請用此 Handle URI 來引用此文件:
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/52597
完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 張正琪(Cheng-Chi Chang) | |
dc.contributor.author | Ya-Jan Yang | en |
dc.contributor.author | 楊雅然 | zh_TW |
dc.date.accessioned | 2021-06-15T16:19:52Z | - |
dc.date.available | 2017-09-24 | |
dc.date.copyright | 2015-09-24 | |
dc.date.issued | 2015 | |
dc.date.submitted | 2015-08-17 | |
dc.identifier.citation | [1]American Diabetes, A. Standards of medical care in diabetes--2012. Diabetes Care 35 Suppl 1, S11-63, doi:10.2337/dc12-s011 (2012).
[2]Taylor, R. Insulin resistance and type 2 diabetes. Diabetes 61, 778-779, doi:10.2337/db12-0073 (2012). [3]Habib, S. L. & Rojna, M. Diabetes and risk of cancer. ISRN Oncol 2013, 583786, doi:10.1155/2013/583786 (2013). [4]Johnson, J. A. et al. Diabetes and cancer (1): evaluating the temporal relationship between type 2 diabetes and cancer incidence. Diabetologia 55, 1607-1618, doi:10.1007/s00125-012-2525-1 (2012). [5]Vander Heiden, M. G., Cantley, L. C. & Thompson, C. B. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324, 1029-1033, doi:10.1126/science.1160809 (2009). [6]Liu, X. et al. Cancer risk in patients with type 2 diabetes mellitus and their relatives. Int J Cancer, doi:10.1002/ijc.29440 (2015). [7]Ferlay J et al. GLOBOCAN 2012 v1.1, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. [8]Yeap, B. B. et al. Reference ranges and determinants of testosterone, dihydrotestosterone, and estradiol levels measured using liquid chromatography-tandem mass spectrometry in a population-based cohort of older men. J Clin Endocrinol Metab 97, 4030-4039, doi:10.1210/jc.2012-2265 (2012). [9]Bensimon, L., Yin, H., Suissa, S., Pollak, M. N. & Azoulay, L. Type 2 diabetes and the risk of mortality among patients with prostate cancer. Cancer Causes Control 25, 329-338, doi:10.1007/s10552-013-0334-6 (2014). [10]Singh, G., Lakkis, C. L., Laucirica, R. & Epner, D. E. Regulation of prostate cancer cell division by glucose. J Cell Physiol 180, 431-438, doi:10.1002/(SICI)1097-4652(199909)180:3<431::AID-JCP14>3.0.CO;2-O (1999). [11]Tsai, C. H. et al. High glucose induces vascular endothelial growth factor production in human synovial fibroblasts through reactive oxygen species generation. Biochim Biophys Acta 1830, 2649-2658, doi:10.1016/j.bbagen.2012.12.017 (2013). [12]Kim, B. S. VEGF Expression in Hypoxia and Hyperglycemia: Reciprocal Effect on Branching Angiogenesis in Epithelial-Endothelial Co-Cultures. Journal of the American Society of Nephrology 13, 2027-2036, doi:10.1097/01.asn.0000024436.00520.d8 (2002). [13]Weil, B. R., Abarbanell, A. M., Herrmann, J. L., Wang, Y. & Meldrum, D. R. High glucose concentration in cell culture medium does not acutely affect human mesenchymal stem cell growth factor production or proliferation. Am J Physiol Regul Integr Comp Physiol 296, R1735-1743, doi:10.1152/ajpregu.90876.2008 (2009). [14]Aikawa, S., Hashimoto, T., Kano, K. & Aoki, J. Lysophosphatidic acid as a lipid mediator with multiple biological actions. Journal of biochemistry 157, 81-89, doi:10.1093/jb/mvu077 (2015). [15]Choi, J. W. et al. LPA receptors: subtypes and biological actions. Annual review of pharmacology and toxicology 50, 157-186, doi:10.1146/annurev.pharmtox.010909.105753 (2010). [16]Sano, T. et al. Multiple mechanisms linked to platelet activation result in lysophosphatidic acid and sphingosine 1-phosphate generation in blood. The Journal of biological chemistry 277, 21197-21206, doi:10.1074/jbc.M201289200 (2002). [17]van Meeteren, L. A. et al. Autotaxin, a secreted lysophospholipase D, is essential for blood vessel formation during development. Molecular and cellular biology 26, 5015-5022, doi:10.1128/MCB.02419-05 (2006). [18]Pyne, S., Kong, K. C. & Darroch, P. I. Lysophosphatidic acid and sphingosine 1-phosphate biology: the role of lipid phosphate phosphatases. Seminars in cell & developmental biology 15, 491-501, doi:10.1016/j.semcdb.2004.05.007 (2004). [19]Pagèsa, C., Simona, M.-F., Valeta, P. & Saulnier-Blachea, J. S. <Lysophosphatidic acid synthesis and release.pdf>. Elsevier, 1–10 (2001). [20]Moolenaar, W. H. <LPA a novel lipid mediator with diverse biological actions>. Trends in cell biology, 213–219, doi:10.1016/0962-8924(94)90144-9 (1994). [21]Lin, M. E., Herr, D. R. & Chun, J. Lysophosphatidic acid (LPA) receptors: signaling properties and disease relevance. Prostaglandins & other lipid mediators 91, 130-138, doi:10.1016/j.prostaglandins.2009.02.002 (2010). [22]Federico, L. et al. Autotaxin and its product lysophosphatidic acid suppress brown adipose differentiation and promote diet-induced obesity in mice. Molecular endocrinology 26, 786-797, doi:10.1210/me.2011-1229 (2012). [23]Ferry, G. et al. Autotaxin is released from adipocytes, catalyzes lysophosphatidic acid synthesis, and activates preadipocyte proliferation. Up-regulated expression with adipocyte differentiation and obesity. The Journal of biological chemistry 278, 18162-18169, doi:10.1074/jbc.M301158200 (2003). [24]Boucher, J. et al. Potential involvement of adipocyte insulin resistance in obesity-associated up-regulation of adipocyte lysophospholipase D/autotaxin expression. Diabetologia 48, 569-577, doi:10.1007/s00125-004-1660-8 (2005). [25]Vikram, A. & Jena, G. Diet-induced hyperinsulinemia accelerates growth of androgen-independent PC-3 cells in vitro. Nutrition and cancer 64, 121-127, doi:10.1080/01635581.2012.630556 (2012). [26]Rancoule, C. et al. Involvement of autotaxin/lysophosphatidic acid signaling in obesity and impaired glucose homeostasis. Biochimie 96, 140-143, doi:10.1016/j.biochi.2013.04.010 (2014). [27]Rancoule, C. et al. Lysophosphatidic acid impairs glucose homeostasis and inhibits insulin secretion in high-fat diet obese mice. Diabetologia 56, 1394-1402, doi:10.1007/s00125-013-2891-3 (2013). [28]Coy, P. E. et al. LPA is a novel lipid regulator of mesangial cell hexokinase activity and HKII isoform expression. Am J Physiol Renal Physiol 283, F271-279, doi:10.1152/ajprenal.00093.2001 (2002). [29]Benjamin, D. I. et al. Inositol phosphate recycling regulates glycolytic and lipid metabolism that drives cancer aggressiveness. ACS Chem Biol 9, 1340-1350, doi:10.1021/cb5001907 (2014). [30]Lin, C. I. et al. Lysophosphatidic acid up-regulates vascular endothelial growth factor-C and lymphatic marker expressions in human endothelial cells. Cellular and molecular life sciences : CMLS 65, 2740-2751, doi:10.1007/s00018-008-8314-9 (2008). [31]Lin, C. I. et al. Lysophosphatidic acid upregulates vascular endothelial growth factor-C and tube formation in human endothelial cells through LPA(1/3), COX-2, and NF-kappaB activation- and EGFR transactivation-dependent mechanisms. Cell Signal 20, 1804-1814, doi:10.1016/j.cellsig.2008.06.008 (2008). [32]Lin, C. E. et al. Lysophosphatidic acid enhances vascular endothelial growth factor-C expression in human prostate cancer PC-3 cells. PloS one 7, e41096, doi:10.1371/journal.pone.0041096 (2012). [33]Lin, C. C. et al. Lysophosphatidic acid induces reactive oxygen species generation by activating protein kinase C in PC-3 human prostate cancer cells. Biochem Biophys Res Commun 440, 564-569, doi:10.1016/j.bbrc.2013.09.104 (2013). [34]Cursiefen, C. et al. VEGF-A stimulates lymphangiogenesis and hemangiogenesis in inflammatory neovascularization via macrophage recruitment. J Clin Invest 113, 1040-1050, doi:10.1172/JCI20465 (2004). [35]Brakenhielm, E. et al. Modulating metastasis by a lymphangiogenic switch in prostate cancer. Int J Cancer 121, 2153-2161, doi:10.1002/ijc.22900 (2007). [36]Zheng, W., Aspelund, A. & Alitalo, K. Lymphangiogenic factors, mechanisms, and applications. J Clin Invest 124, 878-887, doi:10.1172/JCI71603 (2014). [37]Roskoski, R., Jr. Vascular endothelial growth factor (VEGF) signaling in tumor progression. Critical reviews in oncology/hematology 62, 179-213, doi:10.1016/j.critrevonc.2007.01.006 (2007). [38]Chen, J. C., Chang, Y. W., Hong, C. C., Yu, Y. H. & Su, J. L. The Role of the VEGF-C/VEGFRs Axis in Tumor Progression and Therapy. Int J Mol Sci 14, 88-107, doi:10.3390/ijms14010088 (2012). [39]Su, J. L. et al. The VEGF-C/Flt-4 axis promotes invasion and metastasis of cancer cells. Cancer Cell 9, 209-223, doi:10.1016/j.ccr.2006.02.018 (2006). [40]Jennbacken, K., Vallbo, C., Wang, W. & Damber, J. E. Expression of vascular endothelial growth factor C (VEGF-C) and VEGF receptor-3 in human prostate cancer is associated with regional lymph node metastasis. Prostate 65, 110-116, doi:10.1002/pros.20276 (2005). [41]Wong, S. Y. et al. Tumor-secreted vascular endothelial growth factor-C is necessary for prostate cancer lymphangiogenesis, but lymphangiogenesis is unnecessary for lymph node metastasis. Cancer Res 65, 9789-9798, doi:10.1158/0008-5472.CAN-05-0901 (2005). [42]Coppolino, M. G. et al. Calreticulin is essential for integrin-mediated calcium signalling and cell adhesion. Nature 386, 843-847, doi:10.1038/386843a0 (1997). [43]Lu, Y. C. et al. Calreticulin activates beta1 integrin via fucosylation by fucosyltransferase 1 in J82 human bladder cancer cells. Biochem J 460, 69-78, doi:10.1042/BJ20131424 (2014). [44]Totary-Jain, H. et al. Calreticulin destabilizes glucose transporter-1 mRNA in vascular endothelial and smooth muscle cells under high-glucose conditions. Circulation research 97, 1001-1008, doi:10.1161/01.RES.0000189260.46084.e5 (2005). [45]Weng, W.-C. et al. Calreticulin Regulates VEGF-A in Neuroblastoma Cells. Molecular Neurobiology 52, 758-770, doi:10.1007/s12035-014-8901-8 (2014). [46]Kang, X. et al. High glucose promotes tumor invasion and increases metastasis-associated protein expression in human lung epithelial cells by upregulating heme oxygenase-1 via reactive oxygen species or the TGF-beta1/PI3K/Akt signaling pathway. Cell Physiol Biochem 35, 1008-1022, doi:10.1159/000373928 (2015). [47]Inoguchi, T. et al. High glucose level and free fatty acid stimulate reactive oxygen species production through protein kinase C--dependent activation of NAD(P)H oxidase in cultured vascular cells. Diabetes 49, 1939-1945 (2000). [48]Leblanc, R. & Peyruchaud, O. New insights into the autotaxin/LPA axis in cancer development and metastasis. Experimental cell research 333, 183-189, doi:10.1016/j.yexcr.2014.11.010 (2015). [49]Leblanc, R. et al. Interaction of platelet-derived autotaxin with tumor integrin alphaVbeta3 controls metastasis of breast cancer cells to bone. Blood 124, 3141-3150, doi:10.1182/blood-2014-04-568683 (2014). [50]Kato, H. et al. Metformin inhibits the proliferation of human prostate cancer PC-3 cells via the downregulation of insulin-like growth factor 1 receptor. Biochem Biophys Res Commun 461, 115-121, doi:10.1016/j.bbrc.2015.03.178 (2015). [51]Loubiere, C. et al. Metformin-induced energy deficiency leads to the inhibition of lipogenesis in prostate cancer cells. Oncotarget (2015). [52]Hwang, I. C. et al. Metformin association with lower prostate cancer recurrence in type 2 diabetes: a systematic review and meta-analysis. Asian Pac J Cancer Prev 16, 595-600 (2015). | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/52597 | - |
dc.description.abstract | 前列腺癌 (prostate cancer) 是男性常見的癌症之一,在台灣男性癌症中死亡率排行第七位,常見病徵有淋巴和骨髓轉移等現象。而在第二型糖尿病患者中,經由臨床統計發現其具較高的罹癌機率,高血糖會促進有氧糖解,增進癌細胞生長速度,但目前的研究對於高血糖在前列腺癌的影響尚具爭議。水解磷酸脂 (Lysophosphatidic acid, LPA) 為細胞膜上衍生出的小分子傳訊脂質,由溶血磷脂醯膽鹼 (Lysophosphatidylcholine, LPC) 在自分泌運動因子 (Autotaxin, ATX) 酵素的作用下切除膽鹼而形成。已知LPA會和細胞膜上的水解磷酸脂受器 (LPA receptors)結合,促進癌細胞生長、移動和附著。在實驗室先前的研究中發現,在前列腺癌PC-3細胞株中,LPA可透過水解磷酸脂受器1 (LPA1) 和水解磷酸脂受器3 (LPA3) 促進淋巴管新生因子C型 (Vascular endothelial growth factor-C, VEGF-C) 的表現,進而影響癌症的淋巴轉移;此外,在糖尿病患者及老鼠中,也發現 ATX 的表現量增加。因此本實驗的目的探討在前列腺癌PC-3細胞株中,高濃度葡萄糖是否藉由水解磷酸脂訊號傳遞路徑促進有氧糖解和淋巴管新生因子C型的表現,導致前列腺癌的惡化。實驗結果顯示10 mM和20 mM的高濃度葡萄糖會增加VEGF-C 和ATX 的核醣核酸和蛋白質的表現。並透過抑制性藥物和基因敲除 (knockdown) 的實驗證實高濃度的葡萄糖確實透過ATX、LPA1/3、過氧化物 (Reactive oxygen species, ROS) 和晶狀體上皮源性生長因子 (Lens epithelium-derived growth factor, LEDGF) 的訊息傳遞路徑促進VEGF-C的表現。此外,我們也發現高濃度葡萄糖會增加鈣網蛋白 (Calreticulin, CRT) 的表現,並藉由基因knockdown的實驗證實CRT會調控ATX的表現。另一方面,由海馬生物能量測定儀結果顯示高濃度葡萄糖和LPA會提高有氧糖解的速率,反之,加入抑制LPA1/3藥物後有氧糖解速率下降。由這些結果證實,不正常的葡萄糖代謝會促進ATX的表現並增加LPA的含量,進而促進前列腺癌的淋巴管新生,造成前列腺癌病患的惡化。 | zh_TW |
dc.description.abstract | Prostate cancer is one of the most frequently diagnosed cancers in males and usually metastasizes to various organs but particularly to local lymph nodes. Clinical evidences suggest that type II diabetes mellitus has been known to increase the risk of several cancers. Hyperglycemia would increase aerobic glycolysis and promote cancer growth, but the effects on prostate cancer are still controversial. Lysophosphatidic acid (LPA) is a small glycophospholipid that mediates multiple behaviors by activating LPA receptors in cancer cells, such as cell proliferation, migration and adhesion. In our previous studies, LPA could enhance VEGF-C expression through activating LPA receptor 1/3 in prostate cancer. On the other hand, autotaxin (ATX), an enzyme responsible for LPA synthesis, was up-regulated in diabetic patients and mice. In this study, we used PC-3 cell line as a model to investigate whether high glucose induced lymphangiogenesis and aerobic glycolysis through LPA signals to drive cancer progression. Our results demonstrated that the mRNA and protein expression levels of VEGF-C and ATX were increased after 10 mM and 20 mM high glucose treatments in PC-3 cells. By pharmacological blockers and knockdown experiments, we confirmed that the expression of VEGF-C was mediated through ATX, LPA1/3, ROS and LEDGF dependent pathways. Furthermore, the mRNA and protein levels of calreticulin (CRT) were up-regulated under high glucose conditions. By knockdown experiments, we demonstrated that ATX might be a downstream signal of CRT. On the other hand, high glucose and LPA treatments also enhanced the aerobic glycolysis. Taken together, these results suggested that the abnormal glucose metabolism might lead to LPA synthesis and therefore the subsequent pathological conditions of prostate cancer. These novel findings could potentially provide new strategies for prostate cancer treatments. | en |
dc.description.provenance | Made available in DSpace on 2021-06-15T16:19:52Z (GMT). No. of bitstreams: 1 ntu-104-R02450007-1.pdf: 2714503 bytes, checksum: 6178cf79441db8896987fe57ea494250 (MD5) Previous issue date: 2015 | en |
dc.description.tableofcontents | 致謝 I
中文摘要 II Abstract IV Content VI List of Figures IX Introduction 1 Rationale 11 Materials and Methods 12 Results 18 Discussion 25 References 31 Figures 36 Supplemental Figures 50 | |
dc.language.iso | en | |
dc.title | 高濃度葡萄糖藉由水解磷酸脂促進前列腺癌細胞淋巴管生成因子 | zh_TW |
dc.title | High Glucose Induces Vascular Endothelial Growth Factor-C through Lysophosphatidic Acid Signals in Human Prostate Cancer PC-3 Cells | en |
dc.type | Thesis | |
dc.date.schoolyear | 103-2 | |
dc.description.degree | 碩士 | |
dc.contributor.coadvisor | 李心予(Hsinyu Lee) | |
dc.contributor.oralexamcommittee | 黃元勵(Yuan-Li Huang),李明學(Ming-Shyue Lee) | |
dc.subject.keyword | 水解磷酸脂,自分泌運動因子,前列腺癌,有氧糖解,淋巴管新生因子, | zh_TW |
dc.subject.keyword | LPA,prostate cancer,aerobic glycolysis,lymphangiogenesis,VEGF-C, | en |
dc.relation.page | 53 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2015-08-17 | |
dc.contributor.author-college | 牙醫專業學院 | zh_TW |
dc.contributor.author-dept | 口腔生物科學研究所 | zh_TW |
顯示於系所單位: | 口腔生物科學研究所 |
文件中的檔案:
檔案 | 大小 | 格式 | |
---|---|---|---|
ntu-104-1.pdf 目前未授權公開取用 | 2.65 MB | Adobe PDF |
系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。