缺氧抑制雙特異性去磷酸酶-2(DUSP2)的表現,造成ERK活化,增加了癌細胞存活率與化療藥物阻抗力。為了進一步證實DUSP2於缺氧所誘發之癌源幹細胞的重要性,在此,不論是從大腸癌細胞株跟臨床病人組織所分離之大腸癌細胞,皆發現到其負向調控MAPK因子之DUSP2於表現CD133癌幹細胞蛋白表現量減少。另外,在癌幹球型細胞與奥沙利铂(Oxaliplatin)藥物阻抗之細胞中,DUSP2之蛋白量也較控制組來的低下。當進一步將大腸癌細胞株跟臨床所離之大腸癌細胞剔除DUSP2後,其癌症幹細胞的相關特性大幅增加,可以被MEK抑制劑(U0126)所阻擋。不僅如此,這些剔除DUSP2之細胞產生較佳的移動力、侵犯力、非錨定之生長能力以及進一步失去上皮細胞特有之細胞連接蛋白E-cadherin。另一方面,當DUSP2重新表現之後,透過啟動細胞凋亡機制,減弱化療藥物的阻抗性。此研究發現,剔除DUSP2所大幅獲得之癌症幹細胞特性,是由於環氧合酶-2/前列腺素E2訊息不正常活化所致。缺氧致使之癌幹細胞特性,皆可進一步被雙特異性去磷酸酶-2所減弱。概括而言,我的研究發現到缺氧所促使之癌幹細胞特性之生成,主要是透過抑制雙特異性去磷酸酶-2,進而活化環氧合酶-2前列腺素E2 前列腺素接受器EP2/EP4訊息路徑。本研究中的證據指出,於臨床癌症治療發展策略上,DUSP2是個相當有潛力的分子標靶。
A growing body of evidence shows that tumor recurrence and metastasis are contributed by the existence of cancer stem cells (CSCs). However, the underlying mechanism of increasing cancer stemness remains largely uncharacterized. Once cancer mass exceeds 1mm3, cancer cells encountered hypoxic stress, of which they need to develop a mechanism to overcome in order to survive. Cancer stem cell is a slow proliferation, self-renewal side population of cancer cells with pluripotent property, which is an ideal cell population to survive under hypoxic stress. Our previous study showed that hypoxia-inhibited dual specificity protein phosphatase 2 (DUSP2) increases cancer cells survival and drug resistance through triggering the activation of ERK activity. Herein, we demonstrated that protein level of DUSP2 was reduced in colon cancer stem-like (CD133+) cells isolated from both colon cancer cells lines and primary colon cancer cells. Downregulation of DUSP2 was also found in the colonic spheroid and also oxaliplatin-resistant cells. Knockdown of DUSP2 in colon cancer cell lines or in primary CRC cells enhanced cancer stemness properties, which can be blocked by administration of MEK inhibitor (U0126) treatment. The migratory、invasive and anchorage-independent abilities as well as loss-of-E-cadherin were all enhanced in DUSP2-deficient cells. On the other hand, re-expression of DUSP2 damaged the chemo-resistance capacity through triggering the cell apoptosis. Furthermore, DUSP2 downregulation resulted in cyclooxygenase-2 (COX-2) over-expression and PGE2 overproduction, which markedly increased cancer stemness. Taken together, my study demonstrated hypoxia-promoted cancer stemness is to through the activation of COX-2-PGE2-EP2/EP4 signaling pathway by inhibition of DUSP2 expression and provides evidence to suggest that DUSP2 is a potential molecular target in cancer therapy.
Category

Part A. Abstract
Chinese abstract p1
English abstract p2

Part B. Introduction:
Cancer p3
Colorectal cancer p3-p4
Cancer stem cells (CSC) or cancer initiating cell (CIC) p4-p6
Metastasis p6-p7
Hypoxic stress in cancer p7-p9
Abnormal mitogen-activated protein kinase (MAPK) activation p9
Dual-specificity phosphatases (DUSPs) p10
Dual-specificity phosphatases 2 (DUSP2) p11-p12

Part C. Objective p13

Part D. Material Methods
Cell culture and treatment p14-15
Transfection and stable clone selection p15-p16
Sphere formation assay p16
Flow cytometry p17
Magnetic-activated cell sorting (MACS) p18
Mouse experiments p18-p19
Western blotting p19-p20
Immunofluorescence p20
Invasion and migration assay p20-p21
Soft agar p21
Prostaglandin E2 enzyme-linked immunoassay (ELISA) p21-p22
Statistics p22

Part E. Result
1. CD133-expressing cells has high potential of cancer stemness p23
2. DUSP2 protein down-regulates CSC-like population p23-p24
3. Loss of DUSP2 enhanced cancer stemness properties p24-p25
4. Cancer stemness preserved in xenograft DUSP2-silenced cells p26
5. Loss of DUSP2 allowed CSC cells with migrating advantage p26-p27
6. Reversed DUSP2 expression impaired the stemness and motility capacity through triggering the apoptotic signaling p27-p28
7. Dysregulation of DUSP2 increased COX-2 expression and PGE2 secretion
p28-p29
8. Silencing DUSP2-promoted CSC properties is due to COX-2-PGE2-EP2/EP4 signaling activation p29
9. Manipulated DUSP2 could prevent hypoxia promoted-cancer malignancy p30

Part F. Discussion p31-p37

Part G. Conclusion p38

Part H. Reference p39-p47

Part I. Figure Legends
Fig 1. CD133+ HCT116 cells shows better sphere formation ability than CD133- cells p48
Fig 2. CSC-like cells, CD133+ cells demonstrate higher tumorigenesis than the control CD133- cells p49
Fig 3. The level of DUSP2 protein dramatically decreases in CSC-like population p50
Fig 4. CSC-like cells had hyper-MAPK activity in colon cancer cell lines and part of primary CRC cells p51
Fig 5. Oxaliplatin-resistance cells show DUSP2 down-regulation but ERK activation p52
Fig 6. Depletion of DUSP2 increases the stemness-associated factors expression p53
Fig 7. CSC-like population is expanded in DUSP2-silensed cells p54-p55
Fig 8. The number of tumor-spheroid was increased in DUSP2 knocked down cells p56
Fig 9. Down-regulated DUSP2 obtains self-renewal capacity instead of knockdown control p57
Fig 10. Loss-of-DUSP2 enhanced tumor-sphere is mediated by MAPK activity p58
Fig 11. Colo-spheroid had differentiation ability p59
Fig 12. Loss of DUSP2 causes MAPK activation in primary CRC cells p60
Fig 13. Silencing DUSP2 induces CD44+CD133+ expansion in primary CRC cells p61
Fig 14. Loss of DUSP2 enhances tumor-spheroid formation p62
Fig 15. Knockdown DUSP2 allows the non-tumorigenic line with tumor growth p63
Fig 16. Xenografted DUSP2-knockdown cells owns high percentage of CD44+CD133+ than xenografted shLuc control p64
Fig 17. Xenografted-DUSP2-KD cells retains dramatically spheroid forming capacity than knockdown control p65
Fig 18. Fig18. Loss of DUSP2 induces EMT-transcription factor Snail expression p66
Fig 19. Lack-of-DUSP2 decreases the E-cadherin distribution amid of cell-cell junction p67
Fig 20. Lack of DUSP2 enhances cell motility in colon cancer cell lines p68
Fig 21. Knockdown DUSP2 dramatically increases the invasive population p69
Fig 22. DUSP2 knockdown cells have anchorage-independent growth advantage p70
Fig 23. DUSP2 inhibites the stemness and EMT-related factors expression, and blockes ERK activation p71
Fig 24. Inducing DUSP2-GFP expression decreases the CSC-like population p72
Fig 25. Less of spheroid number grows in DUSP2-expressing group p73
Fig 26. DUSP2 expression decreases cell migration ability p74
Fig 27. DUSP2 induces cell death p75
Fig 28. DUSP2 expressing increases chemo-drug sensitive p76
Fig 29. PGE2 increases CSC-like population in colon cancer cell lines p77
Fig 30. PGE2 enhances the spheroid formation in primary CRC cells p78
Fig 31. Lack of DUSP2 induces COX-2 expression p79
Fig 32. DUSP2 knocked down stimulates excess PGE2 secretion p80
Fig 33. Loss of DUSP2-induced stemness factor expressing is mediated by COX-2 effect p81
Fig 34. Double knockdown COX-2 and DUSP2 cancer cells impairs the spheroid formation capacity p82
Fig 35. DUSP-KD enhanced invasive ability is inhibition by COX-2 silencing p83
Fig 36. PGE2 receptor antagonists inhibit spheroid in DUSP2-KD and shLuc cells p84
Fig 37. High dose of EP2 and EP4 antagonist don’t kill cells p85
Fig 38. Hypoxia induces CD44+CD133+ population expansion in primary CRC cells p86
Fig 39. Hypoxia-induced CD44+CD133+ population is controlled by COX-2 effect p87
Fig 40. Single or repeated hypoxia-exploring down-regulates DUSP2 expression but up-regulates COX-2 level in primary CRC cells p88
Fig 41. DUSP2 inhibits hypoxia-promoted COX-2 expression p89
Fig42. DUSP2 suppresses hypoxia-induced Oct4 expression and ERK activation, and reverses hypoxia-impaired E-cadherin level p90
Fig43. Hypoxia-enhanced chemo-resistance is damaged by DUSP2 effect p91
Fig44. (Model) DUSP2 prevents hypoxia-mediated cancer stemness, motility, and drug resistance through blocking COX-2-PGE2-EP2/EP4 pathway p92-p93

Part J. Tables
Table 1. In vitro primary CRC cells of CIC frequency is measured by ELDA p94
Table 2. In vivo CIC frequency in colon cancer cell line, HCT116 cells p95
Table 3. Double knockdown HCT116 cells measured the in vivo CIC frequency by ELDA p96
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