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系統識別號 U0026-2301201621280000
論文名稱(中文) 腫瘤幹細胞標誌CD90的功能探討
論文名稱(英文) Study on Cancer Stem Cell Marker CD90
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) 陳韋靜
研究生(英文) Wei-Ching Chen
學號 S58991374
學位類別 博士
語文別 英文
論文頁數 90頁
口試委員 指導教授-賴明德
召集委員-吳昭良
口試委員-吳佳慶
口試委員-張文粲
口試委員-洪文俊
口試委員-戴明泓
中文關鍵字 腫瘤幹細胞標誌  整連蛋白 
英文關鍵字 cancer stem cell marker  integrin  AMPK  mTOR  OSU-CG5 
學科別分類
中文摘要 CD90為肝癌腫瘤幹細胞標誌,但卻抑制卵巢癌細胞的生長。我們的目的是研究CD90如何促進肝癌的發展,經由CD90之訊息信號傳遞機制,找到可做為新的治療靶的,並進一步釐清CD90如何在卵巢癌細胞中扮演和肝癌細胞中截然不同角色之機制。結果顯示:外生性的CD90促進細胞的非依賴性生長、增加肝癌的形成能力;然而外生性的CD90抑制卵巢癌細胞的生長。CD90誘發肝癌細胞懸浮球體狀形成能力,並促進腫瘤幹細胞標誌CD133表現。相較於肝癌細胞,CD90則抑制卵巢癌細胞中CD133表現。自然致癌分子TGF-β1、HGF和B型肝炎表面抗原刺激CD90和CD133的表現;利用CD90 shRNA或抗體有效抑制CD133表現與細胞的非依賴性生長;以帶有CD133 shRNA之慢病毒感染小鼠則可抑制CD90誘發的腫瘤形成現象。此外,外生性的CD90可以誘導mTOR的磷酸化和AMPK和去磷酸化。CD90具有一整連蛋白-RLD區域,在突變成RLE-區域後減緩CD133表現與細胞的非依賴性生長。結果顯示: CD90經由AMPK/mTOR 和β3整連蛋白誘發的腫瘤形成。OSU-CG5為一能量限制模擬劑,可抑制小鼠腫瘤形成,並降低CD90陽性細胞群。相較於傳統的肝癌標靶藥物- 蕾莎瓦無法降低CD90陽性細胞群。綜合上述實驗結果,CD90-β3整連蛋白-mTOR/AMPK-CD133訊息軸對於肝癌形成扮演重要角色,因此可做為治療上的標的。
英文摘要 CD90 is used as a marker for cancer s tem cells in liver cancer, but inhibits the growth of ovarian cancer. We aimed to study the mechanism by which CD90 promoted cancer progression and the new therapeutic targets on the CD90 signal pathway in liver cancer, and exploit the contrarian role of CD90 in ovarian cancer. Ectopic expression of CD90 enhanced anchorage-independent growth and tumor progression in liver cancer cells, but inhibited ovarian cancer cells. Furthermore, CD90 promoted sphere formation in vitro and upregulated the expression of the cancer stem cell marker CD133 in liver cancer cells. In contrast, CD90 decreased the CD133 expression in ovarian SKOV3 cells. The natural carcinogenic molecules TGF-β1, HGF, and hepatitis B surface antigen increased the expression of CD90 and CD133. Inhibition of CD90 by either shRNA or antibody attenuated the induction of CD133 and anchorage-independent growth. Lentiviral delivery of CD133 shRNA abolished the tumorigenicity induced by CD90. Ectopic expression of CD90 induced mTOR phosphorylation and AMPK dephosphorylation. Mutation of integrin binding-RLD domain in CD90 attenuated the induction of CD133 and anchorage-independent growth. Similar results were observed after silencing 3 integrin. Signaling analyses revealed that AMPK/mTOR and β3 integrin were required for the induction of CD133 and tumor formation by CD90. Importantly, the energy restriction mimetic agent OSU-CG5 reduced the CD90 population in fresh liver tumor sample and repressed the tumor growth, although in contrast, sorafenib did not decrease the CD90 population. In conclusion, the signal axis of CD90-integrin-mTOR/AMPK-CD133 is critical for promoting liver carcinogenesis. Molecules inhibiting the signal axis, including OSU-CG5 and other inhibitors, may serve as potential novel cancer therapeutic targets in liver cancer.
論文目次 Abstract in Chinese
Abstract
I. Introduction
I-1. Cancer stem cell 01
I-2. Cancer stem cell and cancer stem cell 02
I-3. The role of integrin in cancer progression 05
I-4. Cancer and metabolism 05
II. Materials and Methods
II-1. Reagents, chemicals and antibodies 09
II-2. Cell culture 09
II-3. Overexpressed transfectants establishment 09
II-4. RNA interference 10
II-5. Tissue samples 10
II-6. Flow cytometry 11
II-7. Colony formation 11
II-8. Anchorage-independent growth ability 11
II-9. Tumorigenicity in NOD/SCID mice 11
II-10. Generation of CD90 RLE mutant cDNA 12
II-11. Western blotting analysis 12
II-12. Quantitative real-time reverse transcription-PCR 12
II-13. ALDH staining 13
II-14. Sphere formation assay 13
II-15. Statistical analysis 13
III. Results
III-1. CD90 promotes tumorigenicity in HepG2, Hep3B and HuH7 liver cancer cells, but inhibits the tumorigenicity in SKOV3 ovarian cancer cell 14
III-2. CD90 increases sphere-forming ability and the expression of stem cell marker CD133 in liver cancer cell, but decreased in ovarian cancer cell 15
III-3. CD90 is required for CD133 upregulation by HGF and TGF-β1 in liver cancer 16
III-4. Inhibition of CD133 abolishes the anchorage-independent growth induced by CD90 in liver cancer 17
III-5. The AMPK and mTOR signaling pathways are important for the upregulation of CD133 and for anchorage-independent growth 18
III-6. The glycolytic inhibitor, OSU-CG5, inhibited CD90-induced tumor growth 19
III-7. The CD90 RLD domain affects anchorage-independent growth and CD133 expression 20
III-8. Integrin β3 mediates CD90 signal transduction in the regulation of CD133 expression 20
IV. Discussion 23
V. Conclusions 28
VI. Reference 29
VII. Figures 40
VIII. C.V 91
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