本研究旨在探討食物成分對人類肝癌細胞遷移作用的影響。先前的研究指出，粒線體功能失常誘發Amphiregulin（AR）表現及分泌來調節人類肝癌細胞之遷移及化學治療抗性。在此模式下，粒線體功能失常可能透過誘發細胞內過氧化氫的產生及鈣離子移動來調節AR分泌。本研究中，粒線體功能失常被定義為粒線體呼吸鏈之功能異常（像是以ATPase抑制劑oligomycin處理）。首先，本研究探討粒線體功能失常誘發Tumor necrosis factor-alpha converting enzyme（TACE）活化和Interlukin-8（IL-8）分泌，對於調節AR釋放所扮演的角色。隨後，本研究評估食物成分對人類肝癌細胞之粒線體功能失常所誘發之細胞遷移作用並探討可能的機轉。
結果顯示在誘發粒線體功能失常的HepG2細胞中，TACE被活化並呈現時間效應。此外，oligomycin誘發的HepG2細胞TACE活化受IL-8和IL-8RA的特定RNA干擾(specific RNA interferences)而延緩。再者，本研究觀察到粒線體功能失常促進IL-8基因表現和分泌，且在不同分化程度的人類肝癌細胞為共通之現象；包括：分化不良之肝癌細胞（HA22T/VGH和SK-HEP-1）、以及分化良好之肝癌細胞(HepG2, Hep3B和Huh7)。同時，IL-8和AR中和抗體分別抑制粒線體功能失常所誘發的IL-8基因過量表現，推論IL-8與AR的釋放參與粒線體功能失常所誘發的IL-8基因表現調控。綜合以上結果，粒線體功能失常能促進IL-8基因表現與分泌，此外粒線體功能失常可能透過TACE的活化而釋放AR，進而促進人類肝癌細胞遷移行為。
另一方面，預處理綠藻水解物能清除粒線體功能失常所誘發的過氧化氫產生並呈現濃度效應。此外，在HepG2細胞中，綠藻水解物也呈濃度效應抑制粒線體功能失常所誘發之AR釋放，但並不影響IL-8分泌和TACE活化。根據上述結果推測，綠藻水解物可能清除ROS並延緩AR分泌而抑制人類肝癌細胞的遷移作用。

This study aims to investigate the effects of food component on cell migration in human hepatoma cells. Previous studies revealed that mitochondrial dysfunction-induced amphiregulin (AR) upregulation mediates cell migration and chemoresistance in HepG2 cells. Moreover, mitochondrial dysfunction induced intracellular hydrogen peroxide overproduction and calcium mobilization may modulate AR induction in this setting. In this study, the mitochondrial dysfunction was defined as the dysfunction of mitochondrial respiratory chain, such as treatment with the inhititor of ATPase (oligomycin). Firstly, this study investigated the roles of Tumor necrosis factor-alpha converting enzyme (TACE) activation and Interlukin-8 (IL-8) induction in mitochondrial dysfunction-induced AR secretion. Subsequently, this study investigated the effects and mechanisms of food component on mitochondrial dysfunction-induced cell migration in human hepatoma cells.
This study revealed that the activities of TACE were activated by mitochondrial dysfunction in HepG2 cells, in time-dependent manner. Besides, oligomycin-induced TACE activation of HepG2 cells was attenuated by IL-8 and IL-8RA-specific RNA interferences. Furthermore, mitochondrial dysfunction upregulated IL-8 induction and secretion in various types of human hepatoma cell lines, including poorly differentiated cells (HA22T/VGH and SK-Hep-1), and well-differentiated cells (HepG2, Hep3B, and HuH7). Meanwhile, mitochondrial dysfunction-induced IL-8 overexpression was abolished by IL-8 and AR neutralizing antibody, respectively. Together, these findings suggest that mitochondrial dysfunction-induced IL-8 induction, as well as AR upregulation mediates cell migration via TACE activation.
On the other hand, pretreatment of hydrolyzed Chlorella sorokiniana decreased mitochondrial dysfunction-induced hydrogen peroxide (H2O2) production in a concentration-dependent manner. Additionally, hydrolyzed Chlorella sorokiniana concentration-dependently suppressed AR release, but not IL-8 secretion and TACE activation, in HepG2 cells. These findings suggest that hydrolyzed Chlorella sorokiniana may inhibit cell migration by improvement of ROS scavenging and attenuation of AR release in human hepatoma cells.

目次
摘要 …………………………………………………………………...III
Abstract.…………………………………………………………………... V
縮寫表 ………………………………………………………………….VII
目次 ……………………………………………………………………..i
圖次 ……………………………………………………………………iv
表次 ……………………………………………………………………vi
第一章 前言 ……………………………………………………………1
第二章 文獻回顧 3
第一節 癌症惡化十大特徵(The ten hallmarks of cancer) 3
第二節 發炎反應與腫瘤起始步驟(tumor-initiation)及腫瘤惡化(tumor- promotion) 3
第三節 腫瘤微環境(tumor microenvironment) 4
第四節 肝細胞癌 6
一、 肝細胞癌盛行率 6
二、 肝細胞癌病因、病理及治療現況 6
三、 肝細胞癌的基因體研究 7
四、 肝細胞癌的訊息路徑 7
第五節 粒線體與人類肝臟疾病 12
第六節 粒線體功能失常與腫瘤惡化 13
第七節 人類肝癌細胞粒線體功能失常與免疫反應 14
第八節 人類肝癌細胞粒線體功能失常模式: IL-8與TACE調節AR分泌 15
Amphiregulin (AR) 16
IL-8, IL-8RA與IL-8RB 17
Tumor necrosis factor-alpha converting enzyme (TACE) 18
第九節 食物成分對於人類腫瘤之預防效應 19
第十節 海洋來源藥物之開發 20
第十一節 水產來源成分之疾病預防效應 20
第十二節 褐藻之抗腫瘤活性 21
第十三節 綠藻 (Chlorella sorokiniana)保健機能 22
第三章 研究假說與目的 24
第四章 材料與方法 25
第一節 常用儀器設備 25
第二節 藥品 26
第三節 實驗方法 29
一、 綠藻(Chlorella sorokiniana)水解物(CS9PC)製備 29
二、 細胞培養 29
三、 MTT assay 30
四、 錐蟲藍排除法(Trypan blue exclusion assay) 31
五、 細胞遷移試驗Transwell migration assay 33
六、 萃取RNA 33
七、 製備cDNA 34
八、 及時定量PCR (Real-time quantitative PCR) 35
九、 TACE活性分析 36
十、 蛋白質定量 37
十一、 ELISA定量細胞培養液之IL-8及AR 38
十二、 細胞內活性氧分子分析 40
十三、 統計方法 41
第五章 結果 42
第一節 人類肝癌細胞誘發粒線體功能失常之模式 42
第四節 粒線體呼吸鏈抑制劑作用於HepG2細胞之有效濃度 42
第五節 AR分泌調節粒線體功能失常所誘發之細胞遷移 43
第六節 粒線體功能失常促進HepG2細胞IL-8基因表現 43
一、 濃度效應 43
二、 時間效應 44
三、 肝癌細胞分化程度與IL-8基因表現 44
四、 粒線體功能失常促進人類肝癌細胞IL-8分泌 45
第七節 粒線體功能失常促進IL-8與AR分泌而調節IL-8基因轉錄 45
第八節 TACE調節粒線體功能失常誘發之AR釋放 46
一、 粒線體功能失常活化TACE活化 47
二、 時間效應 47
第九節 IL-8及IL-8RA調節粒線體功能失常所活化之TACE 48
第十節 IL-8、IL-8RA及TACE不影響粒線體功能失常所誘發之IL-8分泌 48
第十一節 粒線體功能失常誘發細胞內H2O2過量產生 49
第十二節 綠藻水解物對人類肝癌細胞遷移能力之影響 50
第十三節 綠藻水解物抑制人類肝癌細胞遷移之可能機轉 51
一、 延緩粒線體功能失常誘發之H2O2產生 51
二、 延緩粒線體功能失常誘發之AR分泌 51
第六章 討論 53
一、 人類肝癌細胞株之粒線體功能失常對於IL-8表現之影響………………………………………………………………54
二、 人類肝癌HepG2細胞之粒線體功能失常時促進IL-8分泌、活化TACE而調節AR釋放 56
三、 綠藻水解物對於粒線體功能失常所誘發之肝癌細胞遷移行為之影響 57
第七章 結論 59
參考文獻 60
圖………………………………………………………………………..69

圖次
圖一 研究假說 69
圖二 粒線體呼吸鏈抑制劑對HepG2細胞存活率之影響 70
圖三AR分泌對於人類肝癌細胞之粒線體功能失常所誘發之細胞遷移作用之影響。 71
圖四 人類肝癌細胞株之粒線體功能失常對於IL-8基因表現之影響。分化良好之人類肝癌細胞 72
圖五 HepG2細胞之粒線體功能失常對於IL-8分泌之影響 74
圖六 IL-8及AR對於人類肝癌HepG2細胞之粒線體功能失常所誘發之IL-8基因轉錄之影響 75
圖七 人類肝癌HepG2細胞之粒線體功能失常對TACE活性之影響 76
圖八 IL-8及IL-8RA對於人類肝癌HepG2細胞之粒線體功能失常所活化之TACE活性之影響 77
圖九 TACE, IL-8與IL-8RA對於人類肝癌HepG2細胞之粒線體功能失常所誘發之IL-8分泌之影響 78
圖十 IL-8與IL-8RA對於人類肝癌HepG2細胞之粒線體功能失常所促進之AR釋放之影響 79
圖十一 綠藻水解物(CS9PC)對於人類肝癌HepG2細胞之存活率 80
圖十二 綠藻水解物對於人類肝癌HepG2細胞之粒線體功能失常所產生H2O2之影響 81
圖十三 綠藻水解物對於人類肝癌細胞之粒線體功能失常所誘發之遷移能力之影響 82
圖十四 綠藻水解物對人類肝癌HepG2粒線體功能失常所誘發之AR釋放之影響 84
圖十五 綠藻水解物對人類肝癌HepG2粒線體功能失常所促進之IL-8分泌之影響 85
圖十六 綠藻水解物對人類肝癌HepG2細胞粒線體功能失常所活化之TACE活性之影響 86
圖十七 綠藻水解物抑制人類肝癌細胞遷移可能之機轉 87

表次
表一 人類肝癌細胞粒線體功能失常改變生物訊息及代謝路徑 15

Albini, A., and Sporn, M. B. (2007) The tumour microenvironment as a target for chemoprevention. Nat Rev Cancer 7, 139-147.
Amin, A. R., Kucuk, O., Khuri, F. R., and Shin, D. M. (2009) Perspectives for cancer prevention with natural compounds. J Clin Oncol 27, 2712-2725.
Armstrong, T. D., Pulaski, B. A., and Ostrand-Rosenberg, S. (1998) Tumor antigen presentation: changing the rules. Cancer Immunol Immunother 46, 70-74.
Asai, A., Sugawara, T., Ono, H., and Nagao, A. (2004) Biotransformation of fucoxanthinol into amarouciaxanthin A in mice and HepG2 cells: formation and cytotoxicity of fucoxanthin metabolites. Drug Metab Dispos 32, 205-211.
Avila, M. A., Berasain, C., Sangro, B., and Prieto, J. (2006) New therapies for hepatocellular carcinoma. Oncogene 25, 3866-3884.
Baggiolini, M., Walz, A., and Kunkel, S. L. (1989) Neutrophil-activating peptide-1/interleukin 8, a novel cytokine that activates neutrophils. J Clin Invest 84, 1045-1049.
Bangoura, G., Liu, Z. S., Qian, Q., Jiang, C. Q., Yang, G. F., and Jing, S. (2007) Prognostic significance of HIF-2alpha/EPAS1 expression in hepatocellular carcinoma. World J Gastroenterol 13, 3176-3182.
Berasain, C., Garcia-Trevijano, E. R., Castillo, J., Erroba, E., Santamaria, M., Lee, D. C., Prieto, J., and Avila, M. A. (2005) Novel role for amphiregulin in protection from liver injury. J Biol Chem 280, 19012-19020.
Borish, L. C., and Steinke, J. W. (2003) 2. Cytokines and chemokines. J Allergy Clin Immunol 111, S460-475.
Budhu, A., Forgues, M., Ye, Q. H., Jia, H. L., He, P., Zanetti, K. A., Kammula, U. S., Chen, Y., Qin, L. X., Tang, Z. Y., and Wang, X. W. (2006) Prediction of venous metastases, recurrence, and prognosis in hepatocellular carcinoma based on a unique immune response signature of the liver microenvironment. Cancer Cell 10, 99-111.
Budhu, A., and Wang, X. W. (2006) The role of cytokines in hepatocellular carcinoma. J Leukoc Biol 80, 1197-1213.
Caruso, D. J., Carmack, A. J., Lokeshwar, V. B., Duncan, R. C., Soloway, M. S., and Lokeshwar, B. L. (2008) Osteopontin and interleukin-8 expression is independently associated with prostate cancer recurrence. Clin Cancer Res 14, 4111-4118.
Castillo, J., Erroba, E., Perugorria, M. J., Santamaria, M., Lee, D. C., Prieto, J., Avila, M. A., and Berasain, C. (2006) Amphiregulin contributes to the transformed phenotype of human hepatocellular carcinoma cells. Cancer Res 66, 6129-6138.
Chang, C. J., Yin, P. H., Wang, C. H., Chi, C. W., Wei, Y. H., and Lee, H. C. (2008). Mitochondrial Stress-induced Genes and Pathways Alterations in Human Hepatoma Cell. In The 2008 International Conference on Bioinformatics and Computational Biology 43, 747-755
Chang, C. J., Yin, P. H., Yang, D. M., Wang, C. H., Hung, W. Y., Chi, C. W., Wei, Y. H., and Lee, H. C. (2009) Mitochondrial dysfunction-induced amphiregulin upregulation mediates chemo-resistance and cell migration in HepG2 cells. Cell Mol Life Sci 66, 1755-1765.
Cherng, J. Y., and Shih, M. F. (2005) Preventing dyslipidemia by Chlorella pyrenoidosa in rats and hamsters after chronic high fat diet treatment. Life Sci 76, 3001-3013.
Cherng, J. Y., and Shih, M. F. (2006) Improving glycogenesis in Streptozocin (STZ) diabetic mice after administration of green algae Chlorella. Life Sci 78, 1181-1186.
Chiang, Y. Y., Tsai, M. H., Lin, T. Y., and Chiang, I. P. (2008) Expression profile of metastasis-related genes in invasive oral cancers. Histol Histopathol 23, 1213-1222.
Cuezva, J. M., Krajewska, M., de Heredia, M. L., Krajewski, S., Santamaria, G., Kim, H., Zapata, J. M., Marusawa, H., Chamorro, M., and Reed, J. C. (2002) The bioenergetic signature of cancer: a marker of tumor progression. Cancer Res 62, 6674-6681.
de-Bashan, L. E., Trejo, A., Huss, V. A., Hernandez, J. P., and Bashan, Y. (2008) Chlorella sorokiniana UTEX 2805, a heat and intense, sunlight-tolerant microalga with potential for removing ammonium from wastewater. Bioresour Technol 99, 4980-4989.
Desbaillets, I., Diserens, A. C., Tribolet, N., Hamou, M. F., and Van Meir, E. G. (1997) Upregulation of interleukin 8 by oxygen-deprived cells in glioblastoma suggests a role in leukocyte activation, chemotaxis, and angiogenesis. J Exp Med 186, 1201-1212.
Eckstein, N., Servan, K., Girard, L., Cai, D., von Jonquieres, G., Jaehde, U., Kassack, M. U., Gazdar, A. F., Minna, J. D., and Royer, H. D. (2008) Epidermal growth factor receptor pathway analysis identifies amphiregulin as a key factor for cisplatin resistance of human breast cancer cells. J Biol Chem 283, 739-750.
Feitelson, M. A., Pan, J., and Lian, Z. (2004) Early molecular and genetic determinants of primary liver malignancy. Surg Clin North Am 84, 339-354.
Franovic, A., Robert, I., Smith, K., Kurban, G., Pause, A., Gunaratnam, L., and Lee, S. (2006) Multiple acquired renal carcinoma tumor capabilities abolished upon silencing of ADAM17. Cancer Res 66, 8083-8090.
Gamal-Eldeen, A. M., Ahmed, E. F., and Abo-Zeid, M. A. (2009) In vitro cancer chemopreventive properties of polysaccharide extract from the brown alga, Sargassum latifolium. Food Chem Toxicol 47, 1378-1384.
Glade, M. J. (1999) Food, nutrition, and the prevention of cancer: a global perspective. American Institute for Cancer Research/World Cancer Research Fund, American Institute for Cancer Research, 1997. Nutrition 15, 523-526.
Goueia, L., Batista, A. P., Miranda, A., Empis, J., and Raymundo, A. (2007) Chlorella vulgar is biomass used as colouring source in traditional butter cookies. Food Science 8, 433-436.
Grivennikov, S. I., Greten, F. R., and Karin, M. (2010) Immunity, inflammation, and cancer. Cell 140, 883-899.
Hanahan, D., and Weinberg, R. A. (2000) The hallmarks of cancer. Cell 100, 57-70.
Hanahan, D., and Weinberg, R. A. (2011) Hallmarks of cancer: the next generation. Cell 144, 646-674.
Hu, Q. H., Sheng, J. C., Yu, F., Xin, Z. H., Zhao, L. Y., and Zhu, X. J. (2007) Preparation, identification and their antitumor activities in vitro of polysaccharides from Chlorella pyrenoidosa. Food Chem 105, 533-539.
Huang, A. Y., Golumbek, P., Ahmadzadeh, M., Jaffee, E., Pardoll, D., and Levitsky, H. (1994) Bone marrow-derived cells present MHC class I-restricted tumour antigens in priming of antitumour immune responses. Ciba Found Symp 187, 229-240; discussion 240-224.
Huang, Y. T., Huang, Y. H., Hour, T. C., Pan, B. S., Liu, Y. C., and Pan, M. H. (2006) Apoptosis-inducing active components from Corbicula fluminea through activation of caspase-2 and production of reactive oxygen species in human leukemia HL-60 cells. Food Chem Toxicol 44, 1261-1272.
Hung, W. Y., Wu, C. W., Yin, P. H., Chang, C. J., Li, A. F., Chi, C. W., Wei, Y. H., and Lee, H. C. (2010) Somatic mutations in mitochondrial genome and their potential roles in the progression of human gastric cancer. Biochim Biophys Acta 1800, 264-270.
Huynh, H., Nguyen, T. T., Chow, K. H., Tan, P. H., Soo, K. C., and Tran, E. (2003) Over-expression of the mitogen-activated protein kinase (MAPK) kinase (MEK)-MAPK in hepatocellular carcinoma: its role in tumor progression and apoptosis. BMC Gastroenterol 3, 19.
Ishikawa, N., Daigo, Y., Takano, A., Taniwaki, M., Kato, T., Hayama, S., Murakami, H., Takeshima, Y., Inai, K., Nishimura, H., et al. (2005) Increases of amphiregulin and transforming growth factor-alpha in serum as predictors of poor response to gefitinib among patients with advanced non-small cell lung cancers. Cancer Res 65, 9176-9184.
Johnston, D. S., Su, Y. A., and Alesci, S. (2009) Mitochondrial gene profiling: translational perspectives. Pharmacogenomics 10, 1645-1655.
Kamohara, H., Takahashi, M., Ishiko, T., Ogawa, M., and Baba, H. (2007) Induction of interleukin-8 (CXCL-8) by tumor necrosis factor-alpha and leukemia inhibitory factor in pancreatic carcinoma cells: Impact of CXCL-8 as an autocrine growth factor. Int J Oncol 31, 627-632.
Kennedy, A. S., Nutting, C., Coldwell, D., Gaiser, J., and Drachenberg, C. (2004) Pathologic response and microdosimetry of (90)Y microspheres in man: review of four explanted whole livers. Int J Radiat Oncol Biol Phys 60, 1552-1563.
Kenny, P. A., and Bissell, M. J. (2007) Targeting TACE-dependent EGFR ligand shedding in breast cancer. J Clin Invest 117, 337-345.
Khanavi, M., Nabavi, M., Sadati, N., Shams Ardekani, M., Sohrabipour, J., Nabavi, S. M., Ghaeli, P., and Ostad, S. N. (2010) Cytotoxic activity of some marine brown algae against cancer cell lines. Biol Res 43, 31-37.
Kim, K. J., Li, B., Winer, J., Armanini, M., Gillett, N., Phillips, H. S., and Ferrara, N. (1993) Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 362, 841-844.
Lee, H. C., Li, S. H., Lin, J. C., Wu, C. C., Yeh, D. C., and Wei, Y. H. (2004) Somatic mutations in the D-loop and decrease in the copy number of mitochondrial DNA in human hepatocellular carcinoma. Mutat Res 547, 71-78.
Lee, J. S., and Thorgeirsson, S. S. (2006) Comparative and integrative functional genomics of HCC. Oncogene 25, 3801-3809.
Lee, M., Choi, J. S., Choi, M. J., Pak, Y. K., Rhee, B. D., and Ko, K. S. (2007) DNA delivery to the mitochondria sites using mitochondrial leader peptide conjugated polyethylenimine. J Drug Target 15, 115-122.
Li, X. M., Tang, Z. Y., Zhou, G., Lui, Y. K., and Ye, S. L. (1998) Significance of vascular endothelial growth factor mRNA expression in invasion and metastasis of hepatocellular carcinoma. J Exp Clin Cancer Res 17, 13-17.
Livak, K. J., and Schmittgen, T. D. (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25, 402-408.
Luppi, F., Longo, A. M., de Boer, W. I., Rabe, K. F., and Hiemstra, P. S. (2007) Interleukin-8 stimulates cell proliferation in non-small cell lung cancer through epidermal growth factor receptor transactivation. Lung Cancer 56, 25-33.
Matsumoto, K., and Nakamura, T. (1996) Emerging multipotent aspects of hepatocyte growth factor. J Biochem 119, 591-600.
McGowan, P. M., Ryan, B. M., Hill, A. D., McDermott, E., O'Higgins, N., and Duffy, M. J. (2007) ADAM-17 expression in breast cancer correlates with variables of tumor progression. Clin Cancer Res 13, 2335-2343.
Midorikawa, Y., Makuuchi, M., Tang, W., and Aburatani, H. (2007) Microarray-based analysis for hepatocellular carcinoma: from gene expression profiling to new challenges. World J Gastroenterol 13, 1487-1492.
Molinski, T. F., Dalisay, D. S., Lievens, S. L., and Saludes, J. P. (2009) Drug development from marine natural products. Nat Rev Drug Discov 8, 69-85.
Nakano, S., Noguchi, T., Takekoshi, H., Suzuki, G., and Nakano, M. (2005) Maternal-fetal distribution and transfer of dioxins in pregnant women in Japan, and attempts to reduce maternal transfer with Chlorella (Chlorella pyrenoidosa) supplements. Chemosphere 61, 1244-1255.
Nalpas, B., Feitelson, M., Brechot, C., and Rubin, E. (1995) Alcohol, hepatotropic viruses, and hepatocellular carcinoma. Alcohol Clin Exp Res 19, 1089-1095.
Nishida, H., Omori, M., Fukutomi, Y., Ninomiya, M., Nishiwaki, S., Suganuma, M., Moriwaki, H., and Muto, Y. (1994) Inhibitory effects of (-)-epigallocatechin gallate on spontaneous hepatoma in C3H/HeNCrj mice and human hepatoma-derived PLC/PRF/5 cells. Jpn J Cancer Res 85, 221-225.
Ohtsu, A. (2006) [Japanese nationwide post-marketing survey of S-1 in patients with advanced gastric cancer]. Gan To Kagaku Ryoho 33 Suppl 1, 52-56.
Ohtsu, H., Dempsey, P. J., and Eguchi, S. (2006) ADAMs as mediators of EGF receptor transactivation by G protein-coupled receptors. Am J Physiol Cell Physiol 291, C1-10.
Okochi, O., Hibi, K., Uemura, T., Inoue, S., Takeda, S., Kaneko, T., and Nakao, A. (2002) Detection of mitochondrial DNA alterations in the serum of hepatocellular carcinoma patients. Clin Cancer Res 8, 2875-2878.
Petros, J. A., Baumann, A. K., Ruiz-Pesini, E., Amin, M. B., Sun, C. Q., Hall, J., Lim, S., Issa, M. M., Flanders, W. D., Hosseini, S. H., et al. (2005) mtDNA mutations increase tumorigenicity in prostate cancer. Proc Natl Acad Sci U S A 102, 719-724.
Piepkorn, M., Pittelkow, M. R., and Cook, P. W. (1998) Autocrine regulation of keratinocytes: the emerging role of heparin-binding, epidermal growth factor-related growth factors. J Invest Dermatol 111, 715-721.
Qian, H., Yang, Y., and Wang, X. (2011) Curcumin enhanced adriamycin-induced human liver-derived Hepatoma G2 cell death through activation of mitochondria-mediated apoptosis and autophagy. Eur J Pharm Sci 43, 125-131.
Ren, Y., Poon, R. T., Tsui, H. T., Chen, W. H., Li, Z., Lau, C., Yu, W. C., and Fan, S. T. (2003) Interleukin-8 serum levels in patients with hepatocellular carcinoma: correlations with clinicopathological features and prognosis. Clin Cancer Res 9, 5996-6001.
Roberts, L. R., and Gores, G. J. (2005) Hepatocellular carcinoma: molecular pathways and new therapeutic targets. Semin Liver Dis 25, 212-225.
Russ Mason, M. S. (2001) Chlorella and Spirulina. Green Supplements for Balancing the Body. Alternative and Complementary therapy, 161-165.
Schraufstatter, I. U., Trieu, K., Zhao, M., Rose, D. M., Terkeltaub, R. A., and Burger, M. (2003) IL-8-mediated cell migration in endothelial cells depends on cathepsin B activity and transactivation of the epidermal growth factor receptor. J Immunol 171, 6714-6722.
Seilles, E., Rossel, M., Vuitton, D. A., Mercier, M., Njoya, O., Capron, J. P., Nalpas, B., Gibey, R., and Revillard, J. P. (1995) Serum secretory IgA and secretory component in patients with non-cirrhotic alcoholic liver diseases. J Hepatol 22, 278-285.
Seruga, B., Zhang, H., Bernstein, L. J., and Tannock, I. F. (2008) Cytokines and their relationship to the symptoms and outcome of cancer. Nat Rev Cancer 8, 887-899.
Serviddio, G., Bellanti, F., Sastre, J., Vendemiale, G., and Altomare, E. (2010) Targeting Mitochondria: A New Promising Approach for the Treatment of Liver Diseases. Curr Med Chem.
Sheih, I. C., Wu, T. K., and Fang, T. J. (2009) Antioxidant properties of a new antioxidative peptide from algae protein waste hydrolysate in different oxidation systems. Bioresour Technol 100, 3419-3425.
Sheu, J. H., Chang, K. C., and Duh, C. Y. (2000) A cytotoxic 5alpha,8alpha-epidioxysterol from a soft coral Sinularia species. J Nat Prod 63, 149-151.
Shidara, Y., Yamagata, K., Kanamori, T., Nakano, K., Kwong, J. Q., Manfredi, G., Oda, H., and Ohta, S. (2005) Positive contribution of pathogenic mutations in the mitochondrial genome to the promotion of cancer by prevention from apoptosis. Cancer Res 65, 1655-1663.
Stewart, T. J., and Abrams, S. I. (2008) How tumours escape mass destruction. Oncogene 27, 5894-5903.
Suetsuna, K., and Chen, J. R. (2001) Identification of antihypertensive peptides from peptic digest of two microalgae, Chlorella vulgaris and Spirulina platensis. Mar Biotechnol (NY) 3, 305-309.
Takekoshi, H., Suzuki, G., Chubachi, H., and Nakano, M. (2005) Effect of Chlorella pyrenoidosa on fecal excretion and liver accumulation of polychlorinated dibenzo-p-dioxin in mice. Chemosphere 59, 297-304.
Tamori, A., Nishiguchi, S., Nishikawa, M., Kubo, S., Koh, N., Hirohashi, K., Shiomi, S., and Inoue, M. (2004) Correlation between clinical characteristics and mitochondrial D-loop DNA mutations in hepatocellular carcinoma. J Gastroenterol 39, 1063-1068.
Wallace, D. C. (2005) A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu Rev Genet 39, 359-407.
Wanebo, H. J., and Vezeridis, M. P. (1993) Hepatoma. J Surg Oncol Suppl 3, 40-45.
Waugh, D. J., and Wilson, C. (2008) The interleukin-8 pathway in cancer. Clin Cancer Res 14, 6735-6741.
Whittaker, S., Marais, R., and Zhu, A. X. (2010) The role of signaling pathways in the development and treatment of hepatocellular carcinoma. Oncogene 29, 4989-5005.
WHO (2004). Global cancer mortality. In.
Wu, Y., Brodt, P., Sun, H., Mejia, W., Novosyadlyy, R., Nunez, N., Chen, X., Mendoza, A., Hong, S. H., Khanna, C., and Yakar, S. (2010) Insulin-like growth factor-I regulates the liver microenvironment in obese mice and promotes liver metastasis. Cancer Res 70, 57-67.
Xie, K. (2001) Interleukin-8 and human cancer biology. Cytokine Growth Factor Rev 12, 375-391.
Yamada, S., Nomoto, S., Fujii, T., Kaneko, T., Takeda, S., Inoue, S., Kanazumi, N., and Nakao, A. (2006) Correlation between copy number of mitochondrial DNA and clinico-pathologic parameters of hepatocellular carcinoma. Eur J Surg Oncol 32, 303-307.
Yin, P. H., Lee, H. C., Chau, G. Y., Wu, Y. T., Li, S. H., Lui, W. Y., Wei, Y. H., Liu, T. Y., and Chi, C. W. (2004) Alteration of the copy number and deletion of mitochondrial DNA in human hepatocellular carcinoma. Br J Cancer 90, 2390-2396.
行政院衛生署 (2010). 死因統計結果分析. In.
連美智 (2011) 綠藻發酵水解物降低高血壓的生理效果. 國立臺灣海洋大學食品科學研究所碩士論文.
陳麗婷及陳淑芳 (2010) 2009年全球前三大之臺灣產業產品專刊。. 經濟部 技術處 IT IS 計畫.
潘敏雄 (1995) 文蛤萃取物抗人體肝癌細胞因子的純化與特性研究. 國立臺灣海洋大學水產食品研究所碩士論文.
蔡政融 (2009). 海藻機能性脂質之鑑定及應用. In 江南大學與臺灣海洋大學食品科技博士生論壇.