尿嘧啶雙磷酸葡萄糖去氫酵素參與人類大腸癌HCT-8細胞的致瘤性及藥物感受性

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研究生：	王宗葆 Wang, Tsung-Pao
論文名稱：	尿嘧啶雙磷酸葡萄糖去氫酵素參與人類大腸癌HCT-8細胞的致瘤性及藥物感受性 Participation of UDP-glucose dehydrogenase in HCT-8 colorectal carcinoma cell tumorigenicity and drug susceptibility
指導教授：	張晃猷
口試委員:	楊裕雄李佳霖陳令儀李秀珠
學位類別：	博士 Doctor
系所名稱：	生命科學暨醫學院 - 分子醫學研究所 Institute of Molecular Medicine
論文出版年：	2013
畢業學年度：	102
語文別：	英文
論文頁數：	104
中文關鍵詞：	尿嘧啶雙磷酸葡萄糖去氫酵素、癌症幹細胞、糖胺聚糖、透明質酸、大腸直腸癌
外文關鍵詞：	UDP-glucose dehydrogenas, cancer stem cell, glycosaminoglycans, hyaluronic acid, colorectal carcinoma
相關次數：	點閱：1 下載：0
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尿嘧啶雙磷酸葡萄糖去氫酵素 (UDP-glucose dehydrogenase, UGDH) 催化尿嘧啶雙磷酸葡萄糖 (UDP-glucose)，變成尿嘧啶雙磷酸葡萄糖醛酸 (UDP-glucuronic acid) 的氧化反應，是用來合成在細胞外間質中糖胺聚糖 (glycosaminoglycans, GAGs) 的基質，也是葡萄糖醛酸反應中，幫助一些外來質物形成親水性代謝物。眾多的證據指出，GAGs對於正常細胞的生理反應和腫瘤演進的訊息傳遞，扮演重要的調節角色。儘管細胞外基質與細胞增生、遷移的關係已經被充分的證實，但UGDH在上述行為中的重要性，仍然不清楚。本研究在人類腸癌細胞HCT-8中，使用特定的siRNA去降低UGDH基因表現時，UDP-glucuronic acid、GAGs和透明質酸 (hyaluronic acid) 的含量會降低。在對於UGDH具有專一性的siRNA和玻尿酸合成抑制劑4-甲基傘形酮 (4-methylumbelliferone) 的處理下，能有效的延遲細胞聚成多細胞球體 (multicellular spheroids) 、減弱細胞在三維膠原蛋白膠體的移行能力以及腫瘤細胞的入侵。而被減弱的細胞移行與團聚的能力可以藉由外加外源性玻尿酸來重新恢復。
藉由調控UGDH的活性來測定是否影響人類腸癌細胞HCT-8的腫瘤形成和藥物敏感性，是接下來的研究目標。在UGDH基因表現下降的HCT-8細胞中，進一步的分析幾個癌症幹細胞的特性，顯示其細胞的非貼附性生長能力減弱，以及癌症幹細胞的表面抗原CD44分佈受到改變。除此之外，UGDH基因抑制能減少邊緣族群的細胞群落和增加HCT-8細胞對於抗癌藥物Irinotecan的敏感性。而在UGDH基因抑制的HCT-8細胞中，藥物敏感性的增加伴隨著Irinotecan代謝能力的下降。最後，在異種移植老鼠實驗模型中，UGDH基因抑制可以顯著的減少由細胞球體來源之HCT-8細胞所引起的致瘤性。全部的結果都指出UGDH在大腸直腸癌中扮演重要的角色以及可成為具有治療上的標的。

UDP-glucose dehydrogenase (UGDH) catalyzes oxidation of UDP-glucose to yield UDP-glucuronic acid, a substrate for synthesis of glycosaminoglycans in extracellular matrix and for glucuronidation of certain xenobiotics to aid in their solubilization. Accumulating evidence has demonstrated that glycosaminoglycans play an important role in regulating normal cell physiology and signaling during tumor progression. Although association of extracellular matrix with cell proliferation and migration has been well documented, the importance of UGDH in these behaviors is not clear. Using specific small interference RNA to down regulate UGDH expression, the levels of cellular UDP-glucuronic acid, glycosaminoglycans and hyaluronic acid were decreased in the HCT-8 colorectal carcinoma cells. Treatment of HCT-8 cells with either UGDH-specific siRNA or HA synthesis inhibitor 4-methylumbelliferone effectively delayed cell aggregation into multicellular spheroids and impaired cell motility in both three-dimensional collagen gel and transwell migration assays. The reduction in cell aggregation and migration rates could be restored by addition of exogenous HA.
Continuously, the aim of this study is to determine whether modulating UGDH activity can affect tumor formation and drug susceptibility of HCT-8 colorectal carcinoma cells. Further analysis of several cancer stem cell properties in the UGDH down regulated HCT-8 cells revealed that the anchorage independent growth ability of the cells was reduced and the cellular distribution of the cancer stem cell marker CD44 was altered. Moreover, UGDH knockdown decreased the side population cell fraction and increased the susceptibility of HCT-8 cells to anticancer drug Irinotecan. The enhancement of the drug susceptibility in the UGDH knockdown cells was accompanied with a decrease of Irinotecan metabolism. Finally, the tumorigenicity of the sphere-derived HCT-8 cells was significantly reduced upon UGDH knockdown in a xenograft mouse model. All these results indicate that UGDH plays an important role in colorectal cancer development and can serve as a potential therapeutic target.

Table of Contents
    Page
Table of Contents    II
Abstract (English)    VI
Abstract (Chinese)    VIII
Acknowledgement    
Abbreviations    X
    
Chapter 1  General Introduction    1
1.1. Introduction    2
Chapter 2  Materials and Methods    7
2.1. Cell lines, culture conditions, and transfection    8
2.2. RNA extraction, reverse transcription (RT), and quantitative real-time PCR (qPCR)    9
2.3. Western blotting analysis    10
2.4. Extraction of intracellular naucleotide sugars    10
2.5. Ion pair HPLC analysis of nucleotide sugars    11
2.6. Quantitative measurement of glycosaminoglycans (GAG)    12
2.7. In-cell Western assay    14
2.8. Cell proliferation and survival assays    14
2.9. Multicellular spheroid culture    15
2.10. Measurement of cell migration by wound healing assay    15
2.11. Three-dimensional collagen gel cell motility assay    16
2.12. Transwell migration assay    16
2.13. Measurement of HA concentration in medium    17
2.14. Lentivirus preparation, viral infection, and stable transfection clone generation    17
2.15. Anchorage-independent growth assay    18
2.16. Sphere forming ability assay    19
2.17. Hoechst 33342 staining and fluorescence activated cell sorter (FACS) analysis    19
2.18. Immunocytostaining    20
2.19. Lactate dehydrogenase (LDH) cytotoxicity assay    21
2.20. Determination of Irinotecan concentration by fluorescence spectrometry    21
2.21. Xenograft-tumor animal model    22
2.22. Statistical analysis    23
Chapter 3  Results    24
Part I Down-regulation of UDP-glucose dehydrogenase affects glycosaminoglycans synthesis and motility in HCT-8 colorectal carcinoma cells    25
3.1. Suppression of human UGDH expression by siRNA    26
3.2. Influence of intracellular UDP-GlcUA content by UGDH siRNA and 4-MU treatment    26
3.3. The amounts of HA in HCT-8 cells are reduced by UGDH siRNA and 4-MU   treatments    27
3.4. Inhibition of HCT-8 cells proliferation by UGDH siRNA    28
3.5. Down regulation of UGDH results in delayed multicellular spheroid formation    29
3.6. Effect of UGDH expression on HCT-8 cell migration    30
3.7. Inhibition of invasive activity of HCT-8 cells by down-regulating UGDH    30
Part II  Reducing growth and increasing drug susceptibility of colorectal tumor HCT-8 cells by down regulating UDP-glucose dehydrogenase gene expression    47
3.8. The amounts of HA in HCT-8 cells are reduced by lentivirus-based RNAi delivery    48
3.9. The reduction in HCT-8 cell growth by down regulating UGDH involves reduced HA synthesis levels and HA-CD44 interaction    49
3.10. UGDH involves in HCT-8 CSC growth    49
3.11.     UGDH knockdown reduces side population (SP) fraction of HCT-8 cells    50
3.12. Alteration of CD44 distribution in HCT-8 cells by down regulation of UGDH expression    51
3.13. Down-regulation of UGDH enhances the susceptibility of HCT-8 cells to CPT-11    52
3.14. Silencing of UGDH expression significantly decrease the SP ratio in HCT-8 cells with anticancer drug treatment    53
3.15. Effects of UGDH down regulation on tumorigenicity of HCT-8in mouse model    54
3.16. Reduced tumor progression by intrtumoral delivery of shUGDH    55
Chapter 4  Discussion    88
4.1. Discussion    89
Table and figures    23
Part I Down-regulation of UDP-glucose dehydrogenase affects glycosaminoglycans synthesis and motility in HCT-8 colorectal carcinoma cells    
Fig. 1-1. Downregulation of UGDH transcript and protein levels by siRNA.    33
Fig. 1-2. Cellular levels of UDP-GlcUA are reduced in HCT-8 cells treated with siRNA and 4-MU.    34
Fig. 1-3. Effects of UGDH down regulation on GAG production in HCT-8 cells.    35
Fig. 1-4. Effects of UGDH down regulation on HA production in HCT-8 cells.    37
Fig. 1-5. Effects of UGDH down regulation on HCT-8 cell proliferation.    39
Fig. 1-6. Effects of UGDH down regulation on HCT-8 cell aggregation into multicellular spheroids.    40
Fig. 1-7. Effects of UGDH down regulation on HCT-8 cell migration.    42
Fig. 1-8. Effects of UGDH down regulation on HCT-8 cell outgrowth in collagen gels.    44
Fig. 1-9. Reduction of HCT-8 cell motility by down regulation of UGDH.    46
Part II  Reducing growth and increasing drug susceptibility of colorectal tumor HCT-8 cells by down regulating UDP-glucose dehydrogenase gene expression    
Fig. 2-1. Effects of UGDH down-regulation on HA production in HCT-8 cell spheres.    57
Fig. 2-2. Down regulation of UGDH reduces HCT-8 cells proliferation and the effect involves HA-CD44 interaction.    59
Fig. 2-3. Ability of anchorage-independent growth of HCT-8 cell is reduced on UGDH down regulation.    61
Fig. 2-4. UGDH down regulation in HCT-8 cells reduced sphere formation rates.    63
Fig. 2-5. The effects of UGDH knockdown on the ratio of SP cells in HCT-8 cell line.    65
Fig. 2-6. Distribution of CD44 in normal HCT-8 and stable UGDH knockdown cells with or without exogenous HA supplement.    68
Fig. 2-7. Down-regulation of UGDH in HCT-8 cells contributes to anticancer drug sensitivity.    70
Fig. 2-8. The effects of UGDH knockdown on the ratio of SP cells in HCT-8 cell line with anticancer drug treatments.    72
Fig. 2-9. Effects of intratumoral injection of shUGDH on tumor progession.    74
Table 1. Primer sequences for Real-Time PCR analysis in this study.    75
Supplementary tables and Figures    76
Table S1. Primer sequences for Real-Time PCR analysis in the study.    77
Fig. S1. Effects of 4-MU treatment on HCT-8 cell viability.    78
Fig. S2. Effects of siRNA and 4-MU treatments on the expression of HA synthesis genes in HCT-8 cells after.    79
Fig. S3. Analysis of UDP-GlcUA in HCT-8 cells by Ion-pair RP-HPLC    81
Fig. S4. Effects of UGDH down regulation on GAG production in HCT-8 cells.    82
Fig. S5. Immunohistochemistry for sphere-derived HCT-8 cells in subcutaneous tumor xenografts.        83
Fig. S6.    The effects of UGDH knockdown on the ratio of SP cells in HCT-8 cell line.    84
Fig. S7. The sensitivity of the anti-HA antibody. 96-well plates were coated with carboxymethylcellulose (3 mg/ml) and HA (3 mg/ml & 3 μg/ml).    86
Fig. S8. Tumorigenicity of sphere-forming cells of UGDH knockdown in NOD/SCID mice.    87
References    94

                                

[1] A. McGarry, P.B. Gahan, A quantitative cytochemical study of UDP-D-glucose: NAD-oxidoreductase (E.C. 1.1.1.22) activity during stelar differentiation in Pisum sativum L. cv Meteor, Histochemistry 83 (1985) 551-554.
[2] M. Rizzotti, D. Cambiaghi, F. Gandolfi, S. Rindi, R. Salvini, G. De Luca, The effect of extracellular matrix modifications on UDP-glucose dehydrogenase activity in cultured human skin fibroblasts, Basic and applied histochemistry 30 (1986) 85-92.
[3] D. Vigetti, M. Viola, E. Karousou, M. Rizzi, P. Moretto, A. Genasetti, M. Clerici, V.C. Hascall, G. De Luca, A. Passi, Hyaluronan-CD44-ERK1/2 regulate human aortic smooth muscle cell motility during aging, J Biol Chem 283 (2008) 4448-4458.
[4] H. Bakker, T. Oka, A. Ashikov, A. Yadav, M. Berger, N.A. Rana, X. Bai, Y. Jigami, R.S. Haltiwanger, J.D. Esko, R. Gerardy-Schahn, Functional UDP-xylose transport across the endoplasmic reticulum/Golgi membrane in a Chinese hamster ovary cell mutant defective in UDP-xylose Synthase, J Biol Chem 284 (2009) 2576-2583.
[5] W. Knudson, C. Biswas, X.Q. Li, R.E. Nemec, B.P. Toole, The role and regulation of tumour-associated hyaluronan, Ciba Found Symp 143 (1989) 150-159; discussion 159-169, 281-155.
[6] T.C. Laurent, J.R. Fraser, Hyaluronan, Faseb J 6 (1992) 2397-2404.
[7] S.C. Hauser, J.C. Ziurys, J.L. Gollan, Subcellular distribution and regulation of hepatic bilirubin UDP-glucuronyltransferase, J Biol Chem 259 (1984) 4527-4533.
[8] J. Vatsyayan, S.J. Lee, H.Y. Chang, Effects of xenobiotics and peroxisome proliferator-activated receptor-alpha on the human UDPglucose dehydrogenase gene expression, J Biochem Mol Toxicol 19 (2005) 279-288.
[9] M. Vargas, M.R. Franklin, Intestinal UDP-glucuronosyltransferase activities in rat and rabbit, Xenobiotica 27 (1997) 413-421.
[10] M. Princivalle, A. de Agostini, Developmental roles of heparan sulfate proteoglycans: a comparative review in Drosophila, mouse and human, Int J Dev Biol 46 (2002) 267-278.
[11] A. Bishayee, M. Chatterjee, Anticarcinogenic biological response of Mikania cordata: reflections in hepatic biotransformation systems, Cancer Lett 81 (1994) 193-200.
[12] S. Ghatak, S. Misra, B.P. Toole, Hyaluronan constitutively regulates ErbB2 phosphorylation and signaling complex formation in carcinoma cells, J Biol Chem 280 (2005) 8875-8883.
[13] P. Auvinen, R. Tammi, J. Parkkinen, M. Tammi, U. Agren, R. Johansson, P. Hirvikoski, M. Eskelinen, V.M. Kosma, Hyaluronan in peritumoral stroma and malignant cells associates with breast cancer spreading and predicts survival, Am J Pathol 156 (2000) 529-536.
[14] M.A. Anttila, R.H. Tammi, M.I. Tammi, K.J. Syrjanen, S.V. Saarikoski, V.M. Kosma, High levels of stromal hyaluronan predict poor disease outcome in epithelial ovarian cancer, Cancer Res 60 (2000) 150-155.
[15] K. Ropponen, M. Tammi, J. Parkkinen, M. Eskelinen, R. Tammi, P. Lipponen, U. Agren, E. Alhava, V.M. Kosma, Tumor cell-associated hyaluronan as an unfavorable prognostic factor in colorectal cancer, Cancer Res 58 (1998) 342-347.
[16] S. Aaltomaa, P. Lipponen, R. Tammi, M. Tammi, J. Viitanen, J.P. Kankkunen, V.M. Kosma, Strong Stromal Hyaluronan Expression Is Associated with PSA Recurrence in Local Prostate Cancer, Urol Int 69 (2002) 266-272.
[17] M.A. Simpson, C.M. Wilson, J.B. McCarthy, Inhibition of prostate tumor cell hyaluronan synthesis impairs subcutaneous growth and vascularization in immunocompromised mice, Am J Pathol 161 (2002) 849-857.
[18] S. Misra, L.M. Obeid, Y.A. Hannun, S. Minamisawa, F.G. Berger, R.R. Markwald, B.P. Toole, S. Ghatak, Hyaluronan constitutively regulates activation of COX-2-mediated cell survival activity in intestinal epithelial and colon carcinoma cells, J Biol Chem 283 (2008) 14335-14344.
[19] L.Y. Bourguignon, K. Peyrollier, W. Xia, E. Gilad, Hyaluronan-CD44 interaction activates stem cell marker Nanog, Stat-3-mediated MDR1 gene expression, and ankyrin-regulated multidrug efflux in breast and ovarian tumor cells, J Biol Chem 283 (2008) 17635-17651.
[20] A. Yasuda, H. Sawai, H. Takahashi, N. Ochi, Y. Matsuo, H. Funahashi, M. Sato, Y. Okada, H. Takeyama, T. Manabe, Stem cell factor/c-kit receptor signaling enhances the proliferation and invasion of colorectal cancer cells through the PI3K/Akt pathway, Dig Dis Sci 52 (2007) 2292-2300.
[21] S. Misra, B.P. Toole, S. Ghatak, Hyaluronan constitutively regulates activation of multiple receptor tyrosine kinases in epithelial and carcinoma cells, J Biol Chem 281 (2006) 34936-34941.
[22] L. Du, H. Wang, L. He, J. Zhang, B. Ni, X. Wang, H. Jin, N. Cahuzac, M. Mehrpour, Y. Lu, Q. Chen, CD44 is of functional importance for colorectal cancer stem cells, Clin Cancer Res 14 (2008) 6751-6760.
[23] C. Sheridan, H. Kishimoto, R.K. Fuchs, S. Mehrotra, P. Bhat-Nakshatri, C.H. Turner, R. Goulet, Jr., S. Badve, H. Nakshatri, CD44+/CD24- breast cancer cells exhibit enhanced invasive properties: an early step necessary for metastasis, Breast Cancer Res 8 (2006) R59.
[24] A.L. Omara-Opyene, J.X. Qiu, G.V. Shah, K.A. Iczkowski, Prostate cancer invasion is influenced more by expression of a CD44 isoform including variant 9 than by Muc18, Lab Invest 84 (2004) 894-907.
[25] Y. Li, P. Heldin, Hyaluronan production increases the malignant properties of mesothelioma cells, Br J Cancer 85 (2001) 600-607.
[26] A. Avigdor, P. Goichberg, S. Shivtiel, A. Dar, A. Peled, S. Samira, O. Kollet, R. Hershkoviz, R. Alon, I. Hardan, H. Ben-Hur, D. Naor, A. Nagler, T. Lapidot, CD44 and hyaluronic acid cooperate with SDF-1 in the trafficking of human CD34+ stem/progenitor cells to bone marrow, Blood 103 (2004) 2981-2989.
[27] Y.J. Su, H.M. Lai, Y.W. Chang, G.Y. Chen, J.L. Lee, Direct reprogramming of stem cell properties in colon cancer cells by CD44, EMBO J 30 (2011) 3186-3199.
[28] C.A. O'Brien, A. Pollett, S. Gallinger, J.E. Dick, A human colon cancer cell capable of initiating tumour growth in immunodeficient mice, Nature 445 (2007) 106-110.
[29] N.J. Maitland, A.T. Collins, Prostate cancer stem cells: a new target for therapy, J Clin Oncol 26 (2008) 2862-2870.
[30] N.A. Dallas, L. Xia, F. Fan, M.J. Gray, P. Gaur, G. van Buren, 2nd, S. Samuel, M.P. Kim, S.J. Lim, L.M. Ellis, Chemoresistant colorectal cancer cells, the cancer stem cell phenotype, and increased sensitivity to insulin-like growth factor-I receptor inhibition, Cancer Res 69 (2009) 1951-1957.
[31] W. Matsui, Q. Wang, J.P. Barber, S. Brennan, B.D. Smith, I. Borrello, I. McNiece, L. Lin, R.F. Ambinder, C. Peacock, D.N. Watkins, C.A. Huff, R.J. Jones, Clonogenic multiple myeloma progenitors, stem cell properties, and drug resistance, Cancer Res 68 (2008) 190-197.
[32] T. Chen, Y. Zhang, W.H. Guo, M.B. Meng, X.M. Mo, Y. Lu, Effects of heterochromatin in colorectal cancer stem cells on radiosensitivity, Chin J Cancer 29 (2010) 270-276.
[33] C. Kurkjian, S. Kummar, Advances in the treatment of metastatic colorectal cancer, Am J Ther 16 (2009) 412-420.
[34] N.D. Willis, S.A. Przyborski, C.J. Hutchison, R.G. Wilson, Colonic and colorectal cancer stem cells: progress in the search for putative biomarkers, J Anat 213 (2008) 59-65.
[35] T.M. Yeung, S.C. Gandhi, J.L. Wilding, R. Muschel, W.F. Bodmer, Cancer stem cells from colorectal cancer-derived cell lines, Proc Natl Acad Sci U S A 107 (2010) 3722-3727.
[36] P. Dalerba, S.J. Dylla, I.K. Park, R. Liu, X. Wang, R.W. Cho, T. Hoey, A. Gurney, E.H. Huang, D.M. Simeone, A.A. Shelton, G. Parmiani, C. Castelli, M.F. Clarke, Phenotypic characterization of human colorectal cancer stem cells, Proc Natl Acad Sci U S A 104 (2007) 10158-10163.
[37] S. Zhang, C. Balch, M.W. Chan, H.C. Lai, D. Matei, J.M. Schilder, P.S. Yan, T.H. Huang, K.P. Nephew, Identification and characterization of ovarian cancer-initiating cells from primary human tumors, Cancer Res 68 (2008) 4311-4320.
[38] H. Zhang, W. Li, F. Nan, F. Ren, H. Wang, Y. Xu, F. Zhang, MicroRNA expression profile of colon cancer stem-like Cells in HT29 adenocarcinoma cell line, Biochem Biophys Res Commun (2010).
[39] J. Dou, C. Jiang, J. Wang, X. Zhang, F. Zhao, W.W. Hu, X.F. He, X. Li, D. Zou, N. Gu, Using ABCG2-Molecule-Expressing Side Population Cells to Identify Cancer Stem-Like Cells in a Human Ovarian Cell Line, Cell Biol Int (2010).
[40] S. Hayashi, K. Fujita, S. Matsumoto, M. Akita, A. Satomi, Isolation and identification of cancer stem cells from a side population of a human hepatoblastoma cell line, HuH-6 clone-5, Pediatr Surg Int (2010).
[41] Y. Zhong, K. Guan, S. Guo, C. Zhou, D. Wang, W. Ma, Y. Zhang, C. Li, S. Zhang, Spheres derived from the human SK-RC-42 renal cell carcinoma cell line are enriched in cancer stem cells, Cancer Lett 299 (2010) 150-160.
[42] K. Bartkowiak, M. Wieczorek, F. Buck, S. Harder, J. Moldenhauer, K.E. Effenberger, K. Pantel, J. Peter-Katalinic, B.H. Brandt, Two-dimensional differential gel electrophoresis of a cell line derived from a breast cancer micrometastasis revealed a stem/ progenitor cell protein profile, J Proteome Res 8 (2009) 2004-2014.
[43] Z.F. Ning, Y.J. Huang, T.X. Lin, Y.X. Zhou, C. Jiang, K.W. Xu, H. Huang, X.B. Yin, J. Huang, Subpopulations of stem-like cells in side population cells from the human bladder transitional cell cancer cell line T24, J Int Med Res 37 (2009) 621-630.
[44] Z.H. Zhou, Y.F. Ping, S.C. Yu, L. Yi, X.H. Yao, J.H. Chen, Y.H. Cui, X.W. Bian, A novel approach to the identification and enrichment of cancer stem cells from a cultured human glioma cell line, Cancer Lett 281 (2009) 92-99.
[45] X.D. Wei, L. Zhou, L. Cheng, J. Tian, J.J. Jiang, J. Maccallum, In vivo investigation of CD133 as a putative marker of cancer stem cells in Hep-2 cell line, Head Neck 31 (2009) 94-101.
[46] D. Huang, G.P. Casale, J. Tian, S.M. Lele, V.M. Pisarev, M.A. Simpson, G.P. Hemstreet, 3rd, Udp-glucose dehydrogenase as a novel field-specific candidate biomarker of prostate cancer, Int J Cancer 126 (2010) 315-327.
[47] J.W. Huh, M.M. Choi, S.J. Yang, S.Y. Yoon, S.Y. Choi, S.W. Cho, Inhibition of human UDP-glucose dehydrogenase expression using siRNA expression vector in breast cancer cells, Biotechnol Lett 27 (2005) 1229-1232.
[48] Y.R. Pan, J. Vatsyayan, Y.S. Chang, H.Y. Chang, Epstein-Barr virus latent membrane protein 2A upregulates UDP-glucose dehydrogenase gene expression via ERK and PI3K/Akt pathway, Cell Microbiol 10 (2008) 2447-2460.
[49] T.P. Wang, Y.R. Pan, C.Y. Fu, H.Y. Chang, Down-regulation of UDP-glucose dehydrogenase affects glycosaminoglycans synthesis and motility in HCT-8 colorectal carcinoma cells, Exp Cell Res 316 (2010) 2893-2902.
[50] Y. Ohnishi, T. Arai, M. Koshirakawa, N. Horii, S. Nakajo, K. Urano, T. Usui, N. Tamaoki, Y. Ueyama, Induction of drug metabolism-related enzymes by methylcholanthrene and phenobarbital in transgenic mice carrying human prototype c-Ha-ras gene and their wild type littermates, Exp Anim 50 (2001) 33-39.
[51] X. Shan, T.Y. Aw, E.R. Smith, M. Ingelman-Sundberg, B. Mannervik, T. Iyanagi, D.P. Jones, Effect of chronic hypoxia on detoxication enzymes in rat liver, Biochem Pharmacol 43 (1992) 2421-2426.
[52] T. Gessner, L.A. Vaughan, B.C. Beehler, C.J. Bartels, R.M. Baker, Elevated pentose cycle and glucuronyltransferase in daunorubicin-resistant P388 cells, Cancer Res 50 (1990) 3921-3927.
[53] R. Konno, [Gene expression profiling of human ovarian epithelial tumors by digo nucleotide microarray], Hum Cell 14 (2001) 261-266.
[54] T. Nakamura, K. Takagaki, S. Shibata, K. Tanaka, T. Higuchi, M. Endo, Hyaluronic-acid-deficient extracellular matrix induced by addition of 4-methylumbelliferone to the medium of cultured human skin fibroblasts, Biochem Biophys Res Commun 208 (1995) 470-475.
[55] D. Vigetti, M. Rizzi, M. Viola, E. Karousou, A. Genasetti, M. Clerici, B. Bartolini, V.C. Hascall, G. De Luca, A. Passi, The effects of 4-methylumbelliferone on hyaluronan synthesis, MMP2 activity, proliferation, and motility of human aortic smooth muscle cells, Glycobiology 19 (2009) 537-546.
[56] S. Yoshihara, A. Kon, D. Kudo, H. Nakazawa, I. Kakizaki, M. Sasaki, M. Endo, K. Takagaki, A hyaluronan synthase suppressor, 4-methylumbelliferone, inhibits liver metastasis of melanoma cells, FEBS Lett 579 (2005) 2722-2726.
[57] H. Morohashi, A. Kon, M. Nakai, M. Yamaguchi, I. Kakizaki, S. Yoshihara, M. Sasaki, K. Takagaki, Study of hyaluronan synthase inhibitor, 4-methylumbelliferone derivatives on human pancreatic cancer cell (KP1-NL), Biochem Biophys Res Commun 345 (2006) 1454-1459.
[58] K. Rilla, S. Pasonen-Seppanen, J. Rieppo, M. Tammi, R. Tammi, The hyaluronan synthesis inhibitor 4-methylumbelliferone prevents keratinocyte activation and epidermal hyperproliferation induced by epidermal growth factor, J Invest Dermatol 123 (2004) 708-714.
[59] A. Kultti, S. Pasonen-Seppanen, M. Jauhiainen, K.J. Rilla, R. Karna, E. Pyoria, R.H. Tammi, M.I. Tammi, 4-Methylumbelliferone inhibits hyaluronan synthesis by depletion of cellular UDP-glucuronic acid and downregulation of hyaluronan synthase 2 and 3, Exp Cell Res 315 (2009) 1914-1923.
[60] D. Kudo, A. Kon, S. Yoshihara, I. Kakizaki, M. Sasaki, M. Endo, K. Takagaki, Effect of a hyaluronan synthase suppressor, 4-methylumbelliferone, on B16F-10 melanoma cell adhesion and locomotion, Biochem Biophys Res Commun 321 (2004) 783-787.
[61] R.J. Hung, H.S. Chien, R.Z. Lin, C.T. Lin, J. Vatsyayan, H.L. Peng, H.Y. Chang, Comparative analysis of two UDP-glucose dehydrogenases in Pseudomonas aeruginosa PAO1, J Biol Chem 282 (2007) 17738-17748.
[62] N. Kochanowski, F. Blanchard, R. Cacan, F. Chirat, E. Guedon, A. Marc, J.L. Goergen, Intracellular nucleotide and nucleotide sugar contents of cultured CHO cells determined by a fast, sensitive, and high-resolution ion-pair RP-HPLC, Anal Biochem 348 (2006) 243-251.
[63] M. Moriyama, K. Suzuki, C. Nakajima, K. Kawamura, K. Miyazawa, R. Tsugawa, Studies on the modified dimethylmethylene-blue (DMB) method for determining glycosaminoglycans (GAG) in urine, Hinyokika Kiyo 40 (1994) 565-568.
[64] J.E. Stone, N. Akhtar, S. Botchway, C.A. Pennock, Interaction of 1,9-dimethylmethylene blue with glycosaminoglycans, Ann Clin Biochem 31 ( Pt 2) (1994) 147-152.
[65] T.R. Oegema, Jr., R.C. Thompson, Jr., Characterization of a hyaluronic acid-dermatan sulfate proteoglycan complex from dedifferentiated human chondrocyte cultures, J Biol Chem 256 (1981) 1015-1022.
[66] R.K. Batra, J.C. Olsen, D.K. Hoganson, B. Caterson, R.C. Boucher, Retroviral gene transfer is inhibited by chondroitin sulfate proteoglycans/glycosaminoglycans in malignant pleural effusions, J Biol Chem 272 (1997) 11736-11743.
[67] E.M. Egorina, M.A. Sovershaev, B. Osterud, In-cell Western assay: a new approach to visualize tissue factor in human monocytes, J Thromb Haemost 4 (2006) 614-620.
[68] D.S. Brauer, C. Russel, S. Vogt, J. Weisser, M. Schnabelrauch, Degradable phosphate glass fiber reinforced polymer matrices: mechanical properties and cell response, J Mater Sci Mater Med 19 (2008) 121-127.
[69] M.H. May, M.V. Sefton, Conformal coating of small particles and cell aggregates at a liquid-liquid interface, Ann N Y Acad Sci 875 (1999) 126-134.
[70] D. Del Duca, T. Werbowetski, R.F. Del Maestro, Spheroid preparation from hanging drops: characterization of a model of brain tumor invasion, J Neurooncol 67 (2004) 295-303.
[71] P.H. Weigel, V.C. Hascall, M. Tammi, Hyaluronan synthases, J Biol Chem 272 (1997) 13997-14000.
[72] A.J. Koleske, D. Baltimore, M.P. Lisanti, Reduction of caveolin and caveolae in oncogenically transformed cells, Proc Natl Acad Sci U S A 92 (1995) 1381-1385.
[73] I.D. Martin-Meras, M.I. Rodriguez-Caceres, C. Hurtado-Sanchez Mdel, First-order multivariate calibration applied to the simultaneous fluorometric determination of the anticancer agents CPT-11 and SN-38 in serum and urine samples, Anal Sci 27 (2011) 745.
[74] M.I. Rodriguez-Caceres, D. Bohoyo Gil, I. Duran-Mera, M.C. Hurtado Sanchez, Spectrofluorimetric determination of SN-38, a promising new anti-tumor agent, in the presence and absence of organized media, Appl Spectrosc 65 (2011) 298-306.
[75] J. Hughes, M.E. McCully, The use of an optical brightener in the study of plant structure, Stain Technol 50 (1975) 319-329.
[76] H. Maeda, N. Ishida, Specificity of binding of hexopyranosyl polysaccharides with fluorescent brightener, J Biochem 62 (1967) 276-278.
[77] R.Z. Lin, H.Y. Chang, Recent advances in three-dimensional multicellular spheroid culture for biomedical research, Biotechnol J 3 (2008) 1172-1184.
[78] R.Z. Lin, L.F. Chou, C.C. Chien, H.Y. Chang, Dynamic analysis of hepatoma spheroid formation: roles of E-cadherin and beta1-integrin, Cell Tissue Res 324 (2006) 411-422.
[79] A.G. Bharadwaj, J.L. Kovar, E. Loughman, C. Elowsky, G.G. Oakley, M.A. Simpson, Spontaneous metastasis of prostate cancer is promoted by excess hyaluronan synthesis and processing, Am J Pathol 174 (2009) 1027-1036.
[80] H.R. Kim, M.A. Wheeler, C.M. Wilson, J. Iida, D. Eng, M.A. Simpson, J.B. McCarthy, K.M. Bullard, Hyaluronan facilitates invasion of colon carcinoma cells in vitro via interaction with CD44, Cancer Res 64 (2004) 4569-4576.
[81] B.P. Toole, Hyaluronan: from extracellular glue to pericellular cue, Nat Rev Cancer 4 (2004) 528-539.
[82] S.E. Stringer, The role of heparan sulphate proteoglycans in angiogenesis, Biochem Soc Trans 34 (2006) 451-453.
[83] M. Viola, D. Vigetti, A. Genasetti, M. Rizzi, E. Karousou, P. Moretto, M. Clerici, B. Bartolini, F. Pallotti, G. De Luca, A. Passi, Molecular control of the hyaluronan biosynthesis, Connect Tissue Res 49 (2008) 111-114.
[84] S. Gerecht, J.A. Burdick, L.S. Ferreira, S.A. Townsend, R. Langer, G. Vunjak-Novakovic, Hyaluronic acid hydrogel for controlled self-renewal and differentiation of human embryonic stem cells, Proc Natl Acad Sci U S A 104 (2007) 11298-11303.
[85] Z. Yu, T.G. Pestell, M.P. Lisanti, R.G. Pestell, Cancer stem cells, Int J Biochem Cell Biol 44 (2012) 2144-2151.
[86] D.A. Hess, A.L. Allan, Migratory strategies of normal and malignant stem cells, Methods Mol Biol 750 (2011) 25-44.
[87] A.K. Croker, A.L. Allan, Cancer stem cells: implications for the progression and treatment of metastatic disease, J Cell Mol Med 12 (2008) 374-390.
[88] C. Chung, J.A. Burdick, Influence of three-dimensional hyaluronic acid microenvironments on mesenchymal stem cell chondrogenesis, Tissue Eng Part A 15 (2009) 243-254.
[89] B. Grskovic, C. Pollaschek, M.M. Mueller, K.M. Stuhlmeier, Expression of hyaluronan synthase genes in umbilical cord blood stem/progenitor cells, Biochim Biophys Acta 1760 (2006) 890-895.
[90] I.U. Schraufstatter, N. Serobyan, J. Loring, S.K. Khaldoyanidi, Hyaluronan is required for generation of hematopoietic cells during differentiation of human embryonic stem cells, J Stem Cells 5 (2010) 9-21.
[91] S. Shukla, R. Nair, M.W. Rolle, K.R. Braun, C.K. Chan, P.Y. Johnson, T.N. Wight, T.C. McDevitt, Synthesis and organization of hyaluronan and versican by embryonic stem cells undergoing embryoid body differentiation, J Histochem Cytochem 58 (2010) 345-358.
[92] K. Williams, K. Motiani, P.V. Giridhar, S. Kasper, CD44 integrates signaling in normal stem cell, cancer stem cell and (pre)metastatic niches, Exp Biol Med (Maywood) 238 (2013) 324-338.
[93] H. Okuda, A. Kobayashi, B. Xia, M. Watabe, S.K. Pai, S. Hirota, F. Xing, W. Liu, P.R. Pandey, K. Fukuda, V. Modur, A. Ghosh, A. Wilber, K. Watabe, Hyaluronan synthase HAS2 promotes tumor progression in bone by stimulating the interaction of breast cancer stem-like cells with macrophages and stromal cells, Cancer Res 72 (2012) 537-547.
[94] L.Y. Bourguignon, G. Wong, C. Earle, L. Chen, Hyaluronan-CD44v3 interaction with Oct4-Sox2-Nanog promotes miR-302 expression leading to self-renewal, clonal formation, and cisplatin resistance in cancer stem cells from head and neck squamous cell carcinoma, J Biol Chem 287 (2012) 32800-32824.
[95] V. Subramaniam, I.R. Vincent, M. Gilakjan, S. Jothy, Suppression of human colon cancer tumors in nude mice by siRNA CD44 gene therapy, Exp Mol Pathol 83 (2007) 332-340.
[96] E. Marangoni, N. Lecomte, L. Durand, G. de Pinieux, D. Decaudin, C. Chomienne, F. Smadja-Joffe, M.F. Poupon, CD44 targeting reduces tumour growth and prevents post-chemotherapy relapse of human breast cancers xenografts, Br J Cancer 100 (2009) 918-922.
[97] C. Wu, B.A. Alman, Side population cells in human cancers, Cancer Lett 268 (2008) 1-9.
[98] T. Litman, T.E. Druley, W.D. Stein, S.E. Bates, From MDR to MXR: new understanding of multidrug resistance systems, their properties and clinical significance, Cell Mol Life Sci 58 (2001) 931-959.
[99] M.M. Gottesman, T. Fojo, S.E. Bates, Multidrug resistance in cancer: role of ATP-dependent transporters, Nat Rev Cancer 2 (2002) 48-58.
[100] S. Zhou, J.D. Schuetz, K.D. Bunting, A.-M. Colapietro, J. Sampath, J.J. Morris, I. Lagutina, G.C. Grosveld, M. Osawa, H. Nakauchi, B.P. Sorrentino, The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype, Nat Med 7 (2001) 1028-1034.
[101] T. Oguri, Y. Bessho, H. Achiwa, H. Ozasa, K. Maeno, H. Maeda, S. Sato, R. Ueda, MRP8/ABCC11 directly confers resistance to 5-fluorouracil, Mol Cancer Ther 6 (2007) 122-127.
[102] T. Ishikawa, Y. Ikegami, K. Sano, H. Nakagawa, S. Sawada, Transport mechanism-based drug molecular design: novel camptothecin analogues to circumvent ABCG2-associated drug resistance of human tumor cells, Curr Pharm Des 12 (2006) 313-325.
[103] Y. Bessho, T. Oguri, H. Achiwa, H. Muramatsu, H. Maeda, T. Niimi, S. Sato, R. Ueda, Role of ABCG2 as a biomarker for predicting resistance to CPT-11/SN-38 in lung cancer, Cancer Science 97 (2006) 192-198.
[104] H. Nakagawa, H. Saito, Y. Ikegami, S. Aida-Hyugaji, S. Seigo, T. Ishikawa, Molecular modeling of new camptothecin analogues to circumvent ABCG2-mediated drug resistance in cancer, Cancer Letters 234 (2006) 81-89.
[105] D. Wang, H. Zhu, Y. Zhu, Y. Liu, H. Shen, R. Yin, Z. Zhang, Z. Su, CD133(+)/CD44(+)/Oct4(+)/Nestin(+) stem-like cells isolated from Panc-1 cell line may contribute to multi-resistance and metastasis of pancreatic cancer, Acta Histochem 115 (2013) 349-356.
[106] L.Y. Bourguignon, C.C. Spevak, G. Wong, W. Xia, E. Gilad, Hyaluronan-CD44 interaction with protein kinase C(epsilon) promotes oncogenic signaling by the stem cell marker Nanog and the Production of microRNA-21, leading to down-regulation of the tumor suppressor protein PDCD4, anti-apoptosis, and chemotherapy resistance in breast tumor cells, J Biol Chem 284 (2009) 26533-26546.
[107] J. Hao, H. Chen, M.C. Madigan, P.J. Cozzi, J. Beretov, W. Xiao, W.J. Delprado, P.J. Russell, Y. Li, Co-expression of CD147 (EMMPRIN), CD44v3-10, MDR1 and monocarboxylate transporters is associated with prostate cancer drug resistance and progression, Br J Cancer 103 (2010) 1008-1018.
[108] H. Chen, J. Hao, L. Wang, Y. Li, Coexpression of invasive markers (uPA, CD44) and multiple drug-resistance proteins (MDR1, MRP2) is correlated with epithelial ovarian cancer progression, Br J Cancer 101 (2009) 432-440.
[109] L.Y. Bourguignon, W. Xia, G. Wong, Hyaluronan-mediated CD44 interaction with p300 and SIRT1 regulates beta-catenin signaling and NFkappaB-specific transcription activity leading to MDR1 and Bcl-xL gene expression and chemoresistance in breast tumor cells, J Biol Chem 284 (2009) 2657-2671.
[110] S.I. Pai, Y.Y. Lin, B. Macaes, A. Meneshian, C.F. Hung, T.C. Wu, Prospects of RNA interference therapy for cancer, Gene Ther 13 (2006) 464-477.
[111] S. He, D. Zhang, F. Cheng, F. Gong, Y. Guo, Applications of RNA interference in cancer therapeutics as a powerful tool for suppressing gene expression, Mol Biol Rep 36 (2009) 2153-2163.
[112] P.G. Rychahou, L.N. Jackson, B.J. Farrow, B.M. Evers, RNA interference: mechanisms of action and therapeutic consideration, Surgery 140 (2006) 719-725.

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