博碩士論文 105881601 詳細資訊



以作者查詢圖書館館藏 、以作者查詢臺灣博碩士 、以作者查詢全國書目 、勘誤回報 、線上人數：27 、訪客IP：18.117.98.178
姓名 歐書亞(Aushia Tanzih Al Haq)  查詢紙本館藏   畢業系所 生命科學系
論文名稱 靶向氧化前驅物MnSOD抑制致癌基因威脅之下三陰性乳腺癌進展 與M2 巨噬細胞功能
(Targeting prooxidant MnSOD effect inhibits triple-negative breast cancer (TNBC) progression and M2 macrophage functions under the oncogenic stress)
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摘要(中) 三陰性乳腺癌(TNBC) 極度依賴於氧化磷酸化 (OXPHOS) 與粒線體活性氧 (mROS) ，促使癌細胞增殖、存活和新陳代謝。超錳氧化物歧化酶MnSOD (SOD2) 是粒線體內抗氧化保護分子，其功能異常牽涉各種人類惡性腫瘤發生。然而，MnSOD 影響 TNBC 微環境中免疫抑制性巨噬細胞功能的機制卻從未被闡明。我目前的研究調查人類乳腺癌cDNA 陣列與正常情況乳腺檢體進行比較和進一步分析癌症基因數據資料庫中 MnSOD 的表達及病人預後效果之關聯性。利用癌症幹細胞與巨噬細胞共同培養來評估 TNBC 細胞中 MnSOD大量表現與損失功能的生物效應，並且對腫瘤增生以及巨噬細胞浸潤在原位異種移植模型中之影響。結果顯示：高表達MnSOD 主要存在於侵襲性乳腺癌中，例如 HER2(+)以及 TNBC亞型。在分子機轉研究上，我發現轉錄因子 T細胞惡性腫瘤基因-1（MCT-1 或 MCTS1）誘導轉錄因子Nrf2蛋白的穩定性來驅動 MnSOD 高表達。MnSOD/MCT-1高表達和Nrf2/MCT-1高表達，在屬於TNBC的乳腺癌亞型basal-like中，與其臨床有不良結果具有高度相關性。在致癌作用下，TNBC 細胞中MnSOD 具有過氧化酶的氧化前驅物，增加 mROS的層次並適應TNBC 本身的氧化壓力。更重要的是，缺乏MnSOD的 TNBC 細胞會阻止 M2 巨噬細胞的極化和趨化性，但會提高 M1 巨噬細胞吞噬癌細胞的能力。基因表現分析顯示，當 MCT-1 減少時，interleukin-6 (IL-6) 訊號通路會顯著減弱。進一步分析證實，IL-6促進MCT-1 作用並增加 Nrf2/MnSOD 表現和 mROS 的產生。因此標靶MnSOD能夠降低MCT-1所促進的 TNBC 細胞侵襲性、乳腺癌幹細胞 (BCSCs) 特質、mROS 產出和 IL-6 分泌。運用非金屬抗氧化劑MnSOD模擬物 MitoQ 限制 mROS生成，有效抑制 MnSOD 與 MCT-1 所促進的 BCSCs 效應和 M2 巨噬細胞侵襲能力。MitoQ 也抑制 TNBC 的肺轉移潛能，並增加M1 巨噬細胞的浸潤現象。因此抑制MnSOD 活性會阻礙 TNBC 進展和改善微環境內抗腫瘤之巨噬細胞。總而言之，我的研究指出TNBC 治療的新穎策略，並且證明標靶致癌基因 MCT-1能抑制MnSOD作為促氧化劑及提升抗腫瘤免疫微環境。
摘要(英) Triple-negative breast cancer (TNBC) highly depends on oxidative phosphorylation (OXPHOS) and mitochondrial reactive oxygen species (mROS) for its proliferation, survival, and metabolism. MnSOD (SOD2) is a mitochondrial antioxidant defense (dismutase) that implicates in various human malignancies. However, the impact of altered MnSOD on immunosuppressive macrophage functions in TNBC microenvironment has never been elucidated. Current study investigated the expression and prognostic significance of MnSOD from Human Breast Cancer cDNA Array and other cancer profiling databases by comparing with normal breast biopsies. Biological effects were assessed upon MnSOD gain- and loss-of-function in TNBC cells followed by the evaluation of cancer stemness and Transwell coculture with macrophages. Tumor growth and metastasis as well as macrophage infusion were investigated in orthotopic xenograft model. Results showed that MnSODhigh is largely found in the aggressive subtypes of breast cancer such as HER2(+) subtype and TNBC. Mechanistically, MnSOD expression is induced by the stabilization of the transcription factor Nrf2 driven by activation of oncoprotein multiple copies in T-cell malignancy-1 (MCT-1 or MCTS1). Both MnSODhigh/MCT-1high and Nrf2high/MCT-1high signature pattern are associated with a poor clinical outcome in basal-like breast cancer subtype, a common surrogate feature of TNBC. MnSOD in TNBC cells has the propensity to act as a prooxidant peroxidase that escalates mROS levels, thereby accommodating TNBC per se to sustain oxidative stress under the oncogenic effect. More importantly, TNBC cells deficient in MnSOD restrain the polarity and chemotaxis of M2 macrophages but reinforces M1 macrophage capacity to phagocytose cancer cells. Gene expression profiling identified that interleukin-6 (IL-6) signaling pathway is significantly weakened when MCT-1 is depleted. Further analysis confirmed that IL-6 in the MCT-1 axis increases Nrf2/MnSOD and mROS production. Depletion of MnSOD consequently reduces TNBC invasiveness, breast cancer stem cells (BCSCs), mROS and IL-6 secretion exerted by MCT-1. Restricting mROS with MitoQ, a non-metal-based antioxidant MnSOD mimic, inhibits BCSCs and M2 macrophage infiltration promoted by MnSOD and MCT-1. MitoQ also curbs lung metastases potential of TNBC and enriches infiltration of M1 macrophages. Depleting MnSOD, therefore, hinders TNBC progression and intratumoral M2 macrophages. Collectively, this study highlights a novel therapeutic intervention for TNBC treatment in which targeting the oncogenic MCT-1-activated prooxidant MnSOD pathway halts the immunosuppressive tumor niche.
關鍵字(中) ★ MnSOD
★ MCT-1
★ IL-6
★ 與粒線體活性氧
★ MitoQ
★ 三陰性乳腺癌
★ 乳腺癌幹細胞
★ M1與M2巨噬細胞
★ 抗腫瘤免疫微環境		 關鍵字(英) ★ MnSOD
★ MCT-1
★ IL-6
★ mROS
★ MitoQ
★ TNBC
★ breast cancer stem cells
★ M1 and M2 macrophages
★ tumor microenvironment
論文目次 Table of Contents
Table of Contents
Abstract vii
Acknowledgments viii
Table of Contents xi
List of Figures xiii
Explanation of Symbols and Abbreviations xiv
Chapter I. Introduction 1
1-1 Epidemiology of breast cancer and triple-negative breast cancer (TNBC) 1
1-2 MCT-1 and its oncogenic signaling in breast cancer 2
1-3 Mitochondrial ROS and MnSOD in carcinogenesis 4
1-4 Targeting IL-6 signaling axis in cancer 7
1-5 Monocytes and macrophages in the breast cancer microenvironment 8
1-7 Research objectives 10
Chapter II. Methods 11
2-1 Cell culture 11
2-2 Transfection and generation of stable cell lines 11
2-3 Microarray analysis 13
2-4 Western blotting analysis and antibodies (Abs) 13
2-5 Cycloheximide chase 14
2-6 Mammosphere formation 14
2-7 Flow cytometry of breast cancer stemness markers 14
2-8 Macrophage differentiation 15
2-9 Macrophage migration with single-cell tracking analysis 16
2-10 Macrophage polarity after coculture with breast cancer cells 16
2-11 Breast tumorigenesis assessment 17
2-12 Experimental metastasis assay 18
2-13 Measurement of IL-6 secretion and plasma IL-6 19
2-14 Immunohistochemistry analysis 20
2-15 Isolation and analysis of tumor-associated macrophages 21
2-16 Flow cytometry-based phagocytosis assay 22
2-17 Quantification of mROS 24
2-18 Quantification of H2O2 release and peroxidase activity 24
2-19 Quantification of MnSOD activity 25
2-20 Cancer cell and macrophage invasion 25
2-21 Cancer cell migration with wound healing assay 26
2-22 Gelatin zymography assay 26
2-23 Soft agar colony formation 27
2-24 Semi-quantitative RT-PCR (qRT-PCR) assays 27
2-27 Clinical study 28
2-28 Statistical analysis 28
Chapter III. Results 30
3-1 High MCT-1 and high MnSOD are prognosis markers for breast cancer 30
3-2 MCT-1 promotes MnSOD expression by extending Nrf2 half-life 32
3-3 MCT-1/MnSOD axis induces aggressive phenotypes in TNBC cells 36
3-4 MnSOD modulates M2 macrophages function 39
3-5 MCT-1 switches MnSOD into a prooxidant peroxidase and promotes IL-6/mROS signaling in TNBC cells 47
3-6 MitoQ blunts breast cancer stemness and M2 macrophage infiltration induced by oncogenic MCT-1/MnSOD signaling 56
3-7 MnSOD deficiency regresses TNBC tumor growth and limits infiltration of M2 macrophages in vivo promoted by MCT-1 61
3-8 Monotherapy of MitoQ is sufficient to impair MCT-1-driven cancer stemness and pulmonary metastases in TNBC mouse model 63
Chapter IV. Discussion 67
4-1 General discussion 67
4-2 Limitations and future works 72
Chapter V. Conclusion 74
Bibliography 75
Appendix A. 83
Appendix B. 87
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指導教授 徐欣伶 王健家(Hsin-Ling Hsu Chien-Chia Wang) 審核日期 2022-3-9
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