臺灣博碩士論文加值系統

Part 1.三氧化二砷已經廣泛的使用在治療急性前骨髓白血病的病人，它的機轉已在體內外試驗研究當中。從分離出來的骨髓癌、白血病、淋巴瘤細胞，以及膀胱、胃、食道、神經纖維、前列腺、卵巢的癌病細胞株，在三氧化二砷處理下都會引起細胞凋亡。然而，三氧化二砷引發細胞死亡的機制並不完全清楚。為了研究三氧化二砷在乳癌細胞的影響，首先我們偵測三氧化二砷引發MCF-7乳癌細胞株死亡的跡象。MTT assay的結果顯示在三氧化二砷處理72小時後，細胞生長的半數抑制濃度約為3μM，並且細胞凋亡的情形在流式細胞儀可偵測到。抑癌基因p21在癌症細胞的生長抑制上扮演重要的角色是眾所周知的事；然而最近的研究指出，磷酸化的Akt能夠磷酸化p21，並促使p21分布在細胞質，使其扮演一個對抗細胞凋亡的角色。所以我們分離細胞核質再用西方點墨法分析，發現在三氧化二砷處理下，p21從細胞質改變位置到細胞核，磷酸化Akt亦表現量降低。藉由共軛焦顯微鏡及流式細胞儀實驗，將細胞處理Akt抑制劑LY294002會造成p21改變位置到細胞核，並發生細胞凋亡。所以我們推論三氧化二砷所引發MCF-7細胞株的凋亡，是透過抑制Akt的磷酸化，進而降低p21留在細胞質所扮演的抗細胞凋亡之角色。Part 2.在台灣樟芝是廣為人知的傳統中藥，過去被用來作為解毒、治療腹瀉、腹痛、高血壓、以及皮癬。樟芝的提煉物具有抗氧化、清除自由基的功效，在體內可減清對肝臟的傷害。內質網壓力是起因於許多未摺疊的蛋白在內質網內堆積，並阻礙了內質網的功能；Thapsigargin (TG)是一個內質網壓力的促進因子，可造成內質網鈣離子的流失，並增加粒線體活性氧化物產生。在我們的研究裡，我們要探討在內質網壓力促進因子TG下，樟芝所具有的抗氧化功效。結果顯示在Huh-7肝細胞株中，樟芝可以降低TG與過氧化氫所引發的活性氧化物產生，代表樟芝具有抗氧化的功能。樟芝亦可以降低TG所產生的GRP78蛋白質表現，因此推測樟芝抗氧化的功能可改善細胞的內質網壓力；並且樟芝可減輕TG引起的細胞凋亡。因此，樟芝所具有的抗氧化及抗細胞凋亡的功效，可能更進一步提供來作為預防內質網壓力相關的疾病。

Part 1.Arsenic trioxide (As2O3) has been used in clinical trial of acute promyelocytic leukemia (APL) patients worldwide and its mechanisms are examined in both in vitro and in vivo studies. Freshly isolated cells from myeloma, leukemia and lymphoma, or cell lines from bladder, stomach, esophagus, neuroblastoma, prostate and ovary, all undergo apoptosis in vitro following treatment with As2O3. However, the mechanism of As2O3-induced cell death has not yet been clarified completely. To examine the effects of As2O3 in breast cancer cell, we firstly measured the cell death index of MCF-7 cells in response to As2O3. MTT assay showed that treatment with As2O3 for 72 hr induced growth inhibition, with IC50 value about 3 μM. It also induced apoptosis in MCF-7 cells upon As2O3 treatment by flow cytometry with propidium iodide staining. Cyclin dependent kinase inhibitor p21WAF1/CIP1 (p21) was well known to play an important role in cancer cell growth inhibition. However, recent reports showed that phosphorylated Akt can phosporylate p21 and lead to cytoplasmic localization of p21, which plays an important role in protecting cells against apoptosis. By using subcellular fractionation with Western blots, we also found that phosphorylated Akt was down-regulated, and then p21 was translocated from cytosol to nucleus upon As2O3 treatment for 4 hr. When the cells treated with the Akt inhibitor LY294002, the down-regulation of phosphorylated Akt also enhanced p21 translocation to nucleus and induced apoptosis by confocal microscopy and flow cytometry analysis. We conclude that As2O3 induced MCF-7 apoptosis via inhibition of Akt phosphorylation, which prevented accumulation of p21 in cytoplasm and lost its role in anti-apoptosis.Part 2.Antrodia camphorata (A. camphorata) is well-known in Taiwan as a traditional Chinese medicine. It has been used as a remedy for drug intoxication, diarrhea, abdominal pain, hypertension, and itchy skin. A. camphorata extract protects hepatic injury in vivo, by antioxidative and free radical scavenging activities. The endoplasmic reticulum (ER) stress is induced by accumulation of unfolded protein response leading to disrupt ER functions. Thapsigargin (TG), an ER stress inducer, causes ER Ca2+ release and increases mitochondrial ROS production. In this study, we tried to evaluate antioxidative effects of A. camphorata during TG-induced ER stress. The results showed that A. camphorata reduced TG or H2O2-induced ROS generation in Huh-7 cells, which indicate that A. camphorata has antioxidative effects to TG-induced ER stress. In addition, down-regulation of TG-induced GRP78 expression by A. camphorata suggests that the antioxidative effects could further improve the ER stress. Finally, TG-induced apoptosis in Huh-7 cells prevented by A. camphorata was also found. In conclusion, the antioxidative and anti-apoptotic effects of A. camphorata should be further exploited to be a promising preventive agent in ER stress-induced diseases.

Part 1. Study On The As2O3-induced Apoptosis In MCF-7 Breast Cancer Cell
Abstract………………………………………...………………...1
中文摘要………………………………………………………………3
Introduction………………………………………..……………..4
Materials And Methods…………………………..………………7
Results……………………………………….…………………….14
Discussion………………………………….…………….……...20
References…………………………………..….………………….26
Figure Legends…………………………………….………..…..33
Part 2. Effects Of Antrodia camphorata On Thapsigargin-induced Endoplasmic Reticulum Stress In Huh-7
Abstract……………………………………………………….……44
中文摘要…………………………………………………….…….46
Introduction…………………………………………..…………47
Materials And Methods…………………………..…………..51
Results………………………………………….……………….54
Discussion………………………………………..……………..59
References……………………………………..……….……….63
Figure Legends........................................72

Part 1.
1.Novick SC., and Warrell Jr RP., (2000) Arsenicals in hematological cancers. Semin Oncol. 27, 495–501
2.Baj G., Arnulfo A., Deaglio S., Mallone R., Vigone A., and De Cesaris MG. (2002) Arsenic trioxide and breast cancer: analysis of the apoptotic, differentiative and immunomodulatory effects. Breast Cancer Res Treat. 73, 61-73
3.Sherr CJ., and Roberts JM. (1995) Inhibitors of mammalian G1 cyclin-dependent kinases. Genes Dev. 9, 1149-63
4.Goubin F. and Ducommun B. (1995) Identification of binding domains on the p21Cip1 cyclin-dependent kinase inhibitor. Oncogene. 10, 2281-87
5.Flores-Rozas H., Kelman Z., Dean FB., Pan ZQ., Harper JW., Elledge SJ., O'Donnell M., and Hurwitz J. (1994) Cdk-interacting protein 1 directly binds with proliferating cell nuclear antigen and inhibits DNA replication catalyzed by the DNA polymerase delta holoenzyme. Proc Natl Acad Sci USA. 91, 8655-9
6.Asada M., Yamada T., Ichijo H., Delia D., Miyazono K., Fukumoro K., and Mizutani S. (1999) Apoptosis inhibitory activity of cytoplasmic p21WAF1/CIP1 in monocytic differentiation.. EMBO J. 18, 1223–1234
7.Zhou BP., Liao Y., Xia W., Spohn B., Lee MH., and Hung MC. (2001) Cytoplasmic localization of p21 by Akt-induced phosphorylation in HER-2/neu-overexpressing cells. Nat Cell Biol. 3, 245-52
8.Dotto GP. (2000). p21WAF1/CIP1: more than a break to the cell cycle?. Biochim Biophys Acta. 1471, 43-56
9.Blagosklonny MV. (2002) Are p27 and p21 cytoplasmic oncoproteins? Cell Cycle. 1, 391-393
10.Suzuki A., Tsutomi Y., Miura M., and Akahane K. (1999) Caspase 3 inactivation to suppress Fas-mediated apoptosis: identification of binding domain with p21 and ILP and inactivation machinery by p21. Oncogene. 18, 1239-1244
11.Lin PY., Fosmire SP., Park SH., Park JY., Baksh S., Modiano JF., and Weiss RH. (2007). Attenuation of PTEN increases p21 stability and cytosolic localization in kidney cancer cells: a potential mechanism of apoptosis resistance. Mol Cancer. 6, 16
12.Li Y., Dowbenko D., and Lasky LA. (2002). AKT/PKB Phosphorylation of p21Cip/WAF1 Enhances Protein Stability of p21Cip/WAF1 and Promotes Cell Survival. J Biol Chem. 277, 11352-11361
13.Child SE. and Mann JD. (2006) The Intricacies of p21 Phosphorylation: Protein/Protein Interactions, Subcellular Localization and Stability. Cell Cycle. 5, 1313-1319
14.Warbrick E. (2000). The puzzle of PCNA's many partners. Bioessays. 22, 997-1006
15.Harreman MT., Kline TM., Milford HG., Harben MB., Hodel AE., and Corbett AH. (2004)Regulation of Nuclear Import by Phosphorylation Adjacent to Nuclear Localization Signals. J Biol Chem. 279, 20613-21
16.Faivre S., Djelloul S., and Raymond E. (2006) New paradigms in anticancer therapy: Targeting multiple signaling pathways with kinase inhibitors. Semin Oncol. 33, 407-420
17.Ling YH., Jiang JD., Holland JF., and Perez-Soler R. (2002) Arsenic trioxide produces polymerization of microtubules and mitotic arrest before apoptosis in human tumor cell lines. Mol Pharmacol. 62, 529-38
18.Ye J., Li A., Liu Q., Wang X., and Zhou J. (2005) Inhibition of mitogen-activated protein kinase enhances apoptosis induced by arsenic trioxide in human breast cancer MCF-7 cells. Clin Exp Pharmacol Physiol. 32, 1042-8
19.Stephanie KYC., Chan JYW., and Fung KP. (2004) Suppression of cell proliferation and regulation of estrogen receptor a signaling pathway by arsenic trioxide on human breast cancer MCF-7 cells. J Endocrinol. 182, 325–337
20.El-Deiry WS., Tokino T., Velculescu VE., Levy DB., Parsons R., Trent JM., Lin D., Mercer WE., Kinzler KW. and Vogelstein B. (1993) Waf1, a potential mediator of p53 tumor suppression. Cell. 75, 817-825
21.Huang HS., Chang WC. and Chen CJ. (2002) Involvement of reactive oxygen species in arsenite-induced downregulation of phospholipid hydroperoxide glutathione peroxidase in human epidermoid carcinoma A431 cells. Free Radic Biol Med. 33, 864-873
22.Seo SR., Ferrand N., Faresse N., Prunier C., Abe´cassis L., Pessah M., Bourgeade MF., and Atfi A. (2006) Nuclear retention of the tumor suppressor cPML by the homeodomain protein TGIF restricts TGF-β signaling. Mol Cell. 23, 547–559
23.Vivanco I., and Sawyers CL. (2002). The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer. 2, 489–01
24.Liu S., Bishop WR., Liu M. (2003) Differential effects of cell cycle regulatory protein p21WAF1/Cip1 on apoptosis and sensitivity to cancer chemotherapy. Drug Resist Updat. 6, 183-95
25.Weiss HR. (2003) p21Waf1/Cip1 as a therapeutic target in breast and other cancers. Cancer Cell. 4, 425-429
26.Rakesh K., and Hung MC, (2005) Signaling intricacies take center stage in cancer cells. Cancer Res. 65, 2511-2515
27.Coqueret O. (2003) New roles for p21 and p27 cell-cycle inhibitors: A function for each cell compartment? Trends Cell Biol. 13, 65-70
28.Huang S., Shu L., Dilling MB., Easton J., Harwood FC., Ichijo H., and Houghton PJ. (2003) Sustained activation of the JNK cascade and rapamycin-induced apoptosis are suppressed by p53/p21Cip1. Mol Cell. 11, 1491-1501
29.Ping B., He X., Xia W., Lee DF., Wei Y., Yu D., Mills G., Shi D., and Hung MC., (2006) Cytoplasmic expression of p21CIP1/WAF1 is correlated with IKKbeta overexpression in human breast cancers. Int J Oncol. 29, 1103-10
30.Liu B., Ordonez-Ercan D., Edgerton SM., Yang X., and Thor AD. (2007) Downregulation of ErbB3 Abrogates ErbB2-mediated Tamoxifen Resistance in Breast Cancer Cells. Int J Cancer. 120, 1874-82
31.Mabuchi S., Ohmichi M., Kimura A., Hisamoto K., Hayakawa J., Nishio Y., Adachi K., Takahashi K., Arimoto-Ishida E., Nakatsuji Y., Tasaka K., Murata Y. (2002) Inhibition of phosphorylation of BAD and Raf-1 by Akt sensitizes human ovarian cancer cells to paclitaxel. J Biol Chem. 277,33490–500
32.Clark AS., West K., Streicher S., and Dennis PA. (2002) Constitutive and inducible Akt activity promotes resistance to chemotherapy, trastuzumab, or tamoxifen in breast cancer cells. Mol Cancer Ther. 1, 707–17
33.Nicholson KM., Quinn DM., Kellett GL., and Warr JR. (2003) LY294002, an inhibitor of phosphatidylinositol-3-kinase, causes preferential induction of apoptosis in human multidrug resistant cells. Cancer Lett. 190, 31–6
34.Tsou TC., Tsai FY., Hsieh YW., Li LA., Yeh SC., and Chang LW. (2005) Arsenite induces endothelial cytotoxicity by down-regulation of vascular endothelial nitric oxide synthase. Toxicol Appl Pharmacol. 208, 277-284
35.Tabellini G., Tazzari PL., Bortul R., Evangelisti C., Billi, Anna M., Grafone T., Martinelli G., Baccarani M., and Martelli AM. (2005) Phosphoinositide 3-kinase/Akt inhibition increases arsenic trioxide-induced apoptosis of acute promyelocytic and T-cell leukaemias. British J Haematol. 130, 716-725
36.Xia W., Chen JS., ZhouX., Sun PR., Lee DF., Liao Y., Zhou BP., and Hung MC. (2004) Phosphorylation/Cytoplasmic localization of p21Cip1/WAF1 is associated with HER-2/neu overexpression and provides a novel combination predictor for poor prognosis in breast cancer patients. Clin Cancer Res. 10, 3815-3824
37.Winters ZE., Hunt NC., Bradburn MJ., Royds JA., Turley H., Harris AL., and Norbury CJ. (2001) Subcellular localization of cyclin B, Cdc2 and p21WAF1/CIP1 in breast cancer: association with prognosis. Eur J Cancer. 37,2405-12
Part 2.
1.Cherng IW., Wu DP., and Chiang HC. (1996) Triterpenoids from Antrodia camphorata. Phytochem. 41, 263-7
2.Zang M., and Su CH. (1990) Ganoderma comphoratum, a new taxon in genus. Ganoderma from Taiwan. China Acta Bot Yunnancia. 12, 395-396
3.Toth JO., Luu B., and Ourisson G. (1983) Chemistry and biochemistry of chinese drugs.9. T to Z ganoderic acids-cyto-toxic triterpenes of ganoderma-lucidem (polyporaceae). Tetrahedron Lett. 24, 1081-1084
4.Wu SH., Ryvarden L., and Chang TT., (1997) Antrodia cinnamomea (“Niu-Chang-Chih”), new combination of a medicinal fungus in Taiwan, Botanical Bulletin of Academia Sinica. 38, pp. 273–527
5.Shen YC., Wang YH., Chou YC., Chen CF., Lin LC., Chang TT., Tien JH., and Chou CJ. (2004) Evaluation of theAnti-inflammatory activity of zhankuic acids isolated fromthe fruiting bodies of Antrodia camphorata. Planta Med. 70, 310-314.
6.Song TY., and Yen GC. (2002) Antioxidant properties of Antrodia camphorata in submerged culture. J Agric Food Chem. 50, 3322-3327
7.Hsiao G., Shen MY., Lin KH., Lan MH., Wu LY., Chou DS., Lin CH., Su CH., and Sheu JR. (2003) Antioxidative and hepatoprotective effects of Antrodia camphorata extract. J Agric Food Chem. 51, 3302-3308
8.Hollien J., and Weissman JS. (2006). Decay of endoplasmic reticulum-localized mrnas during the unfolded protein response. Science. 313, 104-107
9.Zhang K., and Randal JK. (2006). The unfolded protein response A stress signaling pathway critical for health and disease. Neurology. 66, 102-109
10.Stevens JL., Liu H., Halleck M., Bowes RC., Chen QM. and Van-de-Water B., (2000) Linking gene expression to mechanisms of toxicity, Toxicol Lett. 112, 479–486
11.Rao RV., Peel A, Logvinova A., del Rio G., Hermel E., Yokota T., Goldsmith PC., Ellerby LM., Ellerby HM. and Bredesen DE., (2002) Coupling endoplasmic reticulum stress to the cell death program: role of the ER chaperone GRP78. FEBS Lett. 514, 122–128
12.Lee AS., (2001) The glucose-regulated proteins: stress induction and clinical applications. Trends Biochem Sci. 26, 504–510
13.Soboloff J., and Berger SA. (2002) Sustained ER Ca2+ depletion suppresses protein synthesis and induces activation-enhanced cell death in mast cells. J Biol Chem. 277, 13812–13820
14.Zhang Y., and Berger SA. (2004) Increased calcium influx and ribosomal content correlate with resistance to endoplasmic reticulum stress-induced cell death in mutant leukemia cell lines. J Biol Chem. 279, 6507–6516
15.Hiderou Y. (2007) ER stress and diseases. FEBS J. 274, 630-658
16.Hung CC., Ichimura T., Stevens JL., Bonventre JV. (2003) Protection of renal epithelial cells against oxidative injury by endoplasmic reticulum stress preconditioning is mediated by ERK1/2 activation. J Biol Chem. 278, 29317-29326
17.Chen LY., Chiang AS., Hung JJ., Hung HI., and Lai YK. (2000) Thapsigargin-induced grp78 expression is mediated by the increase of cytosolic free calcium in 9L rat brain tumor cells. J Cell Biochem. 78, 404-16
18.Li WW., Alexandre S., Cao C., and Lee A. S., (1993) Transactivation of the grp78 promoter by Ca2+ depletion. A comparative analysis with A23187 and the endoplasmic reticulum Ca2+-ATPase inhibitor thapsigargin. J Biol Chem. 268, 12003-9
19.Cao X., Zhou Y., and Lee AS. (1995) Requirement of Tyrosine- and Serine/Threonine Kinases in the Transcriptional Activation of the Mammalian grp78/BiP Promoter by Thapsigargin. J Biol Chem. 270, 494-502
20.Aragno M., Mastrocola R., Catalano MG., Brignardello E., Danni O., and Boccuzzi G., (2004) Oxidative Stress Impairs Skeletal Muscle Repair in Diabetic Rats Diabetes. 53, 1082 - 1088
21.Brookes PS., Yoon Y., Robotham JL., Anders MW., Sheu SS. (2004) Ca2+, ATP & ROS - a mitochondrial love/hate triangle. Am J Physiol Cell Physiol. 287, 817-833
22.Granados MP., Salido GM., Pariente JA., and Gonzalez A. (2004) Generation of ROS in response to CCK-8 stimulation in mouse pancreatic acinar cells. Mitochondrion. 3, 285-296
23.Lee HC., Wei YH. (2007) Oxidative Stress, mitochondrial DNA mutation, and apoptosis in aging. Exp Biol Med. 232, 592-606
24.Liu H., Miller E., van-de-Water B., and Stevens JL. (1998) Endoplasmic Reticulum Stress Proteins Block Oxidant-induced Ca2+ Increases and Cell Death J Biol Chem. 273, 12858-12862
25.Gorlach A., Klappa P., and Kietzmann T. (2006) The endoplasmic reticulum: folding, calcium homeostasis, signaling, and redox control. Antioxid Redox Signal. 8, 1391-418
26.Kowaltowski AJ., Castilho RF., and Vercesi AE. (1995) Ca2+-induced mitochondrial membrane permeabilization: role of coenzyme Q redox state. Am J Physiol. 269, 141-147
27.Kowaltowski AJ., Castilho RF., Grijalba MT., Bechara EJH., and Vercesi AE. (1996) Effect of inorganic phosphate concentration on the nature of inner mitochondrial membrane alterations mediated by Ca2+ ions. J Biol Chem. 271, 2929−2934.
28.Kowaltowski AJ., Castilho RF., and Vercesi AE. (1996) Opening of the mitochondrial permeability transition pore by uncoupling or inorganic phosphate in the presence of Ca2+ is dependent on mitochondrial-generated reactive oxygen species. FEBS Lett. 378, 150−152
29.Tsiotra PC., Tsigos C. (2006). Stress, the endoplasmic reticulum, and insulin resistance. Ann N Y Acad Sci. 1083, 63-76
30.Hseu YC., Chang WC., Hseu YT., Lee CY., Yech YJ., Chen PC., Chen JY. and Yang HL. (2002) Protection of oxidative damage by aqueous extract from Antrodia camphorata mycelia in normal human erythrocytes. Life Sci. 71, 469–82
31.Yang HL., Hseu YC., Chen JY., Yech YJ., Lu FJ., Wang HH., Lin PS., and Wang BC. (2006) Antrodia camphorata in submerged culture protects low density lipoproteins against oxidative modification. Am J Chin Med. 34, 217–31
32.Song TY., and Yen GC. (2003) Protective effects of fermented filtrate from Antrodia camphorata in submerged culture against CCl4-induced hepatic toxicity in rats. J Agric Food Chem. 51, 1571–7
33.Huang LC., Huang SJ., Chen CC., and Mau JL. (1999) Antioxidant properties of Antrodia camphorata. In properties of Antrodia camphorata, In Proceedings of the Third International Conference on Mushroom Biology and Mushroom Products, p.275-283.Sydeny, Australia.
34.Tanaka M., Kuie CW., Nagashima Y. and Taguchi T. (1988) Application of antioxidant Maillard reaction products from histidine and glucose to sadine products. Nippon Suisan Gakkaishi 54, 1141–409
35.Dorner AJ., Wasley LC., Raney P., Haugejorden S., Green M., and Kaufman RJ. (1990) The stress response in Chinese hamster ovary cells. Regulation of ERp72 and protein disulfide isomerase expression and secretion. J Biol Chem. 265, 22029–34
36.Price BD., Mannheim-Rodman LA., and Calderwood SK. (1992) Brefeldin A, thapsigargin, and AIF4- stimulate the accumulation of GRP78 mRNA in a cycloheximide dependent manner, whilst induction by hypoxia is independent of protein synthesis. J Cell Physiol. 152, 545–552
37.Balasubramanyam M., Premanand C., Sampathkumar R., and Mohan V. (2002) Rosiglitazone and troglitazone protect against Oxidative Stress: Possible role of Store-Operated Ca2+ Fluxes. Diabetes. (Suppl. 2) 54, A449
38.Harding HP., and Ron D. (2002). High white blood cell count is associated with a worsening of insulin sensitivity and predicts the development of type 2 diabetes. Diabetes. 51, 455-461
39.Bergeron A., Jorquera R., Orejuela D., and Tanguay RM. (2006) Involvement of endoplasmic reticulum stress in hereditary tyrosinemia type I. J Biol Chem. 281, 5329-34
40.He B. (2006) Viruses, endoplasmic reticulum stress, and interferon responses. Cell Death Differ. 13, 393-403
41.Ma Y., and Hendershot LM. (2004) The role of the unfolded protein response in tumour development: friend or foe? Nat Rev Cancer. 4, 966-77
42.Viswanathan M., Kim SK., Berdichevsky A., and Guarente L. (2005) A role for SIR-2.1 regulation of ER stress response genes in determining C. elegans life span. Dev Cell. 9, 605-15
43.Lindholm D., Wootz H., and Korhonen L. (2006) ER stress and neurodegenerative diseases. Cell Death Differ. 13, 385-92
44.Rao RV., and Bredesen D. (2004) Misfolded proteins, endoplasmic reticulum stress and neurodegeneration. Curr Opin Cell Biol. 16, 653-662.
45.Ji C., and Kaplowitz N. (2006) ER stress: can the liver cope? J Hepatol. 45, 321–333
46.Shirakata Y., and Koike K. (2003) Hepatitis B Virus X protein induces cell death by causing loss of mitochondrial membrane potential. J Biol Chem. 278, 22071-8
47.Wang HC., Huang WY., Lai MD., and Su IJ. (2006) Hepatitis B Virus pre-S mutants, ER stress, and hepatocarcinogenesis Cancer Sci. 97, 683-8
48.Hsieh YH., Su IJ., Wang HC., Chang WW., Lei HY., Lai MD., Chang WT., and Huang W. (2004) Pre-S mutant surface antigens in chronic hepatitis B virus infection induce oxidative stress and DNA damage. Carcinogenesis. 25, 2023-32
49.Zheng Y., Gao B., Ye L., Kong L., Jing W., Yang X., Wu Z., and Ye L. (2005) Hepatitis C virus non-structural protein NS4B can modulate an unfolded protein response. Microbiol. 43, 529-36
50.Li Y., Boehning DF., Qian T., Popov VL., and Weinman SA. (2007) Hepatitis C virus core protein increases mitochondrial ROS production by stimulation of Ca2+ uniporter activity FASEB J. Mar 28
51.Dou J., Liu P., Wang J., and Zhang X., (2006) Effect of hepatitis C virus core shadow protein expressed in human hepatoma cell line on human gene expression profiles. J Gastroenterol Hepatol. 21, 1794-800
52.Szegezdi E., Logue SE., Gorman AM., Samali A. (2006) Mediators of endoplasmic reticulum stress-induced apoptosis. EMBO Rep. 7, 880-5
53.Laybutt DR., Preston AM., Akerfeldt MC., Kench JG., Busch AK., Biankin AV., and Biden TJ. (2007) Endoplasmic reticulum stress contributes to beta cell apoptosis in type 2 diabetes. Diabetologia. 50, 752-763