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系統識別號 U0026-0812200914241193
論文名稱(中文) Oct-3/4 在膀胱癌臨床意義及標靶治療的可行性
論文名稱(英文) The significance of Oct-3/4 expression in bladder cancer and its potential as a therapeutic target
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 96
學期 2
出版年 97
研究生(中文) 張朝晴
研究生(英文) Chao-Ching Chang
學號 s5890133
學位類別 博士
語文別 英文
論文頁數 91頁
口試委員 召集委員-蘇五洲
口試委員-賴明德
口試委員-張文粲
口試委員-楊啟瑞
口試委員-戴明泓
指導教授-吳昭良
中文關鍵字 溶瘤腺病毒  膀胱癌  轉移  基因治療  幹細胞 
英文關鍵字 metastasis  Oct-3/4  bladder cancer  oncolytic adenovirus  tumor progression 
學科別分類
中文摘要 腫瘤細胞和胚胎幹細胞在生長上展現相似的能力,包括可以持續生長、還未分化狀態、以及具有侵入性的能力。由此,有其必要研究胚胎發育與腫瘤發生相關基因的表現。當不正常的表現某些胚胎時期的同源異形基因 ( Homeobox genes ) 可能會造成腫瘤的生成以及改變腫瘤的特性。Oct-3/4基因屬於同源異形基因的一員又稱作POU5F1,是胚胎幹細胞自我更新能力上關鍵的調控者。Oct-3/4只特定的表現在胚胎幹細胞以及某些腫瘤細胞上。此研究中,我們利用半定量RT-PCR以及西方點墨方法研究Oct-3/4在57個膀胱癌腫瘤檢體以及幾株膀胱癌細胞珠中的表現情形。我們發現︰幹細胞表達的標記基因Oct-3/4過量表達於人類膀胱癌組織以及膀胱癌細胞株上。然而,為何會表達Oct-3/4基因以及表達的細胞來源為何仍須進一步研究。在此研究中,我們發現Oct-3/4表現量與膀胱癌在臨床預後診斷有關,相較於中量或低量表現的膀胱癌組織,在表達較多Oct-3/4的膀胱癌組織中,發現病人有更進一步疾病的惡化、增加腫瘤的轉移以及預後存活率降低等。我們研究膀胱癌細胞株過量表達Oct-3/4,結果發現促進細胞的移動、侵入性、以及增加體內腫瘤轉移的能力並且發現Oct-3/4過量表現調控增加纖維母細胞生長因子 (FGF)-4以及間質金屬結合蛋白脢 (MMP)-2、MMP-9、MMP-13的表現。Oct-3/4特異性表現在膀胱癌腫瘤細胞或許可以當做腫瘤基因治療的標的基因。因此,更進一步,我們利用Oct-3/4 啟動子驅動E1B-55 kD-缺失的腺病毒 (Ad5WS4) 發現可以有效治療膀胱癌小鼠動物模式。總結,在此研究中,我們發現Oct-3/4或許可以當作膀胱癌預後徵兆的指標及治療膀胱癌的重要標的基因。
英文摘要 Cancer and embryonic stem cells exhibit similar behavior, including immortal, undifferentiated, and invasive activities. It is important to study genes associated with embryogenesis and tumorigenesis. Deregulated expression of certain embryonic homeobox genes is potentially correlated with tumorigenesis and can affect some aspects of tumor behavior. Homeobox gene, Oct-3/4 (also named as POU5F1) is a key regulator of selfrenewal in embryonic stem cells and specifically expressed in embryonic stem cells and certain tumor cells. We used semiquantitative RT-PCR and Western blotting to examine the expression of Oct-3/4 in 57 bladder tumor tissues and several bladder tumor cell lines. Here we demonstrate that expression of stem cell marker Oct-3/4 in human bladder transitional cell carcinoma samples and cell lines. However, the origin of Oct-3/4-expressing tumor cells needs to be identified. More importantly, we show in clinical samples bladder tumors with intense Oct-3/4 expression are associated with further disease progression, greater metastasis, and shorter cancer-related survival compared with those with moderate and low expressions. We used bladder cancer cell lines to confirm that Oct-3/4 overexpression promotes migration, invasion, and metastasis, as well as upregulates fibroblast growth factor (FGF)-4 and matrix metalloproteinase (MMP)-2, MMP-9, and MMP-13 productions. Oct-3/4 highly expressed in bladder cancer cells may be a potential target for cancer therapy. Therefore, we also illustrate the antitumor efficacy of E1B-55 kD-deleted adenovirus driven by Oct-3/4 promoter (Ad5WS4) in syngeneic tumor models. Our results implicate that Oct-3/4 may serve as a novel tumor biological and prognostic marker as well as a potential therapeutic target for bladder cancer.
論文目次 Chinese abstract ……………I
Abstract ……………II
Contents Table ……………IV
Index of Figures ……………VII
Index of Tables ……………X
Index of Supplementary Figures ……………XI
Abbreviations ……………XII
Introduction ……………1
1. Tumorigenesis and homeobox gene ……………1
2. Oct-3/4 ……………1
2.1. Oct-3/4 background ……………1
2.2. Oct-3/4 and cancer ……………2
2.3. Oct-3/4 and target genes ……………3
2.4. Oct-3/4 and its regulations ……………4
3. Cancer gene therapy ……………4
4. Adenovirus ……………5
5. Conditionally replicative adenoviruses (CRAds) ……………6
5.1. Genetic complementation-type CRAds ……………6
5.2. Transcomplementation-type CRAds ……………7
6. Bladder cancer ……………8
Specific Aim ……………10
Materials and Methods ……………11
Results ……………27
1. Oct-3/4 may be a novel tumor biological and prognostic marker of superficial bladder TCC ……………27
2. Oct-3/4 overexpression enhances whereas knockdown of Oct-3/4 expression reduces migration and invasion of bladder cancer cells ……………29
2.1. Generation of bladder cell lines stably overexpressing Oct-3/4 ……………29
2.2. Transcriptional effects of Oct-3/4 overexpression in human bladder cancer cells ……………30
2.3. Oct-3/4 enhances migration and invasion ……………30
3. Oct-3/4 overexpression promotes metastasis in animal tumor models ……………32
4. Oct-3/4 upregulates FGF-4 and MMP expressions in bladder cancer cells ……………32
5. Therapeutic efficacy of E1B-55 kD-deleted adenovirus regulated by Oct-3/4 promoter for bladder cancer ………………34
5.1. Oct-3/4 promoter is specifically active in bladder cancer cells, not in normal cells ……………34
5.2. Comparison of Ad5WS4 and Ad5WS1 ……………35
5.3. Ad5WS4 exerts cytolytic effect in vitro against bladder cancer cells ……………35
6. Oct-3/4 overexpression did not affect CAR expression and efficiency of adenovirus-mediated gene transfer ……………36
7. Antitumor effects of Ad5WS4 on murine bladder tumor model ……………36
Discussion ……………38
Conclusion ……………44
References ……………45
Appendix of Figures ……………55
Appendix of Tables ……………80
Appendix of Supplementary Figures ……………83
Curriculum Vitae ……………89
參考文獻 Abate-Shen,C. (2003). Homeobox genes and cancer: new OCTaves for an old tune. Cancer Cell 4, 329-330.

Al Hajj,M., Wicha,M.S., Benito-Hernandez,A., Morrison,S.J., and Clarke,M.F. (2003). Prospective identification of tumorigenic breast cancer cells. Proc. Natl. Acad. Sci. U. S. A. 100, 3983-3988.

Al Hajj,M. and Clarke,M.F. (2004). Self-renewal and solid tumor stem cells. Oncogene 23, 7274-7282.

Atlasi,Y., Mowla,S.J., Ziaee,S.A., and Bahrami,A.R. (2007). OCT-4, an embryonic stem cell marker, is highly expressed in bladder cancer. Int. J. Cancer 120, 1598-1602.

Ben Shushan,E., Thompson,J.R., Gudas,L.J., and Bergman,Y. (1998). Rex-1, a gene encoding a transcription factor expressed in the early embryo, is regulated via Oct-3/4 and Oct-6 binding to an octamer site and a novel protein, Rox-1, binding to an adjacent site. Mol. Cell Biol. 18, 1866-1878.

Bischoff,J.R., Kirn,D.H., Williams,A., Heise,C., Horn,S., Muna,M., Ng,L., Nye,J.A., Sampson-Johannes,A., Fattaey,A., and McCormick,F. (1996). An adenovirus mutant that replicates selectively in p53-deficient human tumor cells. Science 274, 373-376.

Bortvin,A., Eggan,K., Skaletsky,H., Akutsu,H., Berry,D.L., Yanagimachi,R., Page,D.C., and Jaenisch,R. (2003). Incomplete reactivation of Oct4-related genes in mouse embryos cloned from somatic nuclei. Development 130, 1673-1680.

Bostrom,P.J., Ravanti,L., Reunanen,N., Aaltonen,V., Soderstrom,K.O., Kahari,V.M., and Laato,M. (2000). Expression of collagenase-3 (matrix metalloproteinase-13) in transitional-cell carcinoma of the urinary bladder. Int. J. Cancer 88, 417-423.

Botquin,V., Hess,H., Fuhrmann,G., Anastassiadis,C., Gross,M.K., Vriend,G., and Scholer,H.R. (1998). New POU dimer configuration mediates antagonistic control of an osteopontin preimplantation enhancer by Oct-4 and Sox-2. Genes Dev. 12, 2073-2090.

Cantile,M., Cindolo,L., Napodano,G., Altieri,V., and Cillo,C. (2003). Hyperexpression of locus C genes in the HOX network is strongly associated in vivo with human bladder transitional cell carcinomas. Oncogene 22, 6462-6468.

Catena,R., Tiveron,C., Ronchi,A., Porta,S., Ferri,A., Tatangelo,L., Cavallaro,M., Favaro,R., Ottolenghi,S., Reinbold,R., Scholer,H., and Nicolis,S.K. (2004). Conserved POU binding DNA sites in the Sox2 upstream enhancer regulate gene expression in embryonic and neural stem cells. J. Biol. Chem. 279, 41846-41857.

Chen,K.N., Gu,Z.D., Ke,Y., Li,J.Y., Shi,X.T., and Xu,G.W. (2005). Expression of 11 HOX genes is deregulated in esophageal squamous cell carcinoma. Clin. Cancer Res. 11, 1044-1049.

Chew,J.L., Loh,Y.H., Zhang,W., Chen,X., Tam,W.L., Yeap,L.S., Li,P., Ang,Y.S., Lim,B., Robson,P., et al. (2005). Reciprocal transcriptional regulation of Pou5f1 and Sox2 via the Oct4/Sox2 complex in embryonic stem cells. Mol. Cell Biol. 25, 6031-6046.

Chiocca,E.A., Abbed,K.M., Tatter,S., Louis,D.N., Hochberg,F.H., Barker,F., Kracher,J., Grossman,S.A., Fisher,J.D., Carson,K., Rosenblum,M., Mikkelsen,T., Olson,J., Markert,J., Rosenfeld,S., Nabors,L.B., Brem,S., Phuphanich,S., Freeman,S., Kaplan,R., and Zwiebel,J. (2004). A phase I open-label, dose-escalation, multi-institutional trial of injection with an E1B-Attenuated adenovirus, ONYX-015, into the peritumoral region of recurrent malignant gliomas, in the adjuvant setting. Mol. Ther. 10, 958-966.

Covello,K.L., Kehler,J., Yu,H., Gordan,J.D., Arsham,A.M., Hu,C.J., Labosky,P.A., Simon,M.C., and Keith,B. (2006). HIF-2α regulates Oct-4: effects of hypoxia on stem cell function, embryonic development, and tumor growth. Genes Dev. 20, 557-570.

Ezeh,U.I., Turek,P.J., Reijo,R.A., and Clark,A.T. (2005). Human embryonic stem cell genes OCT4, NANOG, STELLAR, and GDF3 are expressed in both seminoma and breast carcinoma. Cancer 104, 2255-2265.

Galanis,E., Okuno,S.H., Nascimento,A.G., Lewis,B.D., Lee,R.A., Oliveira,A.M., Sloan,J.A., Atherton,P., Edmonson,J.H., Erlichman,C., Randlev,B., Wang,Q., Freeman,S., and Rubin,J. (2005). Phase I-II trial of ONYX-015 in combination with MAP chemotherapy in patients with advanced sarcomas. Gene Ther. 12, 437-445.

Gallagher,E.J., Lodge,P., Ansell,R., and McWhir,J. (2003). Isolation of murine embryonic stem and embryonic germ cells by selective ablation. Transgenic Res. 12, 451-460.

Gallimore,P.H. and Turnell,A.S. (2001). Adenovirus E1A: remodelling the host cell, a life or death experience. Oncogene 20, 7824-7835.

Gidekel,S., Pizov,G., Bergman,Y., and Pikarsky,E. (2003). Oct-3/4 is a dose-dependent oncogenic fate determinant. Cancer Cell 4, 361-370.

Hallden,G., Hill,R., Wang,Y., Anand,A., Liu,T.C., Lemoine,N.R., Francis,J., Hawkins,L., and Kirn,D. (2003). Novel immunocompetent murine tumor models for the assessment of replication-competent oncolytic adenovirus efficacy. Mol. Ther. 8, 412-424.

Han,S., Ritzenthaler,J.D., Sitaraman,S.V., and Roman,J. (2006). Fibronectin increases matrix metalloproteinase 9 expression through activation of c-Fos via extracellular-regulated kinase and phosphatidylinositol 3-kinase pathways in human lung carcinoma cells. J. Biol. Chem. 281, 29614-29624.

Hayakawa,T., Yamashita,K., Tanzawa,K., Uchijima,E., and Iwata,K. (1992). Growth-promoting activity of tissue inhibitor of metalloproteinases-1 (TIMP-1) for a wide range of cells. A possible new growth factor in serum. FEBS Lett. 298, 29-32.

He,T.C., Zhou,S., da Costa,L.T., Yu,J., Kinzler,K.W., and Vogelstein,B. (1998). A simplified system for generating recombinant adenoviruses. Proc. Natl. Acad. Sci. USA 95, 2509-2514.

Heise,C., Hermiston,T., Johnson,L., Brooks,G., Sampson-Johannes,A., Williams,A., Hawkins,L., and Kirn,D. (2000). An adenovirus E1A mutant that demonstrates potent and selective systemic anti-tumoral efficacy. Nat. Med. 6, 1134-1139.

Hochedlinger,K., Yamada,Y., Beard,C., and Jaenisch,R. (2005). Ectopic expression of Oct-4 blocks progenitor-cell differentiation and causes dysplasia in epithelial tissues. Cell 121, 465-477.

Hsieh,J.L., Wu,C.L., Lai,M.D., Lee,C.H., Tsai,C.S., and Shiau,A.L. (2003). Gene therapy for bladder cancer using E1B-55 kD-deleted adenovirus in combination with adenoviral vector encoding plasminogen kringles 1-5. Br. J. Cancer 88, 1492-1499.

Hsu,K.F., Wu,C.L., Huang,S.C., Hsieh,J.L., Huang,Y.S., Chen,Y.F., Shen,M.R., Chung,W.J., Chou,C.Y., and Shiau,A.L. (2008). Conditionally replicating E1B-deleted adenovirus driven by the squamous cell carcinoma antigen 2 promoter for uterine cervical cancer therapy. Cancer Gene Ther. (in press)

Ivanova,N., Dobrin,R., Lu,R., Kotenko,I., Levorse,J., DeCoste,C., Schafer,X., Lun,Y., and Lemischka,I.R. (2006). Dissecting self-renewal in stem cells with RNA interference. Nature 442, 533-538.

Jin,T., Branch,D.R., Zhang,X., Qi,S., Youngson,B., and Goss,P.E. (1999). Examination of POU homeobox gene expression in human breast cancer cells. Int. J. Cancer 81, 104-112.

Jones,T.D., Ulbright,T.M., Eble,J.N., and Cheng,L. (2004). OCT4: A sensitive and specific biomarker for intratubular germ cell neoplasia of the testis. Clin. Cancer Res. 10, 8544-8547.

Konduri,S.D., Yanamandra,N., Siddique,K., Joseph,A., Dinh,D.H., Olivero,W.C., Gujrati,M., Kouraklis,G., Swaroop,A., Kyritsis,A.P., et al. (2002). Modulation of cystatin C expression impairs the invasive and tumorigenic potential of human glioblastoma cells. Oncogene 21, 8705-8712.

Kanayama,H., Yokota,K., Kurokawa,Y., Murakami,Y., Nishitani,M., and Kagawa,S. (1998). Prognostic values of matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-2 expression in bladder cancer. Cancer 82, 1359-1366.

Kim,W.J. and Bae,S.C. (2008). Molecular biomarkers in urothelial bladder cancer. Cancer Sci. 99, 646-652.

Kraft,H.J., Mosselman,S., Smits,H.A., Hohenstein,P., Piek,E., Chen,Q., Artzt,K., and van Zoelen,E.J. (1996). Oct-4 regulates alternative platelet-derived growth factor alpha receptor gene promoter in human embryonal carcinoma cells. J. Biol. Chem. 271, 12873-12878.

Kuratomi,Y., Nomizu,M., Nielsen,P.K., Tanaka,K., Song,S.Y., Kleinman,H.K., and Yamada,Y. (1999). Identification of metastasis-promoting sequences in the mouse laminin alpha 1 chain. Exp. Cell Res. 249, 386-395.

Kuroda,T., Tada,M., Kubota,H., Kimura,H., Hatano,S.Y., Suemori,H., Nakatsuji,N., and Tada,T. (2005). Octamer and Sox elements are required for transcriptional cis regulation of Nanog gene expression. Mol. Cell Biol. 25, 2475-2485.

Li,C., Heidt,D.G., Dalerba,P., Burant,C.F., Zhang,L., Adsay,V., Wicha,M., Clarke,M.F., and Simeone,D.M. (2007). Identification of pancreatic cancer stem cells. Cancer Res. 67, 1030-1037.

Li,Y., Pong,R.C., Bergelson,J.M., Hall,M.C., Sagalowsky,A.I., Tseng,C.P., Wang,Z., and Hsieh,J.T. (1999). Loss of adenoviral receptor expression in human bladder cancer cells: a potential impact on the efficacy of gene therapy. Cancer Res. 59, 325-330.

Liotta,L.A., Tryggvason,K., Garbisa,S., Hart,I., Foltz,C.M., and Shafie,S. (1980). Metastatic potential correlates with enzymatic degradation of basement membrane collagen. Nature 284, 67-68.

Lo,J. and Hurta,R.A. (2002). Over-expression of K-FGF or bFGF results in altered expression of matrix metalloproteinases: correlations with malignant progression and cellular invasion. Cell Biol. Int. 26, 319-325.

Looijenga,L.H., Stoop,H., de Leeuw,H.P., Gouveia Brazao,C.A., Gillis,A.J., van Roozendaal,K.E., van Zoelen,E.J., Weber,R.F., Wolffenbuttel,K.P., van Dekken,H., et al. (2003). POU5F1 (OCT3/4) identifies cells with pluripotent potential in human germ cell tumors. Cancer Res. 63, 2244-2250.

Makower,D., Rozenblit,A., Kaufman,H., Edelman,M., Lane,M.E., Zwiebel,J., Haynes,H., and Wadler,S. (2003). Phase II clinical trial of intralesional administration of the oncolytic adenovirus ONYX-015 in patients with hepatobiliary tumors with correlative p53 studies. Clin. Cancer Res. 9, 693-702.

Matoba,R., Niwa,H., Masui,S., Ohtsuka,S., Carter,M.G., Sharov,A.A., and Ko,M.S. (2006). Dissecting Oct3/4-regulated gene networks in embryonic stem cells by expression profiling. PLoS. ONE 2006. 1, e26.

McLeskey,S.W., Kurebayashi,J., Honig,S.F., Zwiebel,J., Lippman,M.E., Dickson,R.B., and Kern,F.G. (1993). Fibroblast growth factor 4 transfection of MCF-7 cells produces cell lines that are tumorigenic and metastatic in ovariectomized or tamoxifen-treated athymic nude mice. Cancer Res. 53, 2168-2177.

Miyazaki,Y.J., Hamada,J., Tada,M., Furuuchi,K., Takahashi,Y., Kondo,S., Katoh,H., and Moriuchi,T. (2002). HOXD3 enhances motility and invasiveness through the TGF-β-dependent and -independent pathways in A549 cells. Oncogene 21, 798-808.

Monk,M. and Holding,C. (2001). Human embryonic genes re-expressed in cancer cells. Oncogene 20, 8085-8091.

Nemunaitis,J., Senzer,N., Sarmiento,S., Zhang,Y.A., Arzaga,R., Sands,B., Maples,P., and Tong,A.W. (2007). A phase I trial of intravenous infusion of ONYX-015 and enbrel in solid tumor patients. Cancer Gene Ther. 14, 885-893.

Niwa,H., Miyazaki,J., and Smith,A.G. (2000). Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells. Nat Genet 24, 372-376.

Niwa,Y., Kanda,H., Shikauchi,Y., Saiura,A., Matsubara,K., Kitagawa,T., Yamamoto,J., Kubo,T., and Yoshikawa,H. (2005). Methylation silencing of SOCS-3 promotes cell growth and migration by enhancing JAK/STAT and FAK signalings in human hepatocellular carcinoma. Oncogene 24, 6406-6417.

Okamoto,K., Okazawa,H., Okuda,A., Sakai,M., Muramatsu,M., and Hamada,H. (1990). A novel octamer binding transcription factor is differentially expressed in mouse embryonic cells. Cell 60, 461-472.

Okegawa,T., Pong,R.C., Li,Y., Bergelson,J.M., Sagalowsky,A.I., and Hsieh,J.T. (2001). The mechanism of the growth-inhibitory effect of coxsackie and adenovirus receptor (CAR) on human bladder cancer: a functional analysis of car protein structure. Cancer Res. 61, 6592-6600.

Okuda,A., Fukushima,A., Nishimoto,M., Orimo,A., Yamagishi,T., Nabeshima,Y., Kuro-o M, Nabeshima,Y., Boon,K., Keaveney,M., Stunnenberg,H.G., and Muramatsu,M. (1998). UTF1, a novel transcriptional coactivator expressed in pluripotent embryonic stem cells and extra-embryonic cells. EMBO J. 17, 2019-2032.

Patrawala,L., Calhoun,T., Schneider-Broussard,R., Li,H., Bhatia,B., Tang,S., Reilly,J.G., Chandra,D., Zhou,J., Claypool,K., et al. (2006). Highly purified CD44+ prostate cancer cells from xenograft human tumors are enriched in tumorigenic and metastatic progenitor cells. Oncogene 25, 1696-1708.

Pesce,M. and Scholer,H.R. (2001). Oct-4: gatekeeper in the beginnings of mammalian development. Stem Cells 19, 271-278.

Petrella,B.L. and Brinckerhoff,C.E. (2006). Tumor cell invasion of von Hippel Lindau renal cell carcinoma cells is mediated by membrane type-1 matrix metalloproteinase. Mol. Cancer 5, 66.

Pikarsky,E., Sharir,H., Ben Shushan,E., and Bergman,Y. (1994). Retinoic acid represses Oct-3/4 gene expression through several retinoic acid-responsive elements located in the promoter-enhancer region. Mol. Cell Biol. 14, 1026-1038.

Rao,L., Debbas,M., Sabbatini,P., Hockenbery,D., Korsmeyer,S., and White,E. (1992). The adenovirus E1A proteins induce apoptosis, which is inhibited by the E1B 19-kDa and Bcl-2 proteins. Proc. Natl. Acad. Sci. U. S. A. 89, 7742-7746.

Rieger-Christ,K.M., Lee,P., Zagha,R., Kosakowski,M., Moinzadeh,A., Stoffel,J., Ben Ze'ev,A., Libertino,J.A., and Summerhayes,I.C. (2004). Novel expression of N-cadherin elicits in vitro bladder cell invasion via the Akt signaling pathway. Oncogene 23, 4745-4753.

Rodda,D.J., Chew,J.L., Lim,L.H., Loh,Y.H., Wang,B., Ng,H.H., and Robson,P. (2005). Transcriptional regulation of nanog by OCT4 and SOX2. J. Biol. Chem. 280, 24731-24737.

Rosner,M.H., Vigano,M.A., Ozato,K., Timmons,P.M., Poirier,F., Rigby,P.W., and Staudt,L.M. (1990). A POU-domain transcription factor in early stem cells and germ cells of the mammalian embryo. Nature 345, 686-692.

Sachs,M.D., Ramamurthy,M., Poel,H., Wickham,T.J., Lamfers,M., Gerritsen,W., Chowdhury,W., Li,Y., Schoenberg,M.P., and Rodriguez,R. (2004). Histone deacetylase inhibitors upregulate expression of the coxsackie adenovirus receptor (CAR) preferentially in bladder cancer cells. Cancer Gene Ther. 11, 477-486.

Saijoh,Y., Fujii,H., Meno,C., Sato,M., Hirota,Y., Nagamatsu,S., Ikeda,M., and Hamada,H. (1996). Identification of putative downstream genes of Oct-3, a pluripotent cell-specific transcription factor. Genes Cells 1, 239-252.

Schmitz-Drager,B.J., Goebell,P.J., Ebert,T., and Fradet,Y. (2000). p53 immunohistochemistry as a prognostic marker in bladder cancer. Playground for urology scientists? Eur. Urol. 38, 691-699.

Sebestyen,Z., de Vrij,J., Magnusson,M., Debets,R., and Willemsen,R. (2007). An oncolytic adenovirus redirected with a tumor-specific T-cell receptor. Cancer Res. 67, 11309-11316.

Shieh,G.S., Shiau,A.L., Yo,Y.T., Lin,P.R., Chang,C.C., Tzai,T.S., and Wu,C.L. (2006). Low-dose etoposide enhances telomerase-dependent adenovirus-mediated cytosine deaminase gene therapy through augmentation of adenoviral infection and transgene expression in a syngeneic bladder tumor model. Cancer Res. 66, 9957-9966.

Singh,S.K., Hawkins,C., Clarke,I.D., Squire,J.A., Bayani,J., Hide,T., Henkelman,R.M., Cusimano,M.D., and Dirks,P.B. (2004). Identification of human brain tumour initiating cells. Nature 432, 396-401.

Sung,M.T., Jones,T.D., Beck,S.D., Foster,R.S., and Cheng,L. (2006). OCT4 is superior to CD30 in the diagnosis of metastatic embryonal carcinomas after chemotherapy. Hum. Pathol. 37, 662-667.

Tai,M.H., Chang,C.C., Olson,L.K., and Trosko,J.E. (2005). Oct4 expression in adult human stem cells: evidence in support of the stem cell theory of carcinogenesis. Carcinogenesis 26, 495-502.

Tanaka,T.S., Kunath,T., Kimber,W.L., Jaradat,S.A., Stagg,C.A., Usuda,M., Yokota,T., Niwa,H., Rossant,J., and Ko,M.S. (2002). Gene expression profiling of embryo-derived stem cells reveals candidate genes associated with pluripotency and lineage specificity. Genome Res. 12, 1921-1928.

Thomson,J.M. and Parrott,W.A. (1998). pMECA: a cloning plasmid with 44 unique restriction sites that allows selection of recombinants based on colony size. Biotechniques 24, 922-4, 926, 928.

Tokuzawa,Y., Kaiho,E., Maruyama,M., Takahashi,K., Mitsui,K., Maeda,M., Niwa,H., and Yamanaka,S. (2003). Fbx15 is a novel target of Oct3/4 but is dispensable for embryonic stem cell self-renewal and mouse development. Mol. Cell Biol. 23, 2699-2708.

Tseng,V.S.M., Chen,L.C., and Liu,J.J. (2004). Design of an integrated and effective platform for gene expression data mining. J. Libr. Inf. Sci. 30, 20-33.

Vaha-Koskela,M.J., Heikkila,J.E., and Hinkkanen,A.E. (2007). Oncolytic viruses in cancer therapy. Cancer Lett. 254, 178-216.

Van Themsche,C., Mathieu,I., Parent,S., and Asselin,E. (2007). Transforming growth factor-β3 increases the invasiveness of endometrial carcinoma cells through phosphatidylinositol 3-kinase-dependent upregulation of X-linked inhibitor of apoptosis and protein kinase C-dependent induction of matrix metalloproteinase-9. J. Biol. Chem. 282, 4794-4802.

Wai,P.Y. and Kuo,P.C. (2004). The role of osteopontin in tumor metastasis. J. Surg. Res. 121, 228-241.

Wallard,M.J., Pennington,C.J., Veerakumarasivam,A., Burtt,G., Mills,I.G., Warren,A., Leung,H.Y., Murphy,G., Edwards,D.R., Neal,D.E., et al. (2006). Comprehensive profiling and localisation of the matrix metalloproteinases in urothelial carcinoma. Br. J. Cancer 94, 569-577.

Wang,P., Branch,D.R., Bali,M., Schultz,G.A., Goss,P.E., and Jin,T. (2003). The POU homeodomain protein OCT3 as a potential transcriptional activator for fibroblast growth factor-4 (FGF-4) in human breast cancer cells. Biochem. J. 375, 199-205.

Wu,C.L., Shieh,G.S., Chang,C.C., Yo,Y.T., Su,C.H., Chang,M.Y., Huang,Y.H., Wu,P., and Shiau,A.L. (2008). Tumor-selective replication of an oncolytic adenovirus carrying Oct-3/4 response elements in murine metastatic bladder cancer models. Clin. Cancer Res.14, 1228-1238.

Yuan,H., Corbi,N., Basilico,C., and Dailey,L. (1995). Developmental-specific activity of the FGF-4 enhancer requires the synergistic action of Sox2 and Oct-3. Genes Dev. 9, 2635-2645.
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