Responsive image
博碩士論文 etd-0622115-164411 詳細資訊
Title page for etd-0622115-164411
論文名稱
Title
微藻萃取物在肝癌預防的效用與機轉
Preventative Efficacy of Microalgal Extract for Hepatocellular Carcinoma and a Proposed Mechanism
系所名稱
Department
畢業學年期
Year, semester
語文別
Language
學位類別
Degree
頁數
Number of pages
90
研究生
Author
指導教授
Advisor
召集委員
Convenor
口試委員
Advisory Committee
口試日期
Date of Exam
2015-07-02
繳交日期
Date of Submission
2015-07-25
關鍵字
Keywords
肝癌衍生生長因子、微藻萃取物、第二型環氧化酶、大鼠原位肝癌模式、肝癌
rat orthotopic hepatoma model, hepatoma-derived growth factor, microalgal extract, hepatocellular carcinoma, cyclooxygenase-2
統計
Statistics
本論文已被瀏覽 5838 次,被下載 45
The thesis/dissertation has been browsed 5838 times, has been downloaded 45 times.
中文摘要
根據世界衛生組織(WHO)的最新統計資料顯示,肝癌在全球常見的癌症中位居第六,而主要發生區域多位於亞洲及非洲。且根據衛生福利部統計的結果指出,肝癌是台灣癌症死因的第二位。肝癌目前的治療方式,主要有肝臟移植、手術切除、標靶治療等方式。由於這些肝癌治療的效果還是有限的,因此最有效的方式還是預防,而肝癌患者也需要其他能夠降低治療後癌症復發的藥物。先前已有文獻指出藻類富含許多對人體有益的物質,其中包含許多蛋白質、礦物質與類胡蘿蔔素及必需脂肪酸;而這些物質已有文獻指出具有抗癌及預防癌症等等的功效。因此我們利用先前已篩選出的一株淡水微藻進行本研究,在細胞實驗上,我們的研究發現該微藻萃取物能夠抑制腫瘤進程,在肝癌細胞中主要的機轉是經由阻斷第二型環氧化酶(COX-2)而抑制腫瘤微環境中的前列腺素(PGE2)以及肝癌衍生生長因子(HDGF)而影響肝癌細胞的功能。並於動物實驗的結果得知微藻萃取物在大鼠原位肝癌模式中具有預防的效果並且可以抑制肝腫瘤的生長。
Abstract
According to WHO statistics shows that hepatocellular carcinoma (HCC) is the sixth most common cancer in the world, and the highest incidence of liver cancer was in Asia and Africa. In addition to the statistics from MOHW indicates that HCC is the second death cause of cancer. Current HCC therapies has liver transplant, surgical resection and target therapy, etc. However, these therapies of HCC still has limited, thus the most effective way is prevention, and the patient of liver cancer need more other drugs which reduce the risk of relapse. Previous studies has been indicated that microalgae are benefit for health which contains proteins, minerals, carotenoid and essential fatty acids. These materials also can prevent cancer and the effect of anti-cancer, thus we use previously screened freshwater microalga conduct this study. We found that green alga extract inhibits tumor progression and the mechanism is that green alga extract inhibited functions of hepatoma cells through reduced tumor micro-environmental prostaglandin E2 (PGE2) and hepatoma-derived growth factor (HDGF) in vitro. We also obtains that green alga extract has prevention efficacy and inhibition of tumor growth in rat orthotopic hepatoma model.
目次 Table of Contents
Verification letter from the Oral Examination Committee i
Acknowledgement ii
摘要 iii
Abstract iv
List of Tables and Figures vi
Introduction 1
Materials and methods 6
Results 15
Discussion 25
Figures and legends 31
Conclusion 64
Future perspectives 65
References 66
Appendix 72
參考文獻 References
2005. PGE2 produced by lung cancer suppresses immune function through T-regulatory cells and can be blocked by the COX2 inhibitor Celebrex. Cancer Biol Ther 4(8):v-vi.
Abdel-Wahhab, M. A., H. H. Ahmed, and M. M. Hagazi. 2006. Prevention of aflatoxin B1-initiated hepatotoxicity in rat by marine algae extracts. J Appl Toxicol 26(3):229-38.
Al-Kharusi, M. R., and coauthors. 2013. LGR5 promotes survival in human colorectal adenoma cells and is upregulated by PGE2: implications for targeting adenoma stem cells with NSAIDs. Carcinogenesis 34(5):1150-7.
Atashrazm, F., R. M. Lowenthal, G. M. Woods, A. F. Holloway, and J. L. Dickinson. 2015. Fucoidan and cancer: a multifunctional molecule with anti-tumor potential. Mar Drugs 13(4):2327-46.
Cervello, M., and coauthors. 2012. Targeted therapy for hepatocellular carcinoma: novel agents on the horizon. Oncotarget 3(3):236-60.
Cervello, M., and G. Montalto. 2006. Cyclooxygenases in hepatocellular carcinoma. World J Gastroenterol 12(32):5113-21.
Chan, H. H., and coauthors. 2010. Rapid induction of orthotopic hepatocellular carcinoma in immune-competent rats by non-invasive ultrasound-guided cells implantation. BMC Gastroenterol 10:83.
Chu, T. H., and coauthors. 2014. Celecoxib suppresses hepatoma stemness and progression by up-regulating PTEN. Oncotarget 5(6):1475-90.
De Carlo, F., T. R. Witte, W. E. Hardman, and P. P. Claudio. 2013. Omega-3 eicosapentaenoic acid decreases CD133 colon cancer stem-like cell marker expression while increasing sensitivity to chemotherapy. PLoS One 8(7):e69760.
Diehn, M., and coauthors. 2009. Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature 458(7239):780-3.
Dorgan, J. F., and coauthors. 2004. Serum carotenoids and alpha-tocopherol and risk of nonmelanoma skin cancer. Cancer Epidemiol Biomarkers Prev 13(8):1276-82.
El-Serag, H. B. 2002. Hepatocellular carcinoma: an epidemiologic view. J Clin Gastroenterol 35(5 Suppl 2):S72-8.
Ellis, L. M. 2004. Angiogenesis and its role in colorectal tumor and metastasis formation. Semin Oncol 31(6 Suppl 17):3-9.
Fons, P., B. Malavaud, L. Venat, and J. Plouet. 2000. [Anti-angiogenesis strategies in cancer]. Bull Acad Natl Med 184(3):579-86; discussion 586-7.
Franken, N. A., H. M. Rodermond, J. Stap, J. Haveman, and C. van Bree. 2006. Clonogenic assay of cells in vitro. Nat Protoc 1(5):2315-9.
Fujisawa, K. 1986. [Liver function tests: analysis of biliary tract enzymes and serum secretory enzymes--ALP, gamma-GTP, LAP, and ChE]. Rinsho Byori 34 Spec No 67:42-50.
Fukushima, M. 1983. [Anti-angiogenesis, a possible new modality of cancer treatment]. Gan To Kagaku Ryoho 10(7):1591-7.
Garg, A. D., and coauthors. 2013. ROS-induced autophagy in cancer cells assists in evasion from determinants of immunogenic cell death. Autophagy 9(9):1292-307.
Goessling, W., and coauthors. 2009. Genetic interaction of PGE2 and Wnt signaling regulates developmental specification of stem cells and regeneration. Cell 136(6):1136-47.
Gomez-Lopez, S., R. G. Lerner, and C. Petritsch. 2014. Asymmetric cell division of stem and progenitor cells during homeostasis and cancer. Cell Mol Life Sci 71(4):575-97.
Hsu, H. Y., and coauthors. 2013. Fucoidan induces changes in the epithelial to mesenchymal transition and decreases metastasis by enhancing ubiquitin-dependent TGFbeta receptor degradation in breast cancer. Carcinogenesis 34(4):874-84.
Hu, C., and coauthors. 2008. Analysis of ABCG2 expression and side population identifies intrinsic drug efflux in the HCC cell line MHCC-97L and its modulation by Akt signaling. Carcinogenesis 29(12):2289-97.
Hu, C. W., L. T. Chuang, P. C. Yu, and C. N. Chen. 2013. Pigment production by a new thermotolerant microalga Coelastrella sp. F50. Food Chem 138(4):2071-8.
Hu, T. H., and coauthors. 2003. Expression of hepatoma-derived growth factor in hepatocellular carcinoma. Cancer 98(7):1444-56.
Huang, J., D. Zhang, F. Xie, and Guilin. 2015. The potential role of COX-2 in cancer stem cell mediated canine mammary tumor initiation: an immunohistochemical study. J Vet Sci.
Ishigami, S., and coauthors. 2003. Tumor-associated macrophage (TAM) infiltration in gastric cancer. Anticancer Res 23(5A):4079-83.
Ishimoto, T., and coauthors. 2011. CD44 variant regulates redox status in cancer cells by stabilizing the xCT subunit of system xc(-) and thereby promotes tumor growth. Cancer Cell 19(3):387-400.
Jeong, S. C., Y. T. Jeong, S. M. Lee, and J. H. Kim. 2015. Immune-modulating activities of polysaccharides extracted from brown algae Hizikia fusiforme. Biosci Biotechnol Biochem:1-4.
Kalinski, P. 2012. Regulation of immune responses by prostaglandin E2. J Immunol 188(1):21-8.
Kern, M. A., and coauthors. 2002. Proapoptotic and antiproliferative potential of selective cyclooxygenase-2 inhibitors in human liver tumor cells. Hepatology 36(4 Pt 1):885-94.
Kondo, M., and coauthors. 1999. Increased expression of COX-2 in nontumor liver tissue is associated with shorter disease-free survival in patients with hepatocellular carcinoma. Clin Cancer Res 5(12):4005-12.
Kowshik, J., and coauthors. 2014. Astaxanthin inhibits JAK/STAT-3 signaling to abrogate cell proliferation, invasion and angiogenesis in a hamster model of oral cancer. PLoS One 9(10):e109114.
Ku, C. S., Y. Yang, Y. Park, and J. Lee. 2013. Health benefits of blue-green algae: prevention of cardiovascular disease and nonalcoholic fatty liver disease. J Med Food 16(2):103-11.
Kurtova, A. V., and coauthors. 2015. Blocking PGE2-induced tumour repopulation abrogates bladder cancer chemoresistance. Nature 517(7533):209-13.
Lee, E. H., and coauthors. 2004. Dietary lutein reduces ultraviolet radiation-induced inflammation and immunosuppression. J Invest Dermatol 122(2):510-7.
Lee, J. C., and coauthors. 2013. Marine algal natural products with anti-oxidative, anti-inflammatory, and anti-cancer properties. Cancer Cell Int 13(1):55.
Lee, T. K., and coauthors. 2011. Lupeol targets liver tumor-initiating cells through phosphatase and tensin homolog modulation. Hepatology 53(1):160-70.
Leng, J., C. Han, A. J. Demetris, G. K. Michalopoulos, and T. Wu. 2003. Cyclooxygenase-2 promotes hepatocellular carcinoma cell growth through Akt activation: evidence for Akt inhibition in celecoxib-induced apoptosis. Hepatology 38(3):756-68.
Li, H. J., F. Reinhardt, H. R. Herschman, and R. A. Weinberg. 2012. Cancer-stimulated mesenchymal stem cells create a carcinoma stem cell niche via prostaglandin E2 signaling. Cancer Discov 2(9):840-55.
Li, J. W., and J. C. Vederas. 2009. Drug discovery and natural products: end of an era or an endless frontier? Science 325(5937):161-5.
Lim, J. Y., Y. S. Kim, K. M. Kim, S. J. Min, and Y. Kim. 2014. Beta-carotene inhibits neuroblastoma tumorigenesis by regulating cell differentiation and cancer cell stemness. Biochem Biophys Res Commun 450(4):1475-80.
Llovet, J. M., and J. Bruix. 2008. Molecular targeted therapies in hepatocellular carcinoma. Hepatology 48(4):1312-27.
Lu, D., C. Han, and T. Wu. 2012. Microsomal prostaglandin E synthase-1 promotes hepatocarcinogenesis through activation of a novel EGR1/beta-catenin signaling axis. Oncogene 31(7):842-57.
Lu, Y., X. K. Xing, G. Z. Song, and Z. Chen. 2011. [Alteration of mi-RNA expression profile after interferon treatment in HCV-infected Huh7.5.1 cells]. Zhejiang Da Xue Xue Bao Yi Xue Ban 40(6):598-602.
Ma, S., and coauthors. 2007. Identification and characterization of tumorigenic liver cancer stem/progenitor cells. Gastroenterology 132(7):2542-56.
Ma, S., and coauthors. 2008a. Aldehyde dehydrogenase discriminates the CD133 liver cancer stem cell populations. Mol Cancer Res 6(7):1146-53.
Ma, S., T. K. Lee, B. J. Zheng, K. W. Chan, and X. Y. Guan. 2008b. CD133+ HCC cancer stem cells confer chemoresistance by preferential expression of the Akt/PKB survival pathway. Oncogene 27(12):1749-58.
Majumdar, A., and coauthors. 2012. Hepatic stem cells and transforming growth factor beta in hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 9(9):530-8.
Moussavou, G., and coauthors. 2014. Anticancer effects of different seaweeds on human colon and breast cancers. Mar Drugs 12(9):4898-911.
Muramatsu, S., and coauthors. 2013. Visualization of stem cell features in human hepatocellular carcinoma reveals in vivo significance of tumor-host interaction and clinical course. Hepatology 58(1):218-28.
North, T. E., and coauthors. 2010. PGE2-regulated wnt signaling and N-acetylcysteine are synergistically hepatoprotective in zebrafish acetaminophen injury. Proc Natl Acad Sci U S A 107(40):17315-20.
Olesch, C., and coauthors. 2015. MPGES-1-derived PGE2 suppresses CD80 expression on tumor-associated phagocytes to inhibit anti-tumor immune responses in breast cancer. Oncotarget 6(12):10284-96.
Patra, S., and M. S. Muthuraman. 2013. Gracilaria edulis extract induces apoptosis and inhibits tumor in Ehrlich ascites tumor cells in vivo. BMC Complement Altern Med 13:331.
Poon, D., and coauthors. 2009. Management of hepatocellular carcinoma in Asia: consensus statement from the Asian Oncology Summit 2009. Lancet Oncol 10(11):1111-8.
Reya, T., S. J. Morrison, M. F. Clarke, and I. L. Weissman. 2001. Stem cells, cancer, and cancer stem cells. Nature 414(6859):105-11.
Rudnick, J. A., and coauthors. 2011. Functional heterogeneity of breast fibroblasts is defined by a prostaglandin secretory phenotype that promotes expansion of cancer-stem like cells. PLoS One 6(9):e24605.
Ryu, M. J., and coauthors. 2013. The green algae Ulva fasciata Delile extract induces apoptotic cell death in human colon cancer cells. In Vitro Cell Dev Biol Anim 49(1):74-81.
Schubert, J., and T. Brabletz. 2011. p53 Spreads out further: suppression of EMT and stemness by activating miR-200c expression. Cell Res 21(5):705-7.
Schwartz, J., G. Shklar, S. Reid, and D. Trickler. 1988. Prevention of experimental oral cancer by extracts of Spirulina-Dunaliella algae. Nutr Cancer 11(2):127-34.
Schwartz, J. L., D. Sloane, and G. Shklar. 1989. Prevention and inhibition of oral cancer in the hamster buccal pouch model associated with carotenoid immune enhancement. Tumour Biol 10(6):297-309.
Shi, X., Y. Zhang, J. Zheng, and J. Pan. 2012. Reactive oxygen species in cancer stem cells. Antioxid Redox Signal 16(11):1215-28.
Shklar, G., and J. Schwartz. 1988. Tumor necrosis factor in experimental cancer regression with alphatocopherol, beta-carotene, canthaxanthin and algae extract. Eur J Cancer Clin Oncol 24(5):839-50.
Solinas, G., G. Germano, A. Mantovani, and P. Allavena. 2009. Tumor-associated macrophages (TAM) as major players of the cancer-related inflammation. J Leukoc Biol 86(5):1065-73.
Stahler, F., and K. Roemer. 1998. Mutant p53 can provoke apoptosis in p53-deficient Hep3B cells with delayed kinetics relative to wild-type p53. Oncogene 17(26):3507-12.
Sun, A. M., and coauthors. 2015. Hepatocarcinoma cell-derived hepatoma-derived growth factor (HDGF) induces regulatory T cells. Cytokine 72(1):31-5.
Suzuki, H. 1986. [Liver function tests: analysis of serum isoenzymes--GOT, LDH, ALP, gamma-GTP and ChE]. Rinsho Byori 34 Spec No 67:51-7.
Takahashi-Yanaga, F., and M. Kahn. 2010. Targeting Wnt signaling: can we safely eradicate cancer stem cells? Clin Cancer Res 16(12):3153-62.
van Malenstein, H., and coauthors. 2013. Long-term exposure to sorafenib of liver cancer cells induces resistance with epithelial-to-mesenchymal transition, increased invasion and risk of rebound growth. Cancer Lett 329(1):74-83.
Vermeil, C., and O. Morin. 1976. [Experimental role of the unicellular algae Prototheca and Chlorella (Chlorellaceae) in anti-cancer immunogenesis (murine BP8 sarcoma)]. C R Seances Soc Biol Fil 170(3):646-9.
Wang, D., and R. N. Dubois. 2010. Eicosanoids and cancer. Nat Rev Cancer 10(3):181-93.
Wang, J., and J. Yi. 2008. Cancer cell killing via ROS: to increase or decrease, that is the question. Cancer Biol Ther 7(12):1875-84.
Waris, G., and H. Ahsan. 2006. Reactive oxygen species: role in the development of cancer and various chronic conditions. J Carcinog 5:14.
Wellner, U., and coauthors. 2009. The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs. Nat Cell Biol 11(12):1487-95.
Xue, M., and coauthors. 2013. Fucoidan inhibited 4T1 mouse breast cancer cell growth in vivo and in vitro via downregulation of Wnt/beta-catenin signaling. Nutr Cancer 65(3):460-8.
Yang, X. R., and coauthors. 2010. High expression levels of putative hepatic stem/progenitor cell biomarkers related to tumour angiogenesis and poor prognosis of hepatocellular carcinoma. Gut 59(7):953-62.
You, H., W. Ding, H. Dang, Y. Jiang, and C. B. Rountree. 2011. c-Met represents a potential therapeutic target for personalized treatment in hepatocellular carcinoma. Hepatology 54(3):879-89.
Zhang, Y., and coauthors. 2013. AML1-ETO mediates hematopoietic self-renewal and leukemogenesis through a COX/beta-catenin signaling pathway. Blood.
Zhao, J., and coauthors. 2013. Anti-HDGF targets cancer and cancer stromal stem cells resistant to chemotherapy. Clin Cancer Res 19(13):3567-76.
Zhu, Z., and coauthors. 2010. Cancer stem/progenitor cells are highly enriched in CD133+CD44+ population in hepatocellular carcinoma. Int J Cancer 126(9):2067-78.
尤柏謙. 2014. 經紋球藻色素分析與蝦紅素之最適化生產條件探討. 中山大學.
儲天輝. 2014. 希樂葆在肝癌的治療效用與機轉. 中山大學.
電子全文 Fulltext
本電子全文僅授權使用者為學術研究之目的,進行個人非營利性質之檢索、閱讀、列印。請遵守中華民國著作權法之相關規定,切勿任意重製、散佈、改作、轉貼、播送,以免觸法。
論文使用權限 Thesis access permission:自定論文開放時間 user define
開放時間 Available:
校內 Campus: 已公開 available
校外 Off-campus: 已公開 available


紙本論文 Printed copies
紙本論文的公開資訊在102學年度以後相對較為完整。如果需要查詢101學年度以前的紙本論文公開資訊,請聯繫圖資處紙本論文服務櫃台。如有不便之處敬請見諒。
開放時間 available 已公開 available

QR Code