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系統識別號 U0002-1406201117093300
中文論文名稱 小蘗鹼藉由PI3K/Akt訊號傳遞路徑抑制卵巢癌細胞的轉移能力
英文論文名稱 Berberine Inhibits Metastatic Potential of Ovarian Cancer Cells via PI3K/Akt Signaling Pathway
校院名稱 淡江大學
系所名稱(中) 化學學系碩士班
系所名稱(英) Department of Chemistry
學年度 99
學期 2
出版年 100
研究生中文姓名 吳國暉
研究生英文姓名 Kuo-Hui Wu
學號 697180478
學位類別 碩士
語文別 中文
口試日期 2011-05-17
論文頁數 51頁
口試委員 指導教授-莊子超
委員-許世忠
委員-王文奇
中文關鍵字 小蘗鹼  卵巢癌  轉移  PI3K/Akt 
英文關鍵字 Berberine  Ovarian cancer  Metastasis  PI3K/Akt 
學科別分類 學科別自然科學化學
中文摘要 小蘗鹼為一種異喹啉生物鹼,存在於黃連中的抗癌有效成份。小蘗鹼已被證實對於多種癌症細胞株皆有抗癌效果。文獻報導小蘗鹼透過MAPK訊號傳遞路徑而抑制人類舌癌細胞的移動和侵略。在此,我們證明了小蘗鹼可以抑制人類卵巢癌細胞的增生、移動、侵略和血管新生。此效果為小糱鹼透過抑制EGFR及HER2/neu基因表現暨其下游PI3K/Akt訊號傳遞路徑而抑制MMP-2、VEGF和Cyclin D1的蛋白質表現。此發現也為小蘗鹼帶來新的抗癌方法及策略。
英文摘要 Berberine, one of the effective anti-cancer components of Coptis Chinensis, is a type of isoquinoline alkaloid. It has been reported various anti-cancer effects in different human cancer cell lines. Other research reported that berberine inhibited migration and invasion via MAPK pathways of human tongue cancer cells. Here, we reported that berberine inhibits cell proliferation, migration, invasion and angiogenesis of human ovarian cancer cell lines. The effects were mediated through inhibiting EGFR and HER2/neu expression and their down-stream signalings such as PI3K/Akt signaling pathway resulting in inhibition of MMP-2, VEGF and cyclin D1 protein. We discovered a novel therapeutic approach of anti-cancer role of berberine.
論文目次 摘要 I
縮寫表 III
第一章 緒論 1
第一節 卵巢癌 1
第二節 神經膠原致癌基因 5
第三節 小蘗鹼 8
第四節 實驗目的 10
第二章 材料與方法 11
第三章 結果 16
第一節 實驗結果 16
第二節 實驗圖表 21
第四章 討論 38
第五章 參考資料 41
附錄一 49
附錄二 50

參考文獻 Basha SA, Mishra R, Jha R, Pandey V, Singh U (2002). Effect of berberine and (±)-bicuculline isolated fromCorydalis chaerophylla on spore germination of some fungi. Folia Microbiologica 47: 161-165.

Bast R, Xu F, Yu Y, Barnhill S, Zhang Z, Mills G (1998). CA 125: the past and the future. The International Journal of Biological Markers 13: 179-187.

Bates D, Curry F (1996). Vascular endothelial growth factor increases hydraulic conductivity of isolated perfused microvessels. American Journal of Physiology- Heart and Circulatory Physiology 271: 2520-2528.

Bevan H, van den Akker N, Qiu Y, Polman J, Foster R, Yem J et al (2008). The Alternatively Spliced Anti-Angiogenic Family of VEGF Isoforms VEGF< sub> xxx b in Human Kidney Development. Nephron Physiology 110: 57-67.

Chambers A, Groom A, MacDonald I (2002). Metastasis: dissemination and growth of cancer cells in metastatic sites. Nature Reviews Cancer 2: 563-572.

Chiarugi P, Giannoni E (2008). Anoikis: a necessary death program for anchorage-dependent cells. Biochemical Pharmacology 76: 1352-1364.

Cohen P, Frame S (2001). The renaissance of GSK3. Nature Reviews Molecular Cell Biology 2: 769-776.

Cornolti G, Ungari M, Morassi M, Facchetti F, Rossi E, Lombardi D et al (2007). Amplification and overexpression of HER2/neu gene and HER2/neu protein in salivary duct carcinoma of the parotid gland. Archives of Otolaryngology- Head and Neck Surgery 133: 1031-1036.

Coussens L, Yang-Feng T, Liao Y, Chen E, Gray A, McGrath J et al (1985). Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene. Science 230: 1132-1139.

Dan K, Andreasen P, Gr ndahl-Hansen J, Kristensen P, Nielsen L, Skriver L (1985). Plasminogen activators, tissue degradation, and cancer. Advances in Cancer Research 44: 139-266.

Deem T, Cook-Mills J (2004). Vascular cell adhesion molecule 1 (VCAM-1) activation of endothelial cell matrix metalloproteinases: role of reactive oxygen species. Blood 104: 2385-2393.

Di Lullo G, Sweeney S, Korkko J, Ala-Kokko L, San Antonio J (2002). Mapping the ligand-binding sites and disease-associated mutations on the most abundant protein in the human, type I collagen. Journal of Biological Chemistry 277: 4223-4231.

Diehl J, Zindy F, Sherr C (1997). Inhibition of cyclin D1 phosphorylation on threonine-286 prevents its rapid degradation via the ubiquitin-proteasome pathway. Genes & Development 11: 957-972.

Fatehi Hassanabad Z, Jafarzadeh M, Tarhini A, Fatehi M (2005). The antihypertensive and vasodilator effects of aqueous extract from Berberis vulgaris fruit on hypertensive rats. Phytotherapy Research 19: 222-225.

Ferrara N (1999). Molecular and biological properties of vascular endothelial growth factor. Journal of Molecular Medicine 77: 527-543.

Ferrara N, Gerber H, LeCouter J (2003). The biology of VEGF and its receptors. Nature Medicine 9: 669-676.

Forsythe J, Jiang B, Iyer N, Agani F, Leung S, Koos R et al (1996). Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Molecular and Cellular Biology 16: 4604-4613.

Ghajar C, George S, Putnam A (2008). Matrix metalloproteinase control of capillary morphogenesis. Critical Reviews in Eukaryotic Gene Expression 18: 251-278.

Goff B, Mandel L, Drescher C, Urban N, Gough S, Schurman K et al (2007). Development of an ovarian cancer symptom index. Cancer 109: 221-227.

Grimes C, Jope R (2001). The multifaceted roles of glycogen synthase kinase 3 [beta] in cellular signaling. Progress in Neurobiology 65: 391-426.

Guy P, Platko J, Cantley L, Cerione R, Carraway K (1994). Insect cell-expressed p180erbB3 possesses an impaired tyrosine kinase activity. Proceedings of the National Academy of Sciences of the United States of America 91: 8132-8136.

Haagensen C, Feind C, Herter F, Slanetz C, Weinberg J (1972). The lymphatics in cancer. Saunders Philadelphia.

Hanahan D, Weinberg R (2000). The hallmarks of cancer. Cell 100: 57-70.

Heikinheimo K, Salo T (1995). Expression of basement membrane type IV collagen and type IV collagenases (MMP-2 and MMP-9) in human fetal teeth. Journal of Dental Research 74: 1226-1234.

Hess AR, Seftor EA, Seftor REB, Hendrix MJC (2003). Phosphoinositide 3-kinase regulates membrane Type 1-matrix metalloproteinase (MMP) and MMP-2 activity during melanoma cell vasculogenic mimicry. Cancer Research 63: 4757-4762.

Ho Y, Yang J, Li T, Lin J, Lin J, Lai K et al (2009). Berberine suppresses in vitro migration and invasion of human SCC-4 tongue squamous cancer cells through the inhibitions of FAK, IKK, NF-[kappa] B, u-PA and MMP-2 and-9. Cancer Letters 279: 155-162.

Imanshahidi M, Hosseinzadeh H (2008). Pharmacological and therapeutic effects of Berberis vulgaris and its active constituent, berberine. Phytotherapy Research 22: 999-1012.

Ispanovic E, Haas TL (2006). JNK and PI3K differentially regulate MMP-2 and MT1-MMP mRNA and protein in response to actin cytoskeleton reorganization in endothelial cells. American Journal of Physiology-Cell Physiology 291: 579-588.

Jaehne J, Urmacher C, Thaler H, Friedlander-Klar H, Cordon-Cardo C, Meyer H (1992). Expression of Her2/neu oncogene product p185 in correlation to clinicopathological and prognostic factors of gastric carcinoma. Journal of Cancer Research and Clinical Oncology 118: 474-479.

Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T et al (2008). Cancer statistics, 2008. CA: A Cancer Journal for Clinicians 58: 71-96.

Jie S, Li H, Tian Y, Guo D, Zhu J, Gao S et al (2011). Berberine inhibits angiogenic potential of Hep G2 cell line through VEGF down regulation in vitro. Journal of Gastroenterology and Hepatology 26: 179-185.
Kahn J (2009). HPV vaccination for the prevention of cervical intraepithelial neoplasia. New England Journal of Medicine 361: 271-278.

Kleinsmith L (2006). Principles of cancer biology. Pearson Benjamin Cummings San Francisco, CA.

Klos K, Wyszomierski S, Sun M, Tan M, Zhou X, Li P et al (2006). ErbB2 increases vascular endothelial growth factor protein synthesis via activation of mammalian target of rapamycin/p70S6K leading to increased angiogenesis and spontaneous metastasis of human breast cancer cells. Cancer Research 66: 2028-2037.

Komor E, Thom M, Maretzki A (1981). Mechanism of uptake of l arginine by sugar cane cells. European Journal of Biochemistry 116: 527-533.

Kong W, Wei J, Abidi P, Lin M, Inaba S, Li C et al (2004). Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins. Nature Medicine 10: 1344-1351.

Krey AK, Hahn FE (1969). Berberine: Complex with DNA. Science 166: 755-757.

Kriehuber E, Breiteneder-Geleff S, Groeger M, Soleiman A, Schoppmann S, Stingl G et al (2001). Isolation and characterization of dermal lymphatic and blood endothelial cells reveal stable and functionally specialized cell lineages. The Journal of Experimental Medicine 194: 797-808.

Ku D, Zaleski J, Liu S, Brock T (1993). Vascular endothelial growth factor induces EDRF-dependent relaxation in coronary arteries. American Journal of Physiology- Heart and Circulatory Physiology 265: 586-592.

Lakhani S, Manek S, Penault-Llorca F, Flanagan A, Arnout L, Merrett S et al (2004). Pathology of ovarian cancers in BRCA1 and BRCA2 carriers. Clinical Cancer Research 10: 2473-2481.

Lenferink AEG, Busse D, Flanagan WM, Yakes FM, Arteaga CL (2001). ErbB2/neu kinase modulates cellular p27Kip1 and cyclin D1 through multiple signaling pathways. Cancer Research 61: 6583-6591.

Leung D, Cachianes G, Kuang W, Goeddel D, Ferrara N (1989). Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246: 1306-1309.
Liotta L, Tryggvason K, Garbisa S, Hart I, Foltz C, Shafie S (1980). Metastatic potential correlates with enzymatic degradation of basement membrane collagen. Nature 6: 67-68.

Liu J, He C, Zhou K, Wang J, Kang J (2009). Coptis extracts enhance the anticancer effect of estrogen receptor antagonists on human breast cancer cells. Biochemical and Biophysical Research Communications 378: 174-178.

Liu Y, Cox S, Morita T, Kourembanas S (1995). Hypoxia regulates vascular endothelial growth factor gene expression in endothelial cells: identification of a 5'enhancer. Circulation Research 77: 638-643.

Mantena S, Sharma S, Katiyar S (2006a). Berberine inhibits growth, induces G1 arrest and apoptosis in human epidermoid carcinoma A431 cells by regulating Cdki-Cdk-cyclin cascade, disruption of mitochondrial membrane potential and cleavage of caspase 3 and PARP. Carcinogenesis 27: 2018-2027.

Mantena S, Sharma S, Katiyar S (2006b). Berberine, a natural product, induces G1-phase cell cycle arrest and caspase-3-dependent apoptosis in human prostate carcinoma cells. Molecular Cancer Therapeutics 5: 296-308.

Mitani N, Murakami K, Yamaura T, Ikeda T, Saiki I (2001). Inhibitory effect of berberine on the mediastinal lymph node metastasis produced by orthotopic implantation of Lewis lung carcinoma. Cancer Letters 165: 35-42.

Naucler P, Ryd W, Tornberg S, Strand A, Wadell G, Elfgren K et al (2007). Human papillomavirus and Papanicolaou tests to screen for cervical cancer. New England Journal of Medicine 357: 1589-1597.

Neufeld G, Cohen T, Gengrinovitch S, Poltorak Z (1999). Vascular endothelial growth factor (VEGF) and its receptors. The FASEB Journal 13: 9-22.

Olayioye MA, Neve RM, Lane HA, Hynes NE (2000). The ErbB signaling network: receptor heterodimerization in development and cancer. The EMBO Journal 19: 3159-3167.

Owens M, Horten B, Da Silva M (2004). HER2 amplification ratios by fluorescence in situ hybridization and correlation with immunohistochemistry in a cohort of 6556 breast cancer tissues. Clinical Breast Cancer 5: 63-69.
Padhy L, Shih C, Cowing D, Finkelstein R, Weinberg R (1982). Identification of a phosphoprotein specifically induced by the transforming DNA of rat neuroblastomas. Cell 28: 865-871.

Page-McCaw A, Ewald A, Werb Z (2007). Matrix metalloproteinases and the regulation of tissue remodelling. Nature Reviews Molecular Cell Biology 8: 221-233.

Pardee A (1974). A restriction point for control of normal animal cell proliferation. Proceedings of the National Academy of Sciences of the United States of America 71: 1286-1290.

Pardee A (1989). G1 events and regulation of cell proliferation. Science 246: 603-608.

Parks W, Wilson C, Lopez-Boado Y (2004). Matrix metalloproteinases as modulators of inflammation and innate immunity. Nature Reviews Immunology 4: 617-629.

Patil JB, Kim J, Jayaprakasha G (2010). Berberine induces apoptosis in breast cancer cells (MCF-7) through mitochondrial-dependent pathway. European Journal of Pharmacology 645: 70-78.

Pearson G, Robinson F, Beers Gibson T, Xu B, Karandikar M, Berman K et al (2001). Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocrine Reviews 22: 153-183.

Pellikainen J, Ropponen K, Kataja V, Kellokoski J, Eskelinen M, Kosma V (2004). Expression of matrix metalloproteinase (MMP)-2 and MMP-9 in breast cancer with a special reference to activator protein-2, HER2, and prognosis. Clinical Cancer Research 10: 7621-7628.

Piek J, Diest P, Verheijen R (2008). Ovarian carcinogenesis: an alternative hypothesis. Ovarian Cancer: 79-87.

Roy R, Yang J, Moses M (2009). Matrix metalloproteinases as novel biomarkers and potential therapeutic targets in human cancer. Journal of Clinical Oncology 27: 5287-5297.

Rusznyak I, Foldi M, Szabo G, St Pierre R (1968). Lymphatics and Lymph Circulation-Physiology and Pathology. The American Journal of the Medical Sciences 255: 339.
Sakai K, Shitan N, Sato F, Ueda K, Yazaki K (2002). Characterization of berberine transport into Coptis japonica cells and the involvement of ABC protein. Journal of Experimental Botany 53: 1879-1886.

Salomon D, Brandt R, Ciardiello F, Normanno N (1995). Epidermal growth factor-related peptides and their receptors in human malignancies. Critical Reviews in Oncology/Hematology 19: 183-232.

Sariahmetoglu M, Crawford B, Leon H, Sawicka J, Li L, Ballermann B et al (2007). Regulation of matrix metalloproteinase-2 (MMP-2) activity by phosphorylation. The FASEB Journal 21: 2486-2495.

Schechter A, Stern D, Vaidyanathan L, Decker S, Drebin J, Greene M et al (1984). The neu oncogene: an erb-B-related gene encoding a 185,000-Mr tumour antigen. Nature 312: 513-516.

Schulze W, Deng L, Mann M (2005). Phosphotyrosine interactome of the ErbB-receptor kinase family. Molecular Systems Biology 1: 20005.2008.

Senger D, Galli S, Dvorak A, Perruzzi C, Harvey V, Dvorak H (1983). Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 219: 983-985.

Sethi ML (1983). Enzyme inhibition VI: inhibition of reverse transcriptase activity by protoberberine alkaloids and structure–activity relationships. Journal of Pharmaceutical Sciences 72: 538-541.

Sherr C (2000). The Pezcoller lecture: cancer cell cycles revisited. Cancer Research 60: 3689-3695.

Shih C, Padhy L, Murray M, Weinberg R (1981). Transforming genes of carcinomas and neuroblastomas introduced into mouse fibroblasts. Nature 290: 261-264.

Slamon D, Clark G, Wong S, Levin W, Ullrich A, McGuire W (1987). Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235: 177-182.

Sleeman J (2000). The lymph node as a bridgehead in the metastatic dissemination of tumors. Lymphatic Metastasis and Sentinel Lymphonodectomy 157: 55-81.
Steffensen B, Hakkinen L, Larjava H (2001). Proteolytic events of wound-healing—coordinated interactions among matrix metalloproteinases (MMPs), integrins, and extracellular matrix molecules. Critical Reviews in Oral Biology & Medicine 12: 373-398.

Subbaiah T, Amin A (1967). Effect of berberine sulphate on Entamoeba histolytica. Nature 215: 527-528.

Topalak O, Saygili U, Soyturk M, Karaca N, Batur Y, Uslu T et al (2002). Serum, pleural effusion, and ascites CA-125 levels in ovarian cancer and nonovarian benign and malignant diseases: a comparative study. Gynecologic Oncology 85: 108-113.

Vermeij J, Teugels E, Bourgain C, Xiangming J (2008). Genomic activation of the EGFR and HER2-neu genes in a significant proportion of invasive epithelial ovarian cancers. BMC Cancer 8: 3-11.

Wang S, Lien H, Xia W, Chen I, Lo H, Wang Z et al (2004). Binding at and transactivation of the COX-2 promoter by nuclear tyrosine kinase receptor ErbB-2. Cancer Cell 6: 251-261.

Yarden Y, Sliwkowski M (2001). Untangling the ErbB signalling network. Nature Reviews Molecular Cell Biology 2: 127-137.

Yarden Y, Ullrich A (1988). Growth factor receptor tyrosine kinases. Annual Review of Biochemistry 57: 443-478.

Yu D, Hung M (2000). Overexpression of ErbB2 in cancer and ErbB2-targeting strategies. Oncogene 19: 6115-6121.

Zhang Y, Li X, Zou D, Liu W, Yang J, Zhu N et al (2008). Treatment of type 2 diabetes and dyslipidemia with the natural plant alkaloid berberine. Journal of Clinical Endocrinology & Metabolism 93: 2559-2565.

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