跳到主要內容

臺灣博碩士論文加值系統

(3.236.84.188) 您好!臺灣時間:2021/08/03 09:12
字體大小: 字級放大   字級縮小   預設字形  
回查詢結果 :::

詳目顯示

我願授權國圖
: 
twitterline
研究生:翁家瑞
研究生(外文):Chia-Jui Weng
論文名稱:以細胞及動物模式探討靈芝及其活性成分對人類肝癌細胞侵入與轉移抑制功效及作用機制
論文名稱(外文):Inhibition and mechanism of the invasion and metastasis in human hepatoma cells by Ganoderma lucidum and its bioactive components in cells and animal models
指導教授:周志輝顏國欽顏國欽引用關係
學位類別:博士
校院名稱:國立中興大學
系所名稱:食品暨應用生物科技學系
學門:醫藥衛生學門
學類:營養學類
論文種類:學術論文
畢業學年度:96
語文別:中文
論文頁數:212
中文關鍵詞:靈芝侵入赤芝酸訊息蛋白轉移基質金屬蛋白酶-9免疫不全裸鼠
外文關鍵詞:Ganoderma luciduminvasionlucidenic acidMAPKmetastasisMMP-9SCID nude mice
相關次數:
  • 被引用被引用:1
  • 點閱點閱:531
  • 評分評分:
  • 下載下載:0
  • 收藏至我的研究室書目清單書目收藏:0
靈芝 (Ganoderma lucidum) 是一種具有多種藥理效果的食用性菇蕈類,已被廣泛使用於維持健康與長壽的用途,並用來預防或治療肝臟疾病以及降低癌細胞的侵入與轉移。縱然靈芝的水/酒精萃取物已知具有效抗癌細胞轉移活性,但對於抑制人類肝細胞癌 (hepatocellular carcinoma, HCC) 的侵入性、作用機制與活性成分仍未十分清楚。因此,本研究由一株本土靈芝 (G. lucidum YK-02) 中製備靈芝萃取物 (G. lucidum extract, GLE),並分離出赤芝酸 (lucidenic acid) A, B, C 與 N 等三萜類 (triterpenoid) 成分,主要探討靈芝萃取物對人類肝癌細胞侵入性與轉移性之抑制效應與分子機制,並確認赤芝酸為抗侵入性活性成分。研究內容共分四大部分:(一) G. lucidum YK-02 靈芝萃取物對肝癌細胞侵入性抑制功效之評估,(二) G. lucidum YK-02 靈芝萃取物在免疫不全裸鼠模式中對肝癌細胞生長與轉移之抑制功效, (三) G. lucidum YK-02 靈芝中赤芝酸抗氧化力與抑制肝癌細胞侵入性效應評估,(四) 靈芝赤芝酸透過調控 MAPK/ERK 訊息路徑,降低 NF-kB 及 AP-1 對 DNA 結合活性,抑制 PMA 誘發肝癌細胞侵入性。
研究結果顯示:(一) 此靈芝萃取物對 PMA (phorbol-12-myristate-13-acetate) 誘發的肝癌細胞侵入性與基質金屬蛋白酶 (matrix metalloproteinase, MMP)-9 活性表現的抑制作用,是藉由抑制訊息路徑中 ERK1/2 (extracellular signal-regulated kinase) 與 Akt (protein kinase B) 發生磷酸化,使其維持在不活性化狀態,進而促使HepG2 細胞核內轉錄因子AP-1 (activator protein-1) 及 NF-kB (nuclear factor-kappa B) 的含量下降所導致的結果。可見該靈芝萃取物對肝癌細胞侵入性具有效抑制效能。(二) 為驗證此靈芝萃取物抑制體內肝癌生長或轉移的實際功效,本研究採用 T 細胞免疫不全裸鼠為實驗動物,以皮下接種與尾靜脈注射 HepG2 細胞作為肝癌細胞生長與轉移的體內模式。結果發現,裸鼠每日管灌 200 mg/kg b.w. 以上劑量之靈芝萃取物,對裸鼠皮下肝癌細胞的生長具有顯著抑制作用;而管灌 50 mg/kg b.w. 以上劑量之靈芝萃取物,亦可有效降低裸鼠體內肝癌細胞之轉移程度。另外,經管灌靈芝萃取物之裸鼠,其血液樣品與腫瘤組織中基質金屬蛋白酶-9 活性與表現量亦有明顯下降趨勢,可見管灌靈芝萃取物對抑制裸鼠體內肝癌細胞轉移與基質金屬蛋白酶-9 的活性及表現量有關。由此動物模式驗證此靈芝萃取物的攝取確實可降低裸鼠體內基質金屬蛋白酶-9 的活性及表現量,並進而具有抑制腫瘤生長與轉移之功效。(三)目前靈芝所具備的藥理與保健功效,雖然多半認定是多醣體或三萜類化合物多種混合成分的共同作用所致,但靈芝萃取物中所含抑制癌細胞侵入與轉移的活性成分之相關試驗資料仍相當有限。靈芝中的三萜類成分在各種體內或體外試驗模式中驗證,具有抗癌、抗腫瘤及抗轉移功效,因此本研究推論,靈芝三萜類成分之ㄧ的赤芝酸可能與抑制肝癌細胞的侵入與轉移有關。為釐清該靈芝萃取物與傳統靈芝萃取物成分上的不同,以及探討其抗侵入性之活性成分,本研究以半製備逆向高效液相層析技術 (reverse-phase HPLC),由該靈芝萃取物中分離出赤芝酸 A, B, C 與 N 等四種三萜類成分,且其含量比傳統靈芝高達十倍左右。經試驗後發現,赤芝酸 A, B, C 與 N 對 HepG2 細胞經 PMA 誘發之侵入性皆具有抑制效應,可見赤芝酸應為抗侵入性之有效活性成分,其中以赤芝酸 B 作用較為顯著。然而,這種抑制作用卻不與赤芝酸的抗氧化力成正相關。(四) 最後經由赤芝酸 B 對細胞抗侵入性作用機制的探討,並與靈芝萃取物相互比較,發現兩者抑制肝癌細胞侵入性的功效都是透過抑制 ERK1/2 蛋白磷酸化發生,並且降低 AP-1 及 NF-kB 對 DNA 的結合活性,進而降低基質金屬蛋白酶-9 表現量所致。
本研究經由體外細胞模式及體內動物模式的驗證,除證明 G. lucidum YK-02為富含赤芝酸之靈芝,其萃取物具有抗腫瘤生長與轉移之功效外,更發現赤芝酸可能是靈芝中預防肝癌細胞侵入發生的有效活性成分。本研究的完成除使靈芝的保健與藥理效能更加清楚外,亦可提供業界未來開發靈芝相關保健產品之參考。
Ganoderma lucidum is a well-known edible mushroom with various pharmacological effects for health and longevity purposes as well as for reducing the likelihood of invasion and metastasis. Although aqueous/ethanol extract of G. lucidum possessed potential anti-invasive activity, but little is known regarding the anti-invasive bioactive component and underlying mechanisms of G. lucidum extract (GLE) on hepatocellular carcinoma (HCC). In this study, we first prepared the extract from the fruiting body of a strain of G. lucidum (YK-02). Four triterpenoid components, including lucidenic acid A, B, C and N, in an ethanol extract of G. lucidum YK-02 were separated by means of a semi-preparative reverse-phase HPLC. The anti-invasive and anti-metastatic effects and underlying mechanisms of GLE on HCC as well as the bioactive component in GLE were investigated by in vitro and in vivo models. There were four topics in this study: (1) the anti-invasive effect of G. lucidum YK-02 extract on human hepatoma cells; (2) inhibitory effect of GLE on human hepatoma cells growth and metastasis in immunodeficient nude mice model; (3) anti-invasive and antioxidant effects of lucidenic acids isolated from G. lucidum YK-02; (4) lucidenic acid inhibits PMA-induced invasion of human hepatoma cells through inactivating MAPK/ERK signal transduction pathway and reducing binding activities of NF-kB and AP-1.
Our studies have revealed the following findings: (1) The data of Western blots with cell lysates and nuclear extracts indicated that the GLE inhibited the phorbol-12-myristate-13-acetate (PMA)-induced invasion and matrix metalloproteinase (MMP)-9 expression through inactivating the phosphorylation of extracellular signal-regulated kinase (ERK1/2) and protein kinase B (Akt) as well as reducing activator protein-1 (AP-1) and nuclear factor-kappa B (NF-kB) in nucleus of HepG2 cells. Our findings suggested that the GLE was a potential anti-invasion agent on HCC. (2) To further determine the in vivo efficacy of GLE in treating cancer, T cells immune deficient nude mice implanted with HepG2 cells by subcutaneous and tail vein injections were used as the in vivo model for the anti-growth and anti-metastasis evaluations of GLE on HCC. The growth of subcutaneous tumor was inhibited by daily oral administration of GLE at a dosage higher than 200 mg/kg b.w. The metastasis of tumor was also decreased by daily oral administration of GLE at a dosage higher than 50 mg/kg b.w. In addition, we further discovered that the MMP-9 activity and expression in serum and tumor tissue of nude mice were also decreased by oral administration of GLE. According to the results of this in vivo test, it was demonstrated that the efficacy of GLE on anti-growth and anti-metastasis might be through suppressing the MMP-9 activity and expression in animal. (3) Fungal triterpenoids were found to be one of the biologically active compounds responsible for the pharmaceutical effects of Ganoderma. Nevertheless, the individual bioactive component of triterpenoids corresponding to the anti-invasive effects is unclear. To distinguish the differences of composition between the G. lucidum YK-02 and common G. lucidum strain as well as to find out the anti-invasive bioactive component, the triterpenoid components in an ethanol extract of G. lucidum YK-02 were separated by means of a semi-preparative reverse-phase HPLC. Four triterpenoid components, including lucidenic acids A, B, C and N were isolated and the content of lucidenic acids in G. lucidum YK-02 were ten times higher than those of the common G. lucidum. We further found that the treatments with the lucidenic acids A, B, C and N in the presence of PMA resulted in significant inhibitory effects on PMA-induced invasion of HepG2 cells. Lucidenic acid B was found to have the most significant inhibitory effect. According to the results, the lucidenic acids might be the major anti-invasive bioactive component on HCC. However, the anti-invasive effect of lucidenic acids is not correlated to their antioxidant activity. Moreover, (4) the mechanism underlying the anti-invasive effects of GLE and lucidenic acids on the PMA-induced HepG2 cells both might be through inhibiting the phosphorylation of ERK1/2 and reducing AP-1 and NF-kB DNA binding activities, leading to down-regulation of MMP-9 expression.
In this study, the anti-growth and anti-metastasis activities of GLE were demonstrated via the in vitro cells and in vivo animal models. It was known that G. lucidum YK-02 is a strain of G. lucidum with high content of lucidenic acids. We have demonstrated that the lucidenic acids might be the major bioactive components of anti-invasion in G. lucidum YK-02. The results might provide information for the anti-metastatic effects of lingzhi on hepatoma cells and for the application of GLE in the development of high-value health food.
全文摘要 (中) ……………………………………………………… I
全文摘要 (英) ……………………………………………………… V
前言…………………………………………………………………. 1
研究架構……………………………………………………………. 4
第一章 文獻整理…………………………………………………... 5
壹、 肝細胞癌的危害與成因…………………………………… 7
貳、 腫瘤轉移與侵入的危害與過程………………………….... 17
參、 基質金屬蛋白酶分類及與腫瘤轉移之關聯性………….... 22
肆、 基質金屬蛋白酶活性與基因表現之調控……………….... 28
伍、 靈芝簡介…………………………………………………… 35
陸、 人類肝癌細胞的種類與特性……………………………… 45
柒、 實驗動物模式簡介………………………………………… 47
捌、 研究目的…………………………………………………… 53
第二章 Ganoderma lucidum YK-02 靈芝萃取物對肝癌細胞侵入
性抑制功效之評估………………………….……………. 55
中文摘要…………………………………………………………. 56
英文摘要…………………………………………………………. 57
壹、 前言………………………………………………………… 58
貳、 材料與方法………………………………………………… 60
參、 結果………………………………………………………… 69
肆、 討論………………………………………………………… 73
第三章 Ganoderma lucidum YK-02 靈芝萃取物在免疫不全裸鼠
模式中對肝癌細胞生長與轉移之抑制功效…….……….. 87
中文摘要…………………………………………………………. 88
英文摘要………………………………………………………… 90
壹、 前言……………………………………………………….. 92
貳、 材料與方法……………………………………………….. 95
參、 結果……………………………………………………….. 102
肆、 討論……………………………………………………….. 107
第四章 Ganoderma lucidum YK-02 靈芝中赤芝酸分離及其抗
氧化力與抑制肝癌細胞侵入性效應評估.………..….…. 127
中文摘要………………………………………………………... 128
英文摘要………………………………………………………... 129
壹、 前言………………………………………………………. 130
貳、 材料與方法………………………………………………. 133
參、 結果………………………………………………………. 141
肆、 討論………………………………………………………. 146
第五章 靈芝赤芝酸透過調控 MAPK/ERK 訊息路徑降低NF-kB
及AP-1對 DNA 結合活性抑制 PMA 誘發肝癌細胞
侵入性…………………………………………………… 159
中文摘要………………………………………………………... 160
英文摘要………………………………………………………... 162
壹、 前言………………………………………………………. 164
貳、 材料與方法………………………………………………. 167
參、 結果………………………………………………………. 175
肆、 討論………………………………………………………. 179
第六章 總結論…………………………………………………… 193
第七章 參考文獻………………………………………………… 195
一、中文部份
台灣地區 2007 年主要死因統計 (2008)。2008 年 6 月 2 日,取自:行政院衛生署衛生統計資訊網,http://www.doh.gov.tw。
肝癌 (2007)。2008 年 6 月 2 日,取自:陶聲洋防癌基金會網頁,http://www.sydao.org.tw
陳定信、賴明陽、陳健弘 (1991)。肝細胞癌-台灣三十年的經驗。行政院衛生署八十年度委託研究計畫研究報告。2008 年 6 月 2 日,取自:http://fma.mc.ntu.edu.tw
梁善居 (2003)。人類疾病之動物模式。後基因體時代之生物技術 (黃木秋編輯),第九章。醫藥基因生物技術教學資源中心。
梁嘉德 (2005)。台灣癌症死因首位-肝癌。肝病防治會刊,29 期。2008年 6 月 2 日,取自:https://www.liver.org.tw。
梁鍾鼎 (1993)。實驗動物模式。國家實驗動物繁殖及研究中心簡訊,1: 9-10。
二、英文部分
Abiru, S., Nakao, K., Ichikawa, T., Migita, K., Shigeno, M., Sakamoto, M., Ishikawa, H., Hamasaki, K., Nakata, K. and Eguchi, K. (2002) Aspirin and NS-398 inhibit hepatocyte growth factor-induced invasiveness of human hepatoma cells. Hepatology 35: 1117–1124.
Aguirre G. J. A., Alonso, D. F., Farias, E. F., Gomez, D. E. and de Kier Joffe, E. B. (1999) Deregulation of the signaling pathways controlling urokinase production. Its relationship with the invasive phenotype. Eur. J. Biochem. 263: 295–304.
Ahmad, S. (1995) Oxidative Stress and Antioxidant Defenses in Biology. Chapman and Hall, New York 62–88.
Ain, J. F., Gouillat, C., Bertrand, S., Fourel, I., Guillaud, M., Saguier, G., et al. (1994) Human hepatocellular carcinoma transplanted in nude mice: a relevant experimental model to assess tumoral destruction by alcoholization. J. Surg. Res. 57: 366–372.
Akihisa, T., Tokuda, H., Ichiishi, E., Mukainaka, T., Toriumi, M., Ukiya, M., Yasukawa, K. and Nishino, H. (2001) Anti-tumor promoting effects of multiflorane-type triterpenoids and cytotoxic activity of karounidiol against human cancer cell lines. Cancer Lett. 173: 9–14.
Akool, e., Kleinert, H., Hamada, F. M., Abdelwahab, M. H., Forstermann, U., Pfeilschifter, J. and Eberhardt, W. (2003) Nitric oxide increases the decay of matrix metalloproteinase 9 mRNA by inhibiting the expression of mRNA stabilizing factor HuR. Mol. Cell Biol. 23: 4901–4916.
Anonymous (2002) Cancer incidence in five continents. volume VIII. IARC Sci. Publ. 155: 1-781.
Arora, D. (1986) Mushrooms demystified, 2nd edition. Ten Speed Press.
Baeuerle, P. A. and Baltimore, D. (1996) NF-kappa B: ten years after. Cell 87: 13–20.
Baeuerle, P. A. and Henkel, T. (1994) Function and activation of NF-kappa B in the immune system. Annu. Rev. Immunol. 12: 141–179.
Bahassi el, M., Karyala, S., Tomlinson, C. R., Sartor, M. A., Medvedovic, M. and Hennigan, R. F. (2004) Critical regulation of genes for tumor cell migration by AP-1. Clin. Exp. Metastasis 21: 293–304.
Barnes, P. J. (1997) Nuclear factor-kappa B. Int. J. Biochem. Cell Biol. 29: 867–870.
Baricos, W. H., Cortez, S., El-Dahr, L. S. S. and Schnaper, H. W. (1995) ECM degradation by cultured human mesangial cells is mediated by a PA/plasmin/MMP-2 cascade. Kidney Int. 47: 1039–1047.
Basset, P., Okada, A., Chenard, M. P., Kannan, R., Stoll, I., Anglard, P., Bellocq, J. P. and Rio, M. C. (1997) Matrix metalloproteinases as stromal effectors of human carcinoma progression: therapeutic implications. Matrix Biol. 15: 535–541.
Benbow, U., Schoenermark, M. P., Mitchell, T. I., Rutter, J. L., Shimokawa, K., Nagase, H. and Brinckerhoff, C. E. (1999) A novel host/tumor cell interaction activates matrix metalloproteinases 1 and mediates invasion through type I collagen. J. Biol. Chem. 274: 25371–25378.
Berg, R. V. D., Haenen, G. R. M. M., Berg, H. V. D. and Bast, A. (1999) Applicability of an improved Trolox equivalent antioxidant capacity (TEAC) assay for evaluation of antioxidant capacity measurements of mixtures. Food Chem. 66: 511–517.
Bogenmann, E. (1996) A metastatic neuroblastoma model in SCID mice. Int. J. Cancer 67: 379-385.
Bracke, M. E., Van Roy, F. M. and Mareel, M. M. (1996) The E-cadherin/catenin complex in invasion and metastasis. Curr. Top. Microbio. Immunol. 213: 123-161.
Bradford, M. M. (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem. 72: 248-254.
Bremnes, R. M., Veve, R., Hirsch, F. R. and Franklin, W. A. (2002) The E-cadherin cell-cell adhesion complex and lung cancer invasion, metastasis, and prognosis. Lung Cance. 36: 115-124.
Bressac, B., Galvin, K. M., Liang, T. J., Isselbacher, K. J., Wands, J. R. and Ozturk, M. (1990) Abnormal Structure and Expression of p53 Gene in Human Hepatocellular Carcinoma. Proc. Natl. Acad. Sci. USA 87: 1973-1977.
Bruix, J., Sherman, M., Llovet, J. M., Beaugrand, M., Lencioni, R., Burroughs, A. K., Christensen, E., Pagliaro, L., Colombo, M., Rodes, J. and EASL Panel of Experts on HCC. (2001) Clinical management of hepatocellular carcinoma. conclusions of the barcelona-2000 EASL conference. european association for the study of the liver. J. Hepatol. 35: 421-430.
Cao, G., Sofic, E. and Prior, R. L. (1993) Antioxidant and pro-oxidant behavior of flavonoids: structure-activity relationships. Free Radical Biol. Med. 22: 749–760.
Chen, F., Castranova, V. and Shi, X. (2001) New insights into the role of nuclear factor-kappaB in cell growth regulation. Am. J. Pathol. 159: 387–397.
Chen, Y. J., Chen, P. H., Lin, S. Y. and Chang, J. G. (1999) Analysis of aberrant transcription of TSG101 in heptocellular carcinomas. Eur. J. Cancer 35: 302–308.
Chen, P. N., Kuo, W. H., Chiang, C. L., Chiou, H. L., Hsieh, Y. S. and Chu, S. C. (2006) Black rice anthocyanins inhibit cancer cells invasion via repressions of MMPs and u-PA expression. Chem Biol Interact. 163: 218–29.
Chen, D. H., Shiou, W. Y., Wang, K. C., Huang, S. Y., Shie, Y. T., Tsai, C. M., Shie, J. F. and Chen, K. D. (1999) Chemotaxonomy of Triterpenoid pattern of HPLC of Ganoderma lucidum and Ganoderma tsugae. J. Chin. Chem. Soc. 46: 47–51.
Chen, D. S., Sung, J. L., Lai, M. Y., et al. (1990) Hepatitis C virus infection in an area hyperendemic for hepatitis B and chronic liver disease. The Taiwan experience. J. infect. Dis. 162: 817-822.
Cheng, J. C., Chou, C H., Kuo, M. L. and Hsieh, C. Y. (2006) Radiation-enhanced hepatocellular carcinoma cell invasion with MMP-9 expression through PI3K/Akt/NF-kappaB signal transduction pathway. Oncogene 25: 7009-7018.
Cheung, W. M. W., Hui, W. S., Chu, P. W. K., Chiu, S. W. and Ip, N. Y. (2000). Ganoderma extract activates MAP kinases and induces the neuronal differentiation of rat heochromocytoma PC12 cells. FEBS Lett 486: 291–296.
Chu, S. C., Chiou, H. L., Chen, P. N., Yang, S. F. and Hsieh, Y. S. (2004) Silibinin inhibits the invasion of human lung cancer cells via decreased productions of urokinase-plasminogen activator and matrix metalloproteinase-2. Mol. Carcinog. 40: 143-149.
Chung, T. W., Lee, Y. C., Ko, J. H. and Kim, C. H. (2003) Hepatitis B virus X protein modulates the expression of PTEN by inhibiting the function of p53, a transcriptional activator in liver cells. Cancer Res. 63: 3453–3458.
Chung, T. W., Moon, S. K., Chang, Y. C., Ko, J. H., Lee, Y. C., Cho, G., Kim, S. H., Kim, J. G. and Kim, C. H. (2004) Novel and therapeutic effect of caffeic acid and caffeic acid phenyl ester on hepatocarcinoma cells: complete regression of hepatoma growth and metastasis by dual mechanism. FASEB J. 18: 1670-1681.
Chung, T. W., Moon, S. K., Lee, Y. C., Kim, J. G., Ko, J. J. and Kim, C. H. (2002) Enhanced expression of matrix metalloproteinase-9 by hepatitis B virus infection in liver cells. Arch. Biochem. Biophys. 408: 147–154.
Chung, W. T., Lee, S. H., Kim, J. D., Park, Y. S., Hwang, B., Lee, S. Y. and Lee, H. Y. (2001). Effect of mycelial culture broth of Ganoderma lucidum on the growth characteristics of human cell lines. J. Biosci. Bioeng. 92: 550–555.
Clarke, R. (1996) Human breast cancer cell line xenografts as models of breast cancer. The immunobiologies of recipient mice and the characteristics of several tumorigenic cell lines. Breast Cancer Res. Treat 39: 69-86.
Condeelis, J. and Segall, J. E. (2003) Intravital imaging of cell movement in tumours. Nat. Rev. Cancer 3: 921–930.
Constance, E. B. and Lynn, M. M. (2002) Matrix metalloproteinases: a tail of a frog that became a prince. Nature 3: 207-214.
Cottone, M., Turri, M., Caltagirone, M., Parisi, P., Orlando, A., Fiorentino, G., Virdone, R., Fusco, G., Grasso, R. and Simonetti, R. G. (1994) Screening for hepatocellular carcinoma in patients with child''s A cirrhosis: An 8-year prospective study by ultrasound and alphafetoprotein. J. Hepatol. 21: 1029-1034.
Desdouets, C., Fabre, M., Gauthier, F., Brechot, C. and Sobczak-Thepot, J. (1995) Proliferation and differentiation of a human hepatoblastoma transplanted in the Nude mouse. J. Hepatol. 23: 569–577.
Eberhardt, W., Akool, E., Rebhan, J., Frank, S., Beck, K. F., Franzen, R., Hamada, F. M. and Pfeilschifter, J. (2002) Inhibition of cytokine-induced matrix metallo-proteinase 9 expression by peroxisome proliferator-activated receptor alpha agonists is indirect and due to a NO-mediated reduction of mRNA stability. J. Biol. Chem. 277: 33518–33528.
Eferl, R. and Wagner, E. F. (2003) AP-1: a double-edged sword in tumorigenesis. Nat. Rev. Cancer 3: 859–868.
Ehrlich, K.C. and Cotty, P. J. (2002) Variability in nitrogen regulation of aflatoxin production by aspergillus flavus strains. Appl. Microbiol. Biotechnol. 60: 174-178.
Eitan, S. and Michael, K. (2002) AP-1 as a regulator of cell life & death. Nature Cell Biol. 4: E131–E136.
El-Serag, H.B. and Rudolph, K. L. (2007) Hepatocellular carcinoma: Epidemiology and molecular carcinogenesis. Gastroenterology 132: 2557-2576.
Fidler, I. J. (2001) Angiogenic heterogeneity:regulation of neoplastic angiogenesis by the organ microenviroment. J. Natl. Cancer Inst. 93: 1040-1041.
Fidler, I. J. and Nicolson, G. L. (1976) Organ selectivity for implantation survival and growth of B16 melanoma variant tumor lines. J. Natl Cancer Inst. 57: 1199-1202.
Folgueras, A. R., Pendas, A. M., Sanchez, L. M. and Lopez-Otin, C. (2004) Matrix metalloproteinases in cancer: from new functions to improved inhibition strategies. Int. J. Dev. Biol. 48: 411-424.
Fraga, C. G., Shigenaga, M. K., Park, J. W., Degan, P. and Ames, B. N. (1990) Oxidative damage to DNA during aging: 8-hydroxy-2 deoxyguanosine in rat organ DNA and urine. Proc. Natl. Acad. Sci. 87: 4533-4537.
Fuchs, J., Gratz, K. F., Habild, G., Gielow, P., von Schweinitz, D. and Baum, R. P. (1993) Immunoscintigraphy of xenotransplanted hepatoblastoma with iodine 131-labeled anti-alpha-fetoprotein monoclonal antibody. J. Pediatr. Surg. 34: 1378–1384.
Fuchs, J., Schmidt, D., Pietsch, T., Miller, K. and von Schweinitz, D. (1996) Successful transplantation of human hepatoblastoma into immunodeficient mice. J. Pediatr. Surg. 31: 1241–1246.
Fuchs, J., Wenderoth, M., von Schweinitz, D., Haindl, J. and Leuschner, I. (1998) Comparative activity of cisplatin, ifosfamide, doxorubicin, carboplatin, and etoposide in heterotransplanted hepatoblastoma. Cancer 83: 2400–2407.
Futakuchi, M., Ogawa, K., Tamano, S., Takahashi S. and Shirai, T. (2004) Suppression of metastasis by nuclear factor kB inhibitors in an in vivo lung metastasis model of chemically induced hepatocellular carcinoma. Cancer Sci. 95: 18-24.
Garofalo, A., Chirivi, R. G., Scanziani, E., Mayo, J. G., Vecchi, A. and Giavazzi, R. (1993) Comparative study on the metastatic behavior of human tumors in nude, beige/nude/xid and severe combined immunodeficient mice. Invas. Metast. 13: 82-91.
Genersch, E., Hayess, K., Neuenfeld, Y. and Haller, H. (2000) Sustained ERK phosphorylation is necessary but not sufficient for MMP-9 regulation in endothelial cells: involvement of Ras-dependent and -independent pathways. J. Cell Sci. 113: 4319–4330.
Giehl, K. (2005) Oncogenic Ras in tumour progression and metastasis. Biol. Chem. 386: 193-205.
Gish, R. G. (2006) Hepatocellular carcinoma: Overcoming challenges in disease management. Clin. Gastroenterol. Hepatol. 4: 252-261.
Grille, S. J., Bellacosa, A., Upson, J., Klein-Szanto, A. J., Van Roy, F., Lee-Kwon, W., Donowitz, M., Tsichlis, P. N. and Larue, L. (2003) The protein kinase akt induces epithelial mesenchymal transition & promotes enhanced motility and invasiveness of squamous cell carcinoma lines. Cancer Res. 63: 2172-2178.
Gum, R., Wang, H., Lengyel, E., Juarez, J. and Boyd, D. (1997) Regulation of 92-kDa type IV collagenase expression by the jun aminoterminal kinase- and the extracellular signal-regulated kinase-dependent signaling cascades. Oncogene 14: 1481–1493.
Guo, H., Zucker, S., Gordon, M. K., Toole, B. P. and Biswas, C. (1997) Stimulation of matrix metalloproteinases production by recombinant extracellular matrix metalloproteinases inducer from transfected Chinese Hamster ovary cells. J. Biol. Chem. 272: 24–27.
Hattori, M. (2001) Recent studies on the bitter principles of Ganoderma lucidum-isolation of novel triterpenes, their biological activity and pharmacokinetics. Proc. Intl. Symposium Ganoderma Sci. Auckland., 27-29.
Ha, T. B. T., Gerhauser, C., Zhang, W. D., Ho-Chong-Line, N. and Fouraste, I. (2000) New lanostanoids from Ganoderma lucidum that induce NAD(P)H:quinone oxidoreductase in cultured hepalclc7 murine hepatoma cells. Planta Med. 66: 681–684.
Hah, N. and Lee, S. T. (2003) An absolute role of the PKC-dependent NF-kB activation for induction of MMP-9 in hepatocellular carcinoma cells. Biochem. Bioph. Res. Co. 305: 428-433.
Hall, B. S., Tam, W., Sen, R. and Pereira, M. E. (2000) Cell-specific activation of nuclear factor-kappa B by the parasite Trypanosoma cruzi promotes resistance to intracellular infection. Mol. Biol. Cell 11: 153-160.
Haskill., S., Beg, A. A., Tompkins, S. M., Morris, J. S., Yurochko, A. D., Sampson-Johannes, A., Mondal, K., Ralph, P. and Baldwin, A. S. Jr. (1991) Characterization of an immediate-early gene induced in adherent monocytes that encodes I kappa B-like activity. Cell 65: 1281-1289.
Hata, Y., Uchino, J., Sato, K., Sasaki, F., Une, Y., Naito, H., et al. (1982) Establishment of an experimental model of human hepatoblastoma. Cancer 50: 97–101.
Hayasaka, A., Suzuki, N., Fujimoto, N., Iwama, S., Fukuyama, E., Kanda, Y., and Saisho, H. (1996) Elevated plasma levels of matrix metalloproteinase-9 (92-kd type IV collagenase/ gelatinase B) in hepatocellular carcinoma. Hepatology 24: 1058-1062.
He, H., Sun, J. and Xie, B. J. (2001) Study on extraction and constituent activity of Ganoderma lucidum peptide. Shipin Kexue 22: 56–57.
Heppner, K. J., Matrisian, L. M., Jensen, R. A. and Rodgers, W. H. (1996) Expression of most matrix metalloproteinases family members in breast cancer represents a tumor-induced host response. Am. J. Pathol. 149: 273–282.
Himelstein, B. P., Canete-Soler, R., Bernhard, E. J. and Muschel, R. J. (1994) Induction of fibroblast 92 kDa gelatinase/type IV collagenase expression by direct contact with metastatic tumor cells. J. Cell Sci. 107: 477–486.
Hozumi, A., Nishimura, Y., Nishiuma, T., Kotani, Y. and Yokoyama, M. (2001) Induction of MMP-9 in normal human bronchial epithelial cells by TNF-α via NF-kB-mediated pathway, Am. J. Physiol. Lung. Cell. Mol. Physiol. 281: L1444–L1452.
Hsieh, C. and Yang, F. C. (2004) Reusing soy residue for the solidstate fermentation of Ganoderma lucidum. Bioresource Technol. 91: 105–109.
Hsu, H. Y. (1986) Oriental Materia Medica. Oriental Healing Arts Institute, Long Beach, 640-641.
Hu, T. X., Chen, J. W., Xu, J. Y., Lu, J. Y. and Yang, Q. Y. (1992) Scavenging effects of polysaccharide-peptide of Coriolus and polysaccharide of Ganoderma on active oxygen species. Shengwu Huaxue Yu Shengwu Wuli Xuebao 24: 465–470.
Huang, S. C., Ho, C. T., Lin-Shiau, S. Y. and Lin, J. K. (2005) Carnosol inhibits the invasion of B16/F10 mouse melanoma cells by suppressing metalloproteinase-9 through down-regulating nuclear factor-kappaB and c-Jun. Biochem. Pharmacol. 69: 221-232.
Hyun, J. W., Choi, E. C. and Kim, B. K. (1990). Studies on constituents of higher fungi of Korea IXII. Antitumor components of the basidiocarp of Ganoderma lucidum. Korean J. Mycol. 18: 58–69.
Illman, S. A., Keski-Oja, J. and Lohi, J. (2001) Promoter characterization of the human and mouse epilysin (MMP-28) genes. Gene 5, 275: 185-194.
Ishak, K. G., Goodman, Z. D. and Stocker, J. T. (2001) Tumors of the liver and intrahepatic bile ducts. Armed Forces Institute of Pathology, Washington D. C.
Israel, A. (2000) The IKK complex: an integrator of all signals that activate NF-kappaB. Trends Cell Biol. 10: 129-133.
Itoh, Y. and Nagase, H. (2002) Matrix metalloproteinases in cancer. Essays Biochem. 38: 21–36.
Iwakawa, M., Ando, K., Ohkawa, H., Koike, S. and Chen, Y. J. (1994) A murine model for bone marrow metastasis established by an i.v. injection of C-1300 neuroblastoma in A/J mice. Clin. Exp. Metastasis 12: 231-237.
Iwatsuki, K., Akihisa, T., Tokuda, H., Ukiya, M., Oshikubo, M., Kimura, Y., Asano, T., Nomura, A., and Nishino, H. (2003) Lucidenic Acids P and Q, Methyl Lucidenate P, and Other Triterpenoids from the Fungus Ganoderma lucidum and Their Inhibitory Effects on Epstein-Barr Virus Activation. J. Nat. Prod. 66: 1582-1585.
Jawhari, A. U., Buda, A., Jenkins, M., Shehzad, K., Sarraf, C., Noda, M., Farthing, M. J., Pignatelli, M. and Adams, J. C. (2003) Fascin, an actin-bundling protein, modulates colonic epithelial cell invasiveness and differentiation in vitro. Am. J. Pathol. 162: 69-80.
Jiang, Y. and Muschel, R. J. (2002) Regulation of matrix metalloproteinase-9 (MMP-9) by translational efficiency in murine prostate carcinoma cells. Cancer Res. 62: 1910–1914.
Juarez, J., Clayman, G., Nakajima, M., Tanabe, K. K., Saya, H., Nicolson, G. L. and Boyd, D. (1993) Role and regulation of expression of 92- kDa type-IV collagenase (MMP-9) in 2 invasive squamous-cell-carcinoma cell lines of the oral cavity. Int. J. Cancer, 55: 10–18.
Kaplowits, N. (2000) Mechanisms of liver cell injury. J. Hepatol. 32: 39-47.
Kennedy, A. R. (1994) Prevention of carcinogenesisi by protease inhibitors. Cancer Res. 54: 1999-2005.
Ker, C.-G., Chen, H.-Y., Juan, C.-C., Tseng, C.-S., Sun, M.-S., Lo, H.-W., Shih, T.-F. and Lo W.-C. (2006) Expression of vascular endothelial growth factor in hepatocellular carcinoma cell lines and patients. Formos. J. Surg. 39:126-132.
Khanna, C. and Hunter, K. (2005) Modeling metastasis in vivo. Carcinogenesis 26: 513-523.
Kikuchi, T., Kanomi, S., Kadota, S., Murai, Y., Tsubono, K. and Ogita, Z. (1986a) Chem. Pharm. Bull. 34: 3695-3712.
Kikuchi, T., Kanomi, S., Murai, Y., Kadota, S., Tsubono, K. and Ogita, Z. (1986b) Chem. Pharm. Bull., 34: 4018-4029.
Kim, H. S., Kacew, S., Lee, B. M. (1999). In vitro chemopreventive effects of plant polysaccharides (Aloe barbadensis Miller, Lentinus edodes, Ganoderma lucidum and Coriolus versicolor). Carcinogenesis 20: 1637–1640.
Kim, D., Kim, S., Koh, H., Yoon, S. O., Chiung, A. S., Cho, K. S. and Chung, J. (2001a) Akt/PKB promotes cancer cell invasion via increased motility and metalloproteinase production. FASEB J. 15: 1953-1962.
Kim, J. H., Kim, T. H., Jang, J. W., Jang, Y. J., Lee K. H. and Lee, S. T. (2001b) Analysis of matrix metalloproteinase mRNAs expressed in hepatocellular carcinoma cell lines. Mol. Cells 12: 32-40.
Kimura, Y., Taniguchi, M. and Baba, K. (2002) Antitumor and antimetastatic effects on liver of triterpenoid fractions of Ganoderma lucidum : mechanism of action and isolation of an active substance. Anticancer Res. 22: 3309-18.
Khanna, C. and Hunter, K. (2005) Modeling metastasis in vivo. Carcinogenesis 26: 513–523.
Kleiner, D. E. and Stetler-Stevenson, W. G. (1999) Matrix metalloproteinases and metastasis. Cancer Chemother. Pharmacol. 43: S41-S51.
Kohda, H., Tokumoto, W., Sakamoto, K., Fujii, M., Hirai, Y., Yamasaki, K., Komoda, Y., Nakamura, H., Ishihara, S. and Uchida, M. (1985) Chem. Pharm. Bull. 33: 1367-1374.
Kohn, E. C. and Liotta, L. A. (1995) Molecular insights into cancer invasion: strategies for prevention and intervention. Cancer Res. 55: 1856–1862.
Komoda, Y., Shimizu, M., Sonoda, Y. and Sato, Y. (1989) Chem. Pharm. Bull. 37: 531-533.
Kuo, W. H., Yang, S. F., Chu, S. C., Lu, S. O., Chou, F. P. and Hsieh, Y. S. (2003) Differential inductions of matrix metalloproteinase-2 and -9 in host tissues during the growth of ascitic sarcoma 180 cells in mice. Cancer Lett. 189: 103–112.
Labonte, P., Kadhim, S., Bowlin, T. and Mounir, S. (2000) Inhibition of tumor growth with doxorubicin in a new orthotopically implanted human hepatocellular carcinoma model. Hepatol. Res. 18: 72–85.
Lee, S. D., Lee, F. Y., Wu, J. C., et al. (1992) The prevalence of anti-hepatitis C virus among Chinese patients with hepatocellular carcinoma. Cancer 69: 342-345.
Lee, C. C., Liu, J. Y., Lin, J. K., Chu, J. S. and Shew, J. Y. (1998) p53 point mutation enhanced by heptic regeneration in aflatoxin B1-induced rat liver tumors and preneoplastic lesions. Cancer Lett. 125: 1-7.
Lee, J. M., Kwon, H., Jeong, H., Lee, J. W., Lee, S. Y., Baek, S. J. and Surh, Y. J. (2000) Antioxidant and anti-tumor promoting activities of the methanol extract of heat-processed ginseng. Cancer Lett. 150: 41-48.
Lee, T. K., Man, K., Ho, J. W., Wang, X. H., Poon, R. T. P., Xu, Y., Ng, K. T., Chu, A. C., Sun, C. K., Ng, I. O., Sun, H. C., Tang, Z. Y., Xu, R. and Fan, S. T. (2005) FTY720: A promising agent for treatment of metastatic hepatocellular carcinoma. Clin. Cancer Res. 11: 8458-8466.
Lei, L. S. and Lin, Z. B. (1993) Effect of Ganoderma polysaccharides on the activity of DNA polymerase of splenocytes and immune function in aged mice. Acta Pharm. Sinica 28: 577-582.
Li, Q. and Verma, I. M. (2002) NF-kB regulation in the immune system. Nat. Rev. Immunol. 2: 725-735.
Li, Y. Q. and Wang, S. F. (2006) Anti-hepatitis B activities of ganoderic acid from Ganoderma lucidum. Biotechnol. Lett. 28: 837-841.
Liddell, George, H. and Scott R. (1980) A Greek-English Lexicon (Abridged Edition). United Kingdom: Oxford University Press.
Lin, Z. B. (2002) Progress of studies on the anti-tumor activity and immunomodulating effects of Ganoderma. J Peking Univ (Health Sci) 34: 493–498 (in Chinese with an English abstract).
Lin, W. H., Hung, C. H., Hsu, C. I. and Lin, J. Y. (1997) Dimerization of the N-terminal amphipathic alpha-helix domain of the fungal immunomodulatory protein from Ganoderma tsugae (Fip-gts) defined by a yeast two-hybrid system and site-directed mutagenesis. J. Biol. Chem. 272: 20044–20048.
Lin, J. M., Lin, C. C., Chiu, H. F., Yang, J. J., and Lee, S. G. (1993) Evaluation of the anti-inflammatory and liver protective effects of Anoectochilus formosamus, Ganoderma lucidum and Gunostemma pentaphyllum in rats. Am. J. Chin. Med. 21: 59-69.
Linda, L. J., Richard, D. and Donald, J. H. (1999) Matrix metallo- proteinases. Curr. Opin. Chem. Biol. 2: 466-471.
Lindsay, C. K. and Thorgeirsson, U. P. (1995) Localization of messenger RNA for tissue inhibitor of metalloproteinases-1 and type IV collagenases/gelatinases in monkey hepatocellular carcinomas. Clin. Exp. Metastas. 13: 381-388.
Liotta, L. A., Rao, C. N. and Wewer, U. M. (1986) Biochemical interactions of tumor cells with the basement membrane. Annu. Rev. Biochem. 55: 1037-1057.
Liotta, L. A., Steeg, P. S. and Stetler-Stevenson, W. G. (1991) Cancer metastasis and angiogenesis: An imbalance of postive and negative regulation. Cell 64: 327-336.
Liu, T. Z., Chen, P. Y., Chiu, D. T., Wei, J. S., Chang, K. S. and Lin, K. H. (1994) Detection of a novel lactate dehydrogenase isozyme and an apparent differentiation-associated shift in isozyme profile in hepatoma cell lines. Cancer Lett. 87: 193-198.
Liu, P., Kimmoun, E., Legrand, A., Sauvanet, A., Degott, C., Lardeux, B. and Bernuau, D. (2002) Activation of NF-kB, AP-1, and STAT transcription factors is a frequent and early event in human hepatocellular carcinomas. J. Hepatol. 37: 63–71.
Liu, F., Qi, H. L. and Chen, H. L. (2001) Regulation of differentiation- and proliferation-inducers on Lewis antigens, a-fucosyltransferase, and metastatic potential in hepatocarcinoma cells, Br. J. Cancer 84: 1556–1563.
Liu, G. Q. and Zhang, K. C. (2005) Mechanisms of the anticancer action of Ganoderma lucidum (Leyss. Ex Fr.) Karst.: A new understanding. J. Integrative Plant Biology 47: 129-135.
Llovet, J. M. (2006) Hepatocellular carcinoma: Patients with increasing alpha-fetoprotein but no mass on ultrasound. Clin. Gastroenterol. Hepatol. 4: 29-35.
Llovet, J. M., Burroughs, A. and Bruix, J. (2003) Hepatocellular carcinoma. Lancet. 362: 1907-1917.
Lukasiuk, K. and Savonenko, A. (1999) Defensive conditioning-related increse in AP-1 transcription factor in the cortex. Mol. Brain Res. 67: 64-73
Lund, L. R., Romer, J., Bugge, T. H., Nielsen, B. S. and Frandsen, T. L. (1999) Functional overlap between two classes of matrix-degrading proteases in wound healing. EMBO. J. 18: 4645-4656.
Marrero, J. A., Fontana, R. J., Barrat, A., Askari, F., Conjeevaram, H. S., Su, G. L. and Lok, A. S. (2005) Prognosis of hepatocellular carcinoma: Comparison of 7 staging systems in an american cohort. Hepatology. 41: 707-716.
Martorana, A. M., Zheng, G., Crowe, T. C., O’Grady, R. L. and Lyons, J. G. (1998) Epithelial cells up-regulate matrix metalloproteinases in cells within the same mammary carcinoma that have undergone an epithelial-mesenchymal transition, Cancer Res. 58: 4970–4979.
Mase, K., Iijima, T., Nakamura, N., Takeuchi, T., Onizuka, M., Mitsui, T. and Noguchi, M. (2002) Intrabronchial orthotopic propagation of human lung adenocarcinoma--characterizations of tumorigenicity, invasion and metastasis. Lung Cancer 36: 271-276.
Masure, S., Billiau, A., Van Damme, J. and Opdenakker, G. (1990) Human hepatoma cells produce an 85-kDa gelatinase regulated by phorbol-12-myristate-13-acetate. Biochim. Biophys. Acta. 1054: 317–325.
Mazar, A. P. (2001) The urokinase plasminogen activator receptor (uPAR) as a target for the diagnosis and therapy of cancer. Anticancer Drugs 12: 387–400.
Mercurio, F., Manning A. M. (1999) Multiple signals converging on NF-κB. Curr. Opin. Cell Biol. 11: 226-232.
Miller, N. J., Rice-Evans, C. A., Davis, M. J., Gopinathan, V. and Milner, A. (1993) A novel method for measuring antioxidant capacity and its application to monitoring the antioxidant status in premature neonates. Clin. Sci. 84: 407–412.
Min, B. S., Gao, J. J., Hattori, M., Lee, H. K. and Kim, Y. H. (2001) Planta Med. 67: 811-814.
Min, B. S., Gao, J. J., Nakamura, N. and Hattori, M. (2000) Triterpenes from the spores of Ganoderma lucidum and their cytotoxicity against Meth-A and LLC tumor cells. Chem. Pharm. Bull. 48: 1026–1033.
Min, B. S., Nakamura, N., Miyashiro, H., Bae, K. W. and Hattori, M. (1998) Chem. Pharm. Bull. 46: 1607-1612, and references therein.
Mignatti, P. and Rifkin, D. B. (1996) Plasminogen activators and matrix metalloproteinases in angiogenesis. Enzyme Protein 49: 117-137.
Miyazaki, T. and Nishijima, M. (1981) Studies on fungal polysaccharides. XXVII. Structural examination of a water-soluble, antitumor polysaccharide of Ganoderma lucidum. Chem. Pharm. Bull. 29: 3611–3616.
Mizushina, Y., Hanashima, L., Yamaguchi, T., Takemura, M., Sugawara, F., Saneyoshi, M., Matsukage, A., Yoshida, S. and Sakaguchi, K. (1998) A mushroom fruiting body-inducing substance inhibits activities of replicative DNA polymerases. Biochem. Biophys. Res. Commun. 249: 17–22.
Mizushina, Y., Takahashi, N., Hanashima, L., Koshino, H., Esumi, Y., Uzawa, J., Sugawara, F. and Sakaguchi, K. (1999) Bioorg. Med. Chem. 7: 2047-2052.
Monvoism, A., Neaud, V., De Ledinghen, V., Dubuisson, L., Balabaud, C., Bioulac-Sage, P., Desmouliere, A. and Rosenbaum, J. (1999) Direct evidence that hepatocyte growth factor-induced invasion of hepatocallular carcinoma cells is mediated by urokinase. J. Hapatol. 30: 511–518.
Morigiwa, A., Kitabatake, K., Fujimoto, Y. and Ikekawa, N. (1986) Chem. Pharm. Bull. 34: 3025-3028.
Morris, V. L., Schmidt, E. E., MacDonald, I. C., Groom, A. C. and Chambers, A. F. (1997) Sequential steps in hematogenous metastasis of cancer cells studied by in vivo videomicroscopy. Invas. Metast. 17: 281-296.
Mosier, D. E. (1990) Immunodeficient mice xenografted with human lymphoid cells: new models for in vivo studies of human immunobiology and infectious diseases. J. Clin. Immunol. 10: 185.
Mueller, B. M. and Reisfeld, R. A. (1991) Potential of the scid mouse as a host for human tumors. Cancer Metastasis Rev. 10: 193-200.
Nagakawa, Y., Aoki, T., Kasuya, K., Tsuchida, A. and Koyanagi, Y. (2002) Histologic features of venous invasion, expression of vascular endothelial growth factor and matrix metalloproteinase-2 and matrix metalloproteinase-9, and the relation with liver metastasis in pancreatic cancer. Pancreas 24: 169–178.
Nagase, H. (1997) Activation mechanisms of matrix metalloproteinases. Biol. Chem. 378: 151–160.
Namba, T. (1994) The Encyclopedia of Wakan-Yaku (Traditional Sino-Japanese Medicines) with Color Pictures, revised ed.; Hoikusya:Osaka, Vol. II, 244-250.
Nanni, P., De Giovanni, C., Nicoletti, G., Del Re, B., Scotlandi, K. and Lollini, P. L. (1989) Human rhabdomyosarcoma cells in nude mice as a model for metastasis and differentiation. Invas. Metast. 9: 231-241.
Nelson, A. R., Fingleton, B., Rothenberg, M. L. and Matrisian, L. M. (2000) Matrix metalloproteinases: biologic activity and clinical implications. J. Clin. Oncol. 18: 1135–1149.
Newton, A. C. (1997) Regulation of protein kinase C. Curr. Opin. Cell. Biol. 9: 161–167.
Nishitoba, T., Sato, J., Kasai, T., Kawagishi, H. and Sakamura, S. (1985) New bitter C27 and C30 terpenoids from the fungus Ganoderma lucidum (reishi). Agric.Biol. Chem. 49: 1793-1798.
Nzeako, U. C. et al. (1995) Tumor pathology and survival in HCC. Cancer 74: 579-588.
Ohashi, K., Marion, P. L., Nakai, H., Meuse, L., Cullen, J. M., Bordier, B. B., et al. (2000) Sustained survival of human hepatocytes in mice: a model for in vivo infection with human hepatitis B and hepatitis delta viruses. Nat. Med. 6: 327–331.
Okada, N., Ishida, H., Murata, N., Hashimoto, D., Seyama, Y. and Kubota, S. (2001) Matrix metalloproteinase-2 and -9 in bile as a marker of liver metastasis in colorectal cancer. Biochem. Biophys. Res. Commun. 288: 212–216.
Okuda, K. (1997) Hepatocellular carcinoma: clinicopathological aspects. J. Gastroenterol. Hepatol. 12: 314-318.
Parkin, D. M., Bray, F., Ferlay, J. and Pisani, P. (2001) Estimating the world cancer burden: Globocan 2000. Int. J. Cancer 94: 153-156.
Rao, J. S. (2003) Molecular mechanisms of glioma invasiveness: the role of proteases. Nat. Rev. Cancer 3: 489–501.
Ray, J. M. and Stetler-Stevenson, W. G. (1994) The role of matrix metalloproteases and their inhibitors in tumor invasion, metastasis and angiogenesis. Eur. Respir. J. 7: 2062-2072.
Repesh, L. A. (1989) A new in vitro assay for quantitating tumor cell invasion. Invas. Metast. 9: 192-208.
Robert, V. and Hideaki, N. (2003) Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ. Res. 92: 827-839.
Sato, H. and Seiki, M. (1993) Regulatory mechanism of 92 kDa type IV collagenase gene expression which is associated with invasiveness of tumor cells. Oncogene 8: 395–405.
Schmoll, D., Grempler, R., Barthel, A., Joost, H. G. and Walther, R. (2001) Phorbol ester-induced activation of mitogen-activated protein kinase/extracellular-signal-regulated kinase kinase and extracellular-signal-regulated protein kinase decreases glucose-6-phosphatase gene expression. Biochem. J. 357: 867–873.
Schnater, J. M., Bruder, E., Bertschin, S., Woodtli, T., de Theije, C., Pietsch, T., Aronson, D. C., von Schweinitz, D., Lamers, W. H. and Köhler, E. S. (2006) Subcutaneous and intrahepatic growth of human hepatoblastoma in immunodeficient mice. J. Hepatol. 45: 377-386.
Scorilas, A., Karameris, A., Arnogiannaki, N., Ardavanis, A., Bassilopoulos, P., Trangas, T. and Talieri, M. (2001) Overexpression of matrix-metalloproteinase-9 in human breast cancer: a potential favourable indicator in node-negative patients. Br. J. Cancer 84: 1488–1496.
Segain, J. P., Harb, J., Gregoire, M., Meflah, K. and Menanteau, J. (1996) Induction of fibroblast gelatinase B expression by direct contact with cell lines derived from primary tumor but not from metastases. Cancer Res. 56: 5506–5512.
Shaulian, E. and Karin, M. (2002) AP-1 as a regulator of cell life and death. Nat. Cell Biol. 4: E131–E136.
Shen, G., Jeong, W. S., Hu, R. and Kong, A. N. (2005) Regulation of Nrf2, NF-kappaB, and AP-1 signaling pathways by chemopreventive agents. Antioxid. Redox Signal. 7: 1648-1663.
Shiao, M. S., Lin, L. J., Yeh, S. F. (1988) Phytochemistry. 27: 2911-2914.
Shin, M., Yan, C. and Boyd, D. (2002) An inhibitor of c-jun aminoterminal kinase (SP600125) represses c-Jun activation, DNA-binding, and PMA-inducible 92-kDa type IV collagenase expression. Biochim. Biophys. Acta. 1589: 311–316.
Shinmoto, H., Dosako, S. and Nakajima, I. (1992) Antioxidant activity of bovine lactoferrinon iron/ascorbate induced lipid peroxidation. Biosci. Biotech. Biochem. 12: 2079 –2080.
Simon, C., Goepfert, H. and Boyd, D. (1998) Inhibition of the p38 mitogenactivated protein kinase by SB 203580 blocks PMA-induced Mr 92,000 type IV collagenase secretion and in vitro invasion. Cancer Res. 58: 1135–1139.
Sliva, D., Labarrere, C., Slivova, V., Sedlak, M., Jr., F. P. L. and Ho, N. W. Y. (2002) Ganoderma lucidum suppresses motility of highly invasive breast and prostate cancer cells. Biochem. Biophys. Res. Commun. 298: 603–612.
Sone, Y., Okuda, R., Wada, N., Kishida, E. and Misaki, A. (1985) Structures and antitumor activities of the polysaccharides isolated from fruiting body and the growing culture of mycelium of Ganoderma lucidum. Agric. Biol. Chem. 49: 2641–2653.
Song, Y. S., Kim, S. H., Sa, J. H., Jin, C., Lim, C. H. and Park, E. H. (2004) Antiangiogenic and inhibitory activity on inducible nitric oxide production of the mushroom Ganoderma lucidum. J. Ethnophamacol. 90: 17–20.
Sonoda, Y., Sekigawa, Y. and Sato, Y. (1988) Chem. Pharm. Bull. 36: 966-973.
Stetler-Stevenson, W. G., Aznavoorian, S. and Liotta, L. A. (1993) Tumor cell interactions with the extracellular matrix during invasion and metastasis. Annu. Rev. Cell Biol. 9: 541-573.
Sugita, K. (1999) Recent advances in inhibitors of metalloproteinases for cancer therapy. I Drugs 2: 327–339.
Sun, J., He, H. and Xie, B. J. (2004) Novel antioxidant peptides from fermented mushroom Ganoderma lucidum. J. Agric. Food Chem. 52: 6646-6652.
Suzuki, T., Watanabe, K., Hirota, M., Iwafuchi, M., Ono, T., Aoyagi, Y. and Ito, S. (1992) Establishment of a human hepatoblastoma model in athymic nude mice. Producibility of fatty acid-binding protein, alpha-fetoprotein, and alpha 1-acid glycoprotein. Acta Pathol. Jpn. 42: 255–261.
Takada, Y., Singh, S. and Aggarwal, B. B. (2004) Identification of a p65 peptide that selectively inhibits NF-kappa B activation induced by various inflammatory stimuli and its role in down-regulation of NF-kappa B-mediated gene expression and up-regulation of apoptosis. J. Biol. Chem. 279: 15096–15104.
Takahra, T., Smart, D. E., Oakley, F. and Mann, D. A. (2004) Induction of myofibroblast MMP-9 transcription in three-dimensional collagen I gel cultures: regulation by NF-kappaB, AP-1 and Sp1. Int. J. Biochem. Cell Biol. 36: 353– 363.
Takaku, T., Kimura, Y. and Okuda, H. (2001) Isolation of an antitumor compound from Agaricus blazei murill and its mechanism of action. J. Nutr. 131:1409-1413.
Teow, S. S. (1997) The effective application of Ganoderma nutriceuticals. In: Kim BK, Moon CK, Kim TS, Eds. Recent Progress in Ganoderma lucidum Research. The Pharmaceutical Society of Korea, Seoul, 21–39.
Thompson, J. E., Phillips, R. J., Erdjument-Bromage, H., Tempst, P. and Ghosh, S. (1995) I kappa B-beta regulates the persistent response in a biphasic activation of NF-kappa B. Cell 80: 573-582.
Ukiya, M., Akihisa, T., Tokuda, M., Hirano, M., Oshikubo, M., Nobukuni, Y., Kimura, Y., Tai, T., Kondo, S. and Nishino, H. (2002a) J. Nat. Prod. 65: 462-465.
Ukiya, M., Akihisa, T., Tokuda, H., Suzuki, H., Mukainaka, T., Ichiishi, E., Yasukawa, K., Kasahara, Y. and Nishino, H. (2002b) Cancer Lett. 177: 7-12.
van Zutphen, L. F. M., Baumans, V. and Beynen, A. C. (1993) Principles of Laboratory Animal Science 189-196, Elsevier Science Publisher Amsterdam.
Verma, R. P. and Hansch, C. (2007) Matrix metalloproteinases (MMPs): chemical-biological functions and (Q) SARs. Bioorg. Med. Chem. 15: 2223-2268.
Vincenti, M. P. (2001) The matrix metalloproteinase (MMP) and tissue inhibitor of metalloproteinase (TIMP) genes. Transcriptional and posttranscriptional regulation, signal transduction and cell-type-specific expression. Methods Mol. Biol. 151: 121-148.
Walker, V. G., Ammer, A. G., Cao, Z., Clump, A., Jiang, B. H., Kelley, L. C., Weed, S. A., Zot, H. and Flynn, D. C. (2007) PI-3-Kinase activation is required for PMA directed activation of cSrc by AFAP-110. Am. J. Physiol. Cell Physiol. 293: C119-C132.
Wang, Y. Y., Khoo, K. H., Chen, S. T., Lin, C. C., Wong, C. H. and Lin, C. H. (2002). Studies on the immuno-modulating and anti-tumor activities of Ganoderma lucidum (Reishi). polysaccharides: Functional and proteomic analyses of a fucose-containing glycoprotein fraction responsible for the activities. Bioorgan Med. Chem. 10: 1057–1062.
Wang, A. C. and Li, B. (2002) Ganoderma. Beijing Science and Technology Press, Beijing (in Chinese).
Wang, S. Y., Hsu, M. L., Hsu, H. C., Tzeng, C. H., Lee, S. S., Shiao, M. S. and Ho, C. K. (1997) The anti-tumor effect of Ganoderma lucidum is mediated by cytokines released from activated macrophages and T lymphocytes. Int. J. Cancer 70: 699–705.
Weiss, L. (1990) Metastatic inefficiency. Advances in Cancer Research 54: 159–211.
Weng, C. J., Chau, C. F., Chen, K. D., Chen, D. H. and Yen, G. C. (2007) The anti-invasive effects of lucidenic acids isolated from a new Ganoderma lucidum strain. Molecular Nutrition & Food Research 51: 1472-1477.
Weng, C. J., Chau, C. F., Hsieh, Y. S., Yang, S. F. and Yen, G. C. (2008) Lucidenic acid inhibit PMA-induced invasion of human hepatoma cells through inactivating MAPK/ERK signal transduction pathway and reducing binding activities of NF-kB and AP-1. Carcinogenesis 29: 147-156.
Westermarck, J. and Kahari, V. M. (1999) Regulation of matrix metalloproteinase expression in tumor invasion. FASEB J. 13: 781-792.
Whiteside, S. T., Epinat, J. C., Rice, N. R. and Israel, A. (1997) I kappa B epsilon, a novel member of the I kappa B family, controls RelA and cRel NF-kappa B activity. EMBO. J. 16: 1413-1426.
Woessner, J. F. Jr. (1991) Matrix metalloproteinases and their inhibitors in connective tissue remodeling. FASEB J. 5: 2145-2154.
Woessner, J. F. Jr. (1994) The family of matrix metalloproteinases. Ann. NY. Acad. Sci. 732: 11-21.
Wojtowicz-Praga, S. (1999) Clinical potential of matrix metalloproteinase inhibitors. Drugs R. D. 1: 117–129.
Wong, K. L., Chao, H. H., Chan, P., Chang, L. P. and Liu, C. F. (2004) Antioxidant activity of Ganoderma lucidum in acute ethanol-induced heart toxicity. Phytother. Res. 18: 1024-1026.
Wu, T. S., Shi, L. S. and Kuo, S. C. (2001) Cytotoxicity of Ganoderma lucidum triterpenes. J. Nat. Prod. 64: 1121-1122.
Wu, T. S., Shi, L. S., Kuo, S. C., Cherng, C. Y., Tung, S. F. and Teng, C. M. (1997) J. Chin. Chem. Soc. 44: 157-161, and references therein.
Yang, H. L. and Zhang, K. C. (2002) The relationship between molecular structure and activity of Ganoderma acids. J. Wuxi. Univ. Light Ind. 21: 249–253 (in Chinese with an English abstract).
Yavelow, J., Finlay, T. H., Kennedy, A. R. and Troll, W. (1983) Bowman-Birk soybean protease inhibitor as an anticarcinogen. Cancer Res. 43: 2454-2459.
Yen, G. C. and Wu, J. Y. (1999) Antioxidant and radical scavenging properties of extracts from Ganoderma tsugae. Food Chem. 65: 375–379.
Yoshida, B. A., Sokoloff, M. M., Welch, D. R. and Rinker-Schaeffer, C. W. (2000) Metastasis-suppressor genes: a review and perspective on an emerging field. J. Natl. Cancer Inst. 92: 1717-1730.
You, Y. H. and Lin, Z. B. (2002) Protective effects of Ganoderma lucidum polysaccharides peptide on injury of macrophages induced by reactive oxygen species. Acta Pharmacol. Sin. 23: 787–791.
Yuen, J. W. M. and Gohel, M. D. I. (2005) Anticancer effects of Ganoderma lucidum: A review of scientific evidence. Nutr. Cancer 53: 11-17.
Zeigler, M. E., Chi, Y., Schmidt, T., and Varani, J. (1999) Role of ERK and JNK pathways in regulating cell motility and matrix metalloproteinase 9 production in growth factor-stimulated human epidermal keratinocytes. J. Cell Physiol. 180: 271–284.
Zhang, M., Altuwaijri, S. and Yeh, S. (2004) RRR-alpha-tocopheryl succinate inhibits human prostate cancer cell invasiveness. Oncogene 23: 3080–3088.
Zhang, Q. H. and Lin, Z. B. (1999a) The antitumor activity of Ganoderma lucidum (Curt. Fr.) P. Karst. (LingZhi) (Aphyllophoromycetideae) polysaccharides is related to tumor necrosis factor-α and interferon-γ. Int. J. Med. Mushrooms 1: 207–215.
Zhang, Q. H. and Lin, Z. B. (1999b) Effect of Ganoderma lucidum polysaccharides B on TNF-α and IFN-γ production and their mRNA expression. J. Beijing Med. Univ. 31: 179–183 (in Chinese with an English abstract).
Zhu, S. and Mori, M. (1994) Research on Ganoderma. Shanghai Medical University Press, Shanghai.
QRCODE
 
 
 
 
 
                                                                                                                                                                                                                                                                                                                                                                                                               
第一頁 上一頁 下一頁 最後一頁 top