系統性研究肝X受體訊息調控血管新生與CD44調控攝護腺癌中歐洲紫杉醇抗藥性促進之轉移所扮演的角色

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研究生：	賴至人 Lai, Chih-Jen
論文名稱：	系統性研究肝X受體訊息調控血管新生與CD44調控攝護腺癌中歐洲紫杉醇抗藥性促進之轉移所扮演的角色 Systematic Analysis of the Roles of Liver X Receptor Signaling in Angiogenesis Regulation and CD44 in Regulation of Docetaxel- Resistance-enhanced Prostate Cancer Metastasis
指導教授：	褚志斌 Chuu, Chih-Pin 汪宏達 Wang, Horng-Dar
口試委員:	侯自銓 Hour, Tzyh-Chyuan 陳雅雯 Chen, Ya-Wen 張壯榮 Chang, Chuang-Rung
學位類別：	博士 Doctor
系所名稱：	生命科學暨醫學院 - 生物科技研究所 Biotechnology
論文出版年：	2019
畢業學年度：	107
語文別：	英文
論文頁數：	115
中文關鍵詞：	血管新生、癌症轉移、肝X受體、攝護腺癌、歐洲紫杉醇
外文關鍵詞：	Angiogenesis, Metastasis, Liver X receptor, Prostate cancer, Docetaxel
相關次數：	點閱：3 下載：0
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血管新生以及癌細胞轉移在腫瘤進程上都是不可或缺的，所以我們利用系統性的array去研究血管新生以及癌症轉移。我們之前的實驗結果指出肝X受體(LXR)參與了攝護腺癌細胞的增生。我們檢視了LXR在臍靜脈內皮細胞中的效應，LXR激活物T0901317會抑制臍靜脈的血管生成、移動能力以及降低雞胚胎的血管新生能力。而過度表現LXR標靶基因ApoD則會抑制血管的生成。此外ApoD與SR-B1存在著交換作用的關係，降低SR-B1的表現挽回了T0901317所抑制的臍靜脈內皮細胞的移動能力。而過度表現ApoD則抑制磷酸化eNOS、AKT、IL、MMP、VEGF、MCP1。我們的研究顯示活化LXR即活化了ApoD表現，進而抑制AKT/eNOS這條訊號傳遞路徑，抑制了一氧化氮的生成也抑制了血管新生。此外我們探討產生歐洲紫杉醇抗性攝護腺癌細胞有較高移動性與侵襲性的原因。我們利用MWA比較了由PC-3與DU-145衍生而來、具有歐洲紫杉醇抗性的PC/DX25與DU/DX50細胞以及其原始的PC-3、DU-145細胞蛋白質表現量差異。過度表現差異很大的ApoD與抑制表現ABCA1對於細胞移動能力無顯著影響。我們用流式細胞儀觀察另一個有顯著差異的蛋白CD44。PC/DX25與DU/DX50細胞存在著較高的CD44+子群。PC/DX25細胞表現較多的CD44、YAP、CYR61、CTGF、p-ERK1/2以及Vimentin蛋白。我們抑制表現CD44或YAP可有效抑制PC/DX25與DU/DX50的細胞移動能力。抑制CD44蛋白質會導致YAP、CYR61、CTGF、p-ERK1/2、p-AKT以及Vimentin表現的抑制，但增加了p-YAP S127的表現量。我們認為CD44蛋白表現量的提升可藉由Hippo-YAP這條路徑來促進歐洲紫杉醇抗藥性的 CRPC的細胞移動能力，而CD44/YAP這條路徑或許也能作為治療歐洲紫杉醇抗藥性的 CRPC的潛在標的。

Angiogenesis and metastasis are essential for cancer progression. We discovered that treatment with liver X receptors (LXRs) agonist T0901317 inhibited the tube formation and migration of HUVECs as well as reduced the angiogenesis during embryogenesis of chicken eggs in vivo by CAM assay. Overexpression of LXR target gene ApoD suppressed the tube formation of HUVECs. Immunoprecipitation indicated that ApoD interacts with SR-B1, while knockdown of SR-B1 blocked inhibitory effects of T0901317 on HUVEC migration. T0901317 treatment or overexpression of ApoD decreased proteins expression level of phospho-eNOS S1177, phospho-Akt T308, phospho-Akt S473, eNOS, mTOR, VEGF-A, VEGF-C, IL-8, MMP-8, MMP-9, and MCP1. Our study demonstrated that activation of LXR retards angiogenesis through induction of LXR target gene ApoD, which in turn inhibits PI3K-Akt-eNOS signaling, an essential pathway for angiogenesis and production of nitric oxide. Additionally, we examined the molecular mechanism why docetaxel-resistant PC/DX25 and DU/DX50 cells derived from parental PC-3 and DU-145 PCa cells, respectively exhibited higher migration and invasion ability than parental cells. PC/DX25 cells highly expressed CD44, ABCA1 but lower ApoD as determined by Micro-Western Array (MWA), a high-throughput antibody-based proteomic platform, and Western blotting. Flow cytometry analysis demonstrated that PC/DX25 cells and DU/DX50 cells contain higher CD44+ population. MWA and Western blotting assay indicated that protein expression of CD44, YAP, CYR61, CTGF, phospho-ERK1/2 (T202/Y204), ERK and vimentin was elevated in PC/DX25 cells. Knockdown of CD44 or YAP inhibited migration and invasion of PC/DX25 and DU/DX50 cells. In addition, knockdown of CD44 reduced the expression of YAP, CTGF and CYR61 but increased phosphorylation of S127 on YAP. These observations suggested that CD44 promotes cell mobility of docetaxel-resistant PCa cells via induction of Hippo-Yap signaling pathway. CD44/YAP pathway may be a potential therapeutic target for docetaxel-resistant PCa metastasis.

Abstract……………………………………………………………….......................I
中文摘要…………………………………………………………………………...III
誌謝…………………………………………………………………………………IV
Abbreviation…………………………………………………………………….....V
Chapter 1 Introduction………………………………………………………….1
1.1    Angiogenesis in tumor progression.……………………………………………….1
1.2    Physiological angiogenesis versus tumor angiogenesis…………………………...2
1.3    Tube formation of tumor blood vessels……………………………………………4
1.4    Liver X receptors (LXRs)…………...……………………………………………..5
1.5    Introduction of ApoD……………………………………………………………...7
1.6    Role of ApoD in cancer……………………………………………………………8
1.7    Human umbilical vein endothelial cells…………………………………………. 9
1.8    Cell motility and tumor metastasis……………………………………………….10
1.9    Prostate cancer and the treatment………………………………………………...11
1.10    Chemotherapy drug docetaxel in PCa…………………………………………..12
1.11    Introduction of CD44…………………………………………………………...13
1.12    CD44 in prostate cancer…………………………………………………...…....15
1.13    Role of CD44 in migration and invasion…………………………………….....15
1.14    CD44-mediated signaling pathways………………………………………….…17
1.15    Hippo pathway in prostate cancer………………………………………………18
Chapter 2 Materials and Methods…………………………………………..20
2.1 Chemicals..……………………………………………………………………….20
2.2 Cell culture……………………………………………………………………….20
2.3 Tube formation …………………………………………………………………..21
2.4 Chorioallantoic Membranes (CAM) Assay………………………………………22
2.5 Transwell migration assay..………………………………………………………22
2.6 Transwell invasion assay ...……………………………………………..………..24
2.7 Wound healing assay……………………………………...……………………...24
2.8 Flow cytometry….……………………………………………………………….25
2.9 ApoD plasmid overexpression…………………………………………………...26
2.10 Knockdown of SR-B1, CD44 or YAP with small interfering RNA…………....26
2.11 Immunofluorescence……………………………………………………………27
2.12 Coimmunoprecipitation…………………………………………………………28
2.13 Angiogenesis protein array……………………………………………………...28
2.14 Micro western arrays (MWA)………………………………………………..…29
2.15 Western Blot analysis…………………………………………………………...29
2.16 Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR)……………...30
2.17 Tumor sphere formation assay………………………………………………….33
2.18 Statistical analysis………………………………………………………………33
Chapter 3 Activation of liver X receptor suppresses angiogenesis via induction of ApoD.....................................................34
3.1 Introduction………………………………………………………………………34
3.2 Results……………………………………………………………………………35
3.3 Discussion………………………………………………………………………..38 Chapter 4 CD44 Promotes Migration and Invasion of Docetaxel-Resistant Prostate Cancer Cells Likely via Induction of Hippo-Yap Signaling………………………………………………....................44
4.1 Introduction………………………………………………………………………44
4.2 Results……………………………………………………………………………45
43. Discussion………………………………………………………………………..50
Chapter 5 Elevation of ApoD may retard migration and invasion ability in prostate cancer cells …………………………….………................57
5.1 Introduction………………………………………………………………………57
5.2 Results……………………………………………………………………………57
5.3 Discussion………………………………………………………………………..58
Chapter 6 Conclusion and future study…..….…...……………..................60
Chapter 7 Figures…………………………………………………………...…...62
Figure 1.1 Angiogenic cascade. ………………………………………..…………….62
Figure 1.2 LXRs are regulators of central nervous system, glucose homeostasis and cholesterol homeostasis. ……….…………………………………………………….63
Figure 1.3 Metastatic cascade……...………………………………………………...64
Figure 1.4 Cancer can spread to almost entire body…………...…………………….65
Figure 1.5 CD44, a transmembrane glycoprotein receptor. …..……...…….………..66
Figure 1.6 CD44-regulated downstream signaling pathways.….…………………....67
Figure 1.7 Simplified schematic illustration of the Hippo pathway.……………........68
Figure 3.2.1 Stimulatory activity of T0901317 on gene and protein expression of LXR target genes in HUVECs……………………………………………………………..69
Figure 3.2.2 Treatment with LXR agonist T0901317 suppresses angiogenesis of HUVECs in vitro as determined by tube formation assay…………………………...70
Figure 3.2.3 T0901317 suppresses migration of HUVECs and inhibited angiogenesis in vivo as determined by CAM………………………………...…………………….72
Figure 3.2.4 Overexpression of ApoD suppresses tube formation of HUVECs……..74
Figure 3.2.5 Interaction of ApoD and SR-B1 is involved in migration inhibition of HUVECs caused by T0901317 treatment……………………………………………75
Figure 3.2.6 T0901317 treatment affects signaling proteins regulating angiogenesis in HUVECs……………………………………………………………………………...76
Figure 3.2.7 ApoD overexpression affects signaling proteins regulating angiogenesis………………………………………………………………………….77
Figure 3.3.1 Signaling pathway affected by LXR agonist T0901317………………..78
Figure 3.3.2 HUVEC cell lysates for angiogenesis array assay……………………...79
Figure 3.3.3 Treatment with T0901317 suppressed protein levels of MMP-8, MMP-9, VEGFA, and VEGFC………………………………………………………………...80
Figure 4.2.1 Transwell assay and wound healing assay revealed that docetaxel-resistant PCa cells exhibited higher migration and invasion ability as compared to parental PCa cells………………………………………………………82
Figure 4.2.2 Profile of proteins regulating cell migration and invasion including LXR target genes in PC-3 vs. PC/DX25 cells as determined by Micro-Western Array, western blotting, and real-time quantitative PCR……………………………………84
Figure 4.2.3 Knockdown of CD44 suppresses cell mobility of docetaxel-resistant PCa cells but alteration of LXR target genes did not affect cell mobility significantly of docetaxel-resistant PCa cells…………………………………………………………85
Figure 4.24 FACS analysis of CD44 protein expression in PC-3, PC/DX25, DU-145, DU/DX50 cells……………………………………………………………………….86
Figure 4.2.5 Profile of proteins and mRNA regulating cell migration and invasion in PC-3 vs. PC/DX25 cells as determined by Western blotting and real-time quantitative PCR.………………………………………………………………………………….87
Figure 4.2.6 Knockdown of CD44 or YAP protein suppresses cell mobility of docetaxel-resistant PCa cells………………………………………………………....88
Figure 4.2.7 Knockdown of CD44 protein in docetaxel-resistant PCa cells inhibits Hippo-YAP signaling pathway……………………………………………………….90
Figure 4.3.1 FACS analysis of ALDH intensity in PC-3, PC/DX25, DU-145, DU/DX50 cells……………………………………………………………………….91
Figure 4.3.2 Tumor sphere formation of PC-3 and PC/DX25 cells………………….92
Figure 4.3.3 Viability of knockdown of CD44 in PC/DX25 cells………………...…93
Figure 4.3.4 Putative cellular mechanism how CD44 proteins promotes migration and invasion of docetaxel-resistance PCa cells…………………………………………...94
Figure 5.1 ApoD may play a role of tumor suppressor from Disease summary…......95
Figure 5.2.1 ApoD profile of clinical data bases, Oncomine and Survexpress………96
Figure 5.2.2 Overexpression of ApoD suppress cell migration and invasion of C4-2B and PC-3 cells………………………………………………………………………...97
Figure 5.2.3 Profile of proteins regulating cell migration and invasion in C4-2B control mock vs. C4-2B overexpressed-ApoD cells as determined by Micro-Western Array (MWA)………………………………………………………………………...98
Chapter 8 References………………………………………………………….100


                                

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