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研究生:潘致愷
研究生(外文):Pan, Jhih-Kai
論文名稱:探討三陰性乳腺癌中樞神經系統轉移的分子機制
論文名稱(外文):Molecular mechanism of central nervous system metastasis in triple-negative breast cancer (TNBC)
指導教授:呂佩融
指導教授(外文):Lu, Pei-Jung
口試委員:蕭宏昇王紹椿蘇文彬鍾為邦呂佩融
口試委員(外文):Hsiao, MichaelWang, Shao-ChunSu, Wen-PinChung, Wei-PangLu, Pei-Jung
口試日期:2024-01-30
學位類別:博士
校院名稱:國立成功大學
系所名稱:臨床醫學研究所
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:2024
畢業學年度:112
語文別:英文
論文頁數:304
中文關鍵詞:MiR-211中樞神經系統轉移ICAM2NGN2SOX11
外文關鍵詞:MiR-211CNS metastasisICAM2NGN2SOX11
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中樞神經系統轉移是最常見的腦惡性腫瘤,通常源自於乳腺癌(15%–25%),特別是三陰性乳腺癌患者,由於缺乏有效治療方法,因此導致患者存活率較低。目前,針對中樞神經系統轉移的診斷、預後方法和治療策略是一個迫切的臨床問題。在這項研究中,我們將研究中樞神經系統轉移的分子機制,並開發中樞神經系統轉移的三陰性乳腺癌患者開發新的診斷和治療策略。微小核糖核酸陣列分析確定miR-211在腦轉移細胞顯著高表達。高表達之miR-211於三陰性乳腺癌細胞能夠促進早期且專一性之腦轉移於疾病小鼠模型中。高表達之miR-211於三陰性乳腺癌細胞促進細胞穿透血腦屏障遷移之能力,血腦屏障附著和癌幹細胞之特性。此外,我們也證明NGN2和SOX11作為miR-211的下游調控蛋白並受miR-211專一性的調控。最重要的是,高表達之miR-211與乳腺癌或三陰性乳腺癌患者的腫瘤復發顯著相關。通過蛋白質體學分析,結果顯示軟腦膜轉移之三陰性乳腺癌細胞中ICAM2的表達顯著增加。高表達之ICAM2於三陰性乳腺癌細胞促進了早期且專一之軟腦膜轉移且造成存活率顯著降低於疾病小鼠模型中。高表達之ICAM2於三陰性乳腺癌細胞促進了細胞血腦脊液屏障粘附之能力、通過血腦脊液屏障遷移及癌幹細胞之能力。此外,pull down和抗體中和實驗闡明,ICAM2通過與脈絡叢上皮細胞中的ICAM1相互作用來促進的特異性的軟腦膜轉移。利用中和性抗體中和三陰性乳腺癌細胞中之ICAM2顯示出抑制軟腦膜轉移進展和延長小鼠存活的時間。這表明,針對ICAM2可能是治療三陰性乳腺癌軟腦膜轉移的潛在策略。綜上所述,我們的發現miR-211可能是乳腺癌或三陰性乳腺癌患者腦轉移的潛在診斷或預後標誌。此外,針對標靶ICAM2可能為治療三陰性乳腺癌軟腦膜轉移提供了一條新的治療途徑。
Brain metastases originating from the central nervous system (CNS) are commonly associated with triple-negative breast cancer (TNBC), resulting in poor patient survival due to limited treatment options. Our study focuses on understanding the molecular basis of CNS metastasis in TNBC and developing new strategies for diagnosis and treatment. We identified an elevated presence of miR-211 in brain metastatic cells through microRNA array analysis. Our findings suggest that high levels of miR-211 play a role in the early and specific colonization of the brain in vivo. Additionally, heightened miR-211 levels promote migration across the blood-brain barrier (BBB), enhance BBB adherence, and contribute to stemness properties in TNBC. Furthermore, we identified NGN2 and SOX11 as downstream targets specifically regulated by miR-211. Notably, elevated miR-211 levels in primary tumor correlated with tumor recurrence in BC or TNBC patients with brain metastasis. Moreover, our proteomic analysis unveiled increased expression of ICAM2 in leptomeningeal metastatic TNBC cells. ICAM2 was found to facilitate spinal cord colonization, leading to decreased survival rates in vivo. Our study indicates that elevated ICAM2 levels promote adhesion to the blood-cerebrospinal fluid barrier (BCB), facilitate migration across this barrier, and enhance the stemness abilities of cancer cells, all critical factors in leptomeningeal metastasis (LM) development. The interaction between ICAM2 and ICAM1 in choroid plexus epithelial cells appears pivotal in determining the specificity of LM. Targeting ICAM2, as suggested by pulldown and antibody neutralizing assays, demonstrated a potential to impede LM progression and extend survival in experimental models. This highlights the promising therapeutic potential of targeting ICAM2 in managing LM in TNBC. Our findings propose that miR-211 could serve as a promising diagnostic or prognostic marker for brain metastasis in BC or TNBC patients. Additionally, targeting ICAM2 presents a potential therapeutic strategy for addressing leptomeningeal metastasis in TNBC.
中文摘要-1
Abstract 2
致謝-3
Table content-4-6
Chapter 1 Introduction7-18
1. Breast cancer-7-9
1.2 Tumor metastasis-9-11
1.3 Metastasis to the central nervous system (CNS)- 11-12
1.4 CNS metastasis in BC and NSCLC and currently treatment approaches-12-15
1.5 CNS metastasis correlated with BBB/BCB adhesion and penetration15-16
1.6 Non-coding RNAs and CNS metastasis-16-17
1.7 Rationale17
1.8 Significance-17-18
Chapter 2 Materials and Methods-19-42
2-1 Cell lines-19
2-2 Clinical specimens 19-20
2-3 Immunohistochemistry (IHC) -20
2-4 In vivo selection -20-21
2-5 In situ hybridization (ISH)21-22
2-6 Western Blotting 22-23
2-7 Trans-BBB migration assays -23
2-8 BBB adherence assay23-24
2-9 Immunofluorescence (IF) staining-24-25
2-10 BCB adhesion assay 25-27
2-11 Brain slices preparation and brain slices adhesion27
2-12 Sphere forming assay 27-28
2-13 Trans-BCB migration assay 28-29
2-14 Animal models for brain metastasis -29-30
2-15 Animal model for leptomeningeal metastasis-30-32
2-16 Antibody treatment for leptomeningeal metastasis in vivo -32-33
2-17 Quantitative real-time PCR (qPCR)33
2-18 Migration and Invasion 34
2-19 Cell proliferation -35
2-20 Soft agar assay 35
2-21 H&E staining -35-36
2-22 Protein identification 36
2-23 Extraction of Membrane and Cytosolic fractions 36-37
2-24 Flow cytometry 37
2-25 Purification of ICAM2-His and ICAM1-His proteins -37-38
2-26 Pull down assay 38-39
2-27 Extraction and detection of circulating miRNAs 39-40
2-28 cDNA synthesis and qRT-PCR for miRNA -40
2-29 Stable cell-line generation -40-41
2-30 Reporter assay -41
2-31 MicroRNA array -41
2-32 Gene expression microarray analysis 41-42
2-33 Statistical analysis -42
Chapter 3 Results43-75
3-1 CNS metastasis were observed two metastatic subtypes in disease animal model 43-47
3-2 High miR-211 in TNBC promotes early parenchyma metastasis in vivo-47-50
3-3 High levels of miR-211 in plasma can potentially serve as an indicator or biomarker for brain metastasis in Triple Negative Breast Cancer-50-52
3-4 High levels of miR-211 enhance tumor cell adhesion and the ability to transverse the BBB-52-54
3-5 Elevated level of miR-211 promotes the acquisition or enhancement of Cancer Stem Cell (CSC) properties in TNBC-54-56
3-6 MiR-211 plays a pivotal role in mediating TNBC brain metastasis by regulating the SOX11/NGN2-dependent axis 56-59
3-7 MiR-211 level are heterogenous in the TNBC primary tumor and highly express in brain metastatic lesions-59-60
3-8 Identification of ICAM2 involved in TNBC LM in vitro and in vivo60-64
3-9 Demonstrating the role of ICAM2 in promoting leptomeningeal metastasis through both in vitro and in vivo approaches-64-66
3-10 Increased levels of ICAM2 appear to enhance the properties associated with cancer stem cells66-69
3-11 ICAM2 has been observed to interact with the endogenous ICAM1 present in choroid plexus cells-69-72
3-12 Neutralizing ICAM2 abolishes the leptomeningeal metastasis in vitro and in vivo72-74
3-13 High level ICAM2 in the TNBC promotes the LM and blocking ICAM2 attenuates LM74-75
Chapter 4 Conclusion76-77
Chapter 5 Discussion78-83
Figures and tables84-281
Appendix282-295
References 296-302
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