上皮黏附因子與Oct4或Klf4可以透過活化轉錄激活蛋白3與低氧誘導蛋白2a生成誘導性多能幹細胞

EpCAM/EpEX and Oct4 or Klf4 alone are sufficient to generate induced pluripotent stem cells through STAT3 and HIF2a

10.6342/NTU201700408

管奕奕

上皮細胞粘附分子 ； 誘導型多能性幹細胞 ； 山中伸彌因子 ； 重編程 ； EpEX ； EpCAM ； induced pluripotent stem cells ； reprogramming

國立臺灣大學生命科學系學位論文

2017年

博士

吳漢忠

英文

人類胚胎幹細胞和誘導型多能幹細胞（induced pluripotent stem cells, iPSC）是能夠自我更新和分化成三種胚層的多能幹細胞。iPSCs在再生醫學上可能是一個功能強大的工具。傳統的誘導型多能幹細胞是由四個轉錄因子：Oct4 (O), Sox2 (S), Klf4 (K), c-Myc (M) 誘導細胞而成。O，S，K，M現在被稱為山中伸彌因子，誘導機制仍不清楚。越來越多研究致力於尋求更容易，更好的重編程策略。但是，鮮少有人研究是否有其他分泌蛋白可以取代四個山中伸彌因子。我們研究發現，上皮細胞粘附分子（EpCAM）高度表現在未分化的胚胎幹細胞，而不會表現在已經分化的細胞。此外，EpCAM能直接調控多能性基因，包括c-Myc、Oct4、Nanog、Sox2、Klf4，有助於維持胚胎幹細胞的多能性。在本研究我們發現EpCAM能促進小鼠纖維母細胞重編程。EpCAM和其胞外結構 (EpEX) 有助於提升iPSCs集落形成和提高重編程的效率。我們進一步發現EpCAM結合單一山中伸彌因子Oct4，或Klf4，並與EpEX共同刺激，可以成功地重編程小鼠纖維母細胞成為iPSC細胞。我們進一步鑑定誘導型多能性幹細胞的多能性，OE + EpEX和KE + EpEX-iPSC基因表現與小鼠幹細胞相同。此外，在嵌合小鼠中證實OE + EpEX和KE + EpEX-iPSC可以分化成多種組織器官。EpCAM和EpEX可以透過STAT3-HIF2α的訊息傳遞促使HIF2α結合到山中伸彌因子的啟動子並增加小鼠纖維母細胞的重編程，研究成果有助於開發更高效率的重編程策略和維持幹細胞的多能性。這些新的發現可能在未來幹細胞研究，組織工程與臨床應用之發展有極大助益。

Induced pluripotent stem cells (iPSCs) are generated from somatic cells, and have pluripotency and self-renewal ability. iPSCs holds great promising for its multiple application including drug screening, disease remolding, and even the possibility of autologous transplantation. However, until now, most of the iPSCs are generated by the transduction of four Yamanaka factors. The epithelial cell adhesion molecule (EpCAM), a type I transmembrane glycoprotein, is a potent stem cell surface marker. The intracellular domain of EpCAM (EpICD) upregulates reprogramming genes, including Oct4 (O), Sox2 (S), Klf4 (K), c-Myc (M), and Nanog (N), through association with their promoters. Therefore, we are prompted to investigate the functional roles of EpCAM in reprogramming of fibroblasts into iPSCs and the underlying molecular mechanisms. Here, we found that OSKM with EpCAM/EpEX increased the iPSC formation up to 2.4-fold compared to OSKM iPSCs. Interestingly, single Yamanaka factor, Oct4 or Klf4, but not Sox2, can successfully form iPSCs with the presence of EpCAM and EpEX. The characteristics of iPSCs generated by one Yamanaka factor with EpCAM (E) + EpEX were further confirmed by in vitro and in vivo assays. Moreover, these iPSCs could differentiate into three germ layers in teratoma and contribute to germline transmission in chimera mice. Furthermore, we demonstrated that EpEX and EpCAM can initiate reprogramming via activation of STAT3 signaling and nuclear-translocation of HIF2a, thereby providing a positive feedback loops for pluripotent circuit. Through our study, we present a new way of triggering reprogramming by membrane protein and soluble factor with single Yamanaka factor, and highlight the novel finding of EpCAM/EpEX-STAT3-HIF2a signals. Understanding these signals is of great interests for enhancing our fundamental knowledge of EpCAM in reprogramming process and establishing a new reprogramming strategy by delivery of membrane protein and soluble factors.

1. Aasen, T., Raya, A., Barrero, M.J., Garreta, E., Consiglio, A., Gonzalez, F., Vassena, R., Bilic, J., Pekarik, V., Tiscornia, G., et al. (2008). Efficient and rapid generation of induced pluripotent stem cells from human keratinocytes. Nature biotechnology 26, 1276-1284.
   連結：
2. Abramovich, A., Muradian, K.K., and Fraifeld, V.E. (2008). Have we reached the point for in vivo rejuvenation? Rejuvenation research 11, 489-492.
   連結：
3. Agger, K., Cloos, P.A., Christensen, J., Pasini, D., Rose, S., Rappsilber, J., Issaeva, I., Canaani, E., Salcini, A.E., and Helin, K. (2007). UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development. Nature 449, 731-734.
   連結：
4. Amoury, M., Kolberg, K., Pham, A.T., Hristodorov, D., Mladenov, R., Di Fiore, S., Helfrich, W., Kiessling, F., Fischer, R., Pardo, A., et al. (2016). Granzyme B-based cytolytic fusion protein targeting EpCAM specifically kills triple negative breast cancer cells in vitro and inhibits tumor growth in a subcutaneous mouse tumor model. Cancer letters 372, 201-209.
   連結：
5. Ancot, F., Foveau, B., Lefebvre, J., Leroy, C., and Tulasne, D. (2009). Proteolytic cleavages give receptor tyrosine kinases the gift of ubiquity. Oncogene 28, 2185-2195.
   連結：
6. Anderson, R., Schaible, K., Heasman, J., and Wylie, C. (1999). Expression of the homophilic adhesion molecule, Ep-CAM, in the mammalian germ line. Journal of reproduction and fertility 116, 379-384.
   連結：
7. Aoki, T., Ohnishi, H., Oda, Y., Tadokoro, M., Sasao, M., Kato, H., Hattori, K., and Ohgushi, H. (2010). Generation of induced pluripotent stem cells from human adipose-derived stem cells without c-MYC. Tissue engineering Part A 16, 2197-2206.
   連結：
8. Axelson, H., Fredlund, E., Ovenberger, M., Landberg, G., and Pahlman, S. (2005). Hypoxia-induced dedifferentiation of tumor cells--a mechanism behind heterogeneity and aggressiveness of solid tumors. Seminars in cell & developmental biology 16, 554-563.
   連結：
9. Baeuerle, P.A., and Gires, O. (2007). EpCAM (CD326) finding its role in cancer. British journal of cancer 96, 417-423.
   連結：
10. Barski, A., Cuddapah, S., Cui, K., Roh, T.Y., Schones, D.E., Wang, Z., Wei, G., Chepelev, I., and Zhao, K. (2007). High-resolution profiling of histone methylations in the human genome. Cell 129, 823-837.
    連結：
11. Bechard, M., and Dalton, S. (2009). Subcellular localization of glycogen synthase kinase 3beta controls embryonic stem cell self-renewal. Molecular and cellular biology 29, 2092-2104.
    連結：
12. Boeuf, H., Hauss, C., Graeve, F.D., Baran, N., and Kedinger, C. (1997). Leukemia inhibitory factor-dependent transcriptional activation in embryonic stem cells. The Journal of cell biology 138, 1207-1217.
    連結：
13. Bourillot, P.Y., Aksoy, I., Schreiber, V., Wianny, F., Schulz, H., Hummel, O., Hubner, N., and Savatier, P. (2009). Novel STAT3 target genes exert distinct roles in the inhibition of mesoderm and endoderm differentiation in cooperation with Nanog. Stem cells 27, 1760-1771.
    連結：
14. Boyer, L.A., Plath, K., Zeitlinger, J., Brambrink, T., Medeiros, L.A., Lee, T.I., Levine, S.S., Wernig, M., Tajonar, A., Ray, M.K., et al. (2006). Polycomb complexes repress developmental regulators in murine embryonic stem cells. Nature 441, 349-353.
    連結：
15. Cabarcas, S.M., Mathews, L.A., and Farrar, W.L. (2011). The cancer stem cell niche--there goes the neighborhood? International journal of cancer 129, 2315-2327.
    連結：
16. Cairns, R.A., Harris, I.S., and Mak, T.W. (2011). Regulation of cancer cell metabolism. Nature reviews Cancer 11, 85-95.
    連結：
17. Cartwright, P., McLean, C., Sheppard, A., Rivett, D., Jones, K., and Dalton, S. (2005). LIF/STAT3 controls ES cell self-renewal and pluripotency by a Myc-dependent mechanism. Development 132, 885-896.
    連結：
18. Chambers, I., Colby, D., Robertson, M., Nichols, J., Lee, S., Tweedie, S., and Smith, A. (2003). Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells. Cell 113, 643-655.
    連結：
19. Chaves-Perez, A., Mack, B., Maetzel, D., Kremling, H., Eggert, C., Harreus, U., and Gires, O. (2013). EpCAM regulates cell cycle progression via control of cyclin D1 expression. Oncogene 32, 641-650.
    連結：
20. Chen, H., Aksoy, I., Gonnot, F., Osteil, P., Aubry, M., Hamela, C., Rognard, C., Hochard, A., Voisin, S., Fontaine, E., et al. (2015). Reinforcement of STAT3 activity reprogrammes human embryonic stem cells to naive-like pluripotency. Nature communications 6, 7095.
    連結：
21. Chen, H.F., Chuang, C.Y., Lee, W.C., Huang, H.P., Wu, H.C., Ho, H.N., Chen, Y.J., and Kuo, H.C. (2011). Surface marker epithelial cell adhesion molecule and E-cadherin facilitate the identification and selection of induced pluripotent stem cells. Stem cell reviews 7, 722-735.
    連結：
22. Chen, X., Xu, H., Yuan, P., Fang, F., Huss, M., Vega, V.B., Wong, E., Orlov, Y.L., Zhang, W., Jiang, J., et al. (2008). Integration of external signaling pathways with the core transcriptional network in embryonic stem cells. Cell 133, 1106-1117.
    連結：
23. Chong, J.M., and Speicher, D.W. (2001). Determination of disulfide bond assignments and N-glycosylation sites of the human gastrointestinal carcinoma antigen GA733-2 (CO17-1A, EGP, KS1-4, KSA, and Ep-CAM). The Journal of biological chemistry 276, 5804-5813.
    連結：
24. Compernolle, V., Brusselmans, K., Acker, T., Hoet, P., Tjwa, M., Beck, H., Plaisance, S., Dor, Y., Keshet, E., Lupu, F., et al. (2002). Loss of HIF-2alpha and inhibition of VEGF impair fetal lung maturation, whereas treatment with VEGF prevents fatal respiratory distress in premature mice. Nature medicine 8, 702-710.
    連結：
25. Corsten, M.F., and Shah, K. (2008). Therapeutic stem-cells for cancer treatment: hopes and hurdles in tactical warfare. The lancet oncology 9, 376-384.
    連結：
26. 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-2alpha regulates Oct-4: effects of hypoxia on stem cell function, embryonic development, and tumor growth. Genes & development 20, 557-570.
    連結：
27. Dan, Y.Y., Riehle, K.J., Lazaro, C., Teoh, N., Haque, J., Campbell, J.S., and Fausto, N. (2006). Isolation of multipotent progenitor cells from human fetal liver capable of differentiating into liver and mesenchymal lineages. Proceedings of the National Academy of Sciences of the United States of America 103, 9912-9917.
    連結：
28. Danet, G.H., Pan, Y., Luongo, J.L., Bonnet, D.A., and Simon, M.C. (2003). Expansion of human SCID-repopulating cells under hypoxic conditions. The Journal of clinical investigation 112, 126-135.
    連結：
29. Das, B., Bayat-Mokhtari, R., Tsui, M., Lotfi, S., Tsuchida, R., Felsher, D.W., and Yeger, H. (2012). HIF-2alpha suppresses p53 to enhance the stemness and regenerative potential of human embryonic stem cells. Stem cells 30, 1685-1695.
    連結：
30. Davis, R.P., Nemes, C., Varga, E., Freund, C., Kosmidis, G., Gkatzis, K., de Jong, D., Szuhai, K., Dinnyes, A., and Mummery, C.L. (2013). Generation of induced pluripotent stem cells from human foetal fibroblasts using the Sleeping Beauty transposon gene delivery system. Differentiation; research in biological diversity 86, 30-37.
    連結：
31. Deshmukh, R.S., Kovacs, K.A., and Dinnyes, A. (2012). Drug discovery models and toxicity testing using embryonic and induced pluripotent stem-cell-derived cardiac and neuronal cells. Stem cells international 2012, 379569.
    連結：
32. Desnuelle, C., Dib, M., Garrel, C., and Favier, A. (2001). A double-blind, placebo-controlled randomized clinical trial of alpha-tocopherol (vitamin E) in the treatment of amyotrophic lateral sclerosis. ALS riluzole-tocopherol Study Group. Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases 2, 9-18.
    連結：
33. Dunwoodie, S.L. (2009). The role of hypoxia in development of the Mammalian embryo. Developmental cell 17, 755-773.
    連結：
34. Eminli, S., Foudi, A., Stadtfeld, M., Maherali, N., Ahfeldt, T., Mostoslavsky, G., Hock, H., and Hochedlinger, K. (2009). Differentiation stage determines potential of hematopoietic cells for reprogramming into induced pluripotent stem cells. Nature genetics 41, 968-976.
    連結：
35. Evans, M.J., and Kaufman, M.H. (1981). Establishment in culture of pluripotential cells from mouse embryos. Nature 292, 154-156.
    連結：
36. Folmes, C.D., Nelson, T.J., Martinez-Fernandez, A., Arrell, D.K., Lindor, J.Z., Dzeja, P.P., Ikeda, Y., Perez-Terzic, C., and Terzic, A. (2011). Somatic oxidative bioenergetics transitions into pluripotency-dependent glycolysis to facilitate nuclear reprogramming. Cell metabolism 14, 264-271.
    連結：
37. Forristal, C.E., Wright, K.L., Hanley, N.A., Oreffo, R.O., and Houghton, F.D. (2010). Hypoxia inducible factors regulate pluripotency and proliferation in human embryonic stem cells cultured at reduced oxygen tensions. Reproduction 139, 85-97.
    連結：
38. Foshay, K.M., and Gallicano, G.I. (2008). Regulation of Sox2 by STAT3 initiates commitment to the neural precursor cell fate. Stem cells and development 17, 269-278.
    連結：
39. Fusaki, N., Ban, H., Nishiyama, A., Saeki, K., and Hasegawa, M. (2009). Efficient induction of transgene-free human pluripotent stem cells using a vector based on Sendai virus, an RNA virus that does not integrate into the host genome. Proceedings of the Japan Academy Series B, Physical and biological sciences 85, 348-362.
    連結：
40. Giorgetti, A., Montserrat, N., Rodriguez-Piza, I., Azqueta, C., Veiga, A., and Izpisua Belmonte, J.C. (2010). Generation of induced pluripotent stem cells from human cord blood cells with only two factors: Oct4 and Sox2. Nature protocols 5, 811-820.
    連結：
41. Gonzalez, B., Denzel, S., Mack, B., Conrad, M., and Gires, O. (2009). EpCAM is involved in maintenance of the murine embryonic stem cell phenotype. Stem cells 27, 1782-1791.
    連結：
42. Gonzalez, F., Boue, S., and Izpisua Belmonte, J.C. (2011). Methods for making induced pluripotent stem cells: reprogramming a la carte. Nature reviews Genetics 12, 231-242.
    連結：
43. Gordon, M.Y. (2008). Stem cells for regenerative medicine--biological attributes and clinical application. Experimental hematology 36, 726-732.
    連結：
44. Grafi, G. (2013). Stress cycles in stem cells/iPSCs development: implications for tissue repair. Biogerontology.
    連結：
45. Greer, S.N., Metcalf, J.L., Wang, Y., and Ohh, M. (2012). The updated biology of hypoxia-inducible factor. The EMBO journal 31, 2448-2460.
    連結：
46. Gregorieff, A., Liu, Y., Inanlou, M.R., Khomchuk, Y., and Wrana, J.L. (2015). Yap-dependent reprogramming of Lgr5(+) stem cells drives intestinal regeneration and cancer. Nature 526, 715-718.
    連結：
47. Haines, N., and Irvine, K.D. (2003). Glycosylation regulates Notch signalling. Nature reviews Molecular cell biology 4, 786-797.
    連結：
48. Haltiwanger, R.S. (2002). Regulation of signal transduction pathways in development by glycosylation. Current opinion in structural biology 12, 593-598.
    連結：
49. Hansson, J., Rafiee, M.R., Reiland, S., Polo, J.M., Gehring, J., Okawa, S., Huber, W., Hochedlinger, K., and Krijgsveld, J. (2012). Highly coordinated proteome dynamics during reprogramming of somatic cells to pluripotency. Cell reports 2, 1579-1592.
    連結：
50. Hattori, N., Nishino, K., Ko, Y.G., Hattori, N., Ohgane, J., Tanaka, S., and Shiota, K. (2004). Epigenetic control of mouse Oct-4 gene expression in embryonic stem cells and trophoblast stem cells. The Journal of biological chemistry 279, 17063-17069.
    連結：
51. Heddleston, J.M., Li, Z., McLendon, R.E., Hjelmeland, A.B., and Rich, J.N. (2009). The hypoxic microenvironment maintains glioblastoma stem cells and promotes reprogramming towards a cancer stem cell phenotype. Cell cycle 8, 3274-3284.
    連結：
52. Heng, J.C., Feng, B., Han, J., Jiang, J., Kraus, P., Ng, J.H., Orlov, Y.L., Huss, M., Yang, L., Lufkin, T., et al. (2010). The nuclear receptor Nr5a2 can replace Oct4 in the reprogramming of murine somatic cells to pluripotent cells. Cell stem cell 6, 167-174.
    連結：
53. Hester, M.E., Song, S., Miranda, C.J., Eagle, A., Schwartz, P.H., and Kaspar, B.K. (2009). Two factor reprogramming of human neural stem cells into pluripotency. PloS one 4, e7044.
    連結：
54. Hirai, H., Karian, P., and Kikyo, N. (2011). Regulation of embryonic stem cell self-renewal and pluripotency by leukaemia inhibitory factor. The Biochemical journal 438, 11-23.
    連結：
55. Hiratsuka, M., Uno, N., Ueda, K., Kurosaki, H., Imaoka, N., Kazuki, K., Ueno, E., Akakura, Y., Katoh, M., Osaki, M., et al. (2011). Integration-free iPS cells engineered using human artificial chromosome vectors. PloS one 6, e25961.
    連結：
56. Ho, P.J., Yen, M.L., Lin, J.D., Chen, L.S., Hu, H.I., Yeh, C.K., Peng, C.Y., Lin, C.Y., Yet, S.F., and Yen, B.L. (2010). Endogenous KLF4 expression in human fetal endothelial cells allows for reprogramming to pluripotency with just OCT3/4 and SOX2--brief report. Arteriosclerosis, thrombosis, and vascular biology 30, 1905-1907.
    連結：
57. Hu, C.J., Sataur, A., Wang, L., Chen, H., and Simon, M.C. (2007). The N-terminal transactivation domain confers target gene specificity of hypoxia-inducible factors HIF-1alpha and HIF-2alpha. Molecular biology of the cell 18, 4528-4542.
    連結：
58. Huang, H.P., Chen, P.H., Yu, C.Y., Chuang, C.Y., Stone, L., Hsiao, W.C., Li, C.L., Tsai, S.C., Chen, K.Y., Chen, H.F., et al. (2011). Epithelial cell adhesion molecule (EpCAM) complex proteins promote transcription factor-mediated pluripotency reprogramming. The Journal of biological chemistry 286, 33520-33532.
    連結：
59. Husa, M., Liu-Bryan, R., and Terkeltaub, R. (2010). Shifting HIFs in osteoarthritis. Nature medicine 16, 641-644.
    連結：
60. Ichida, J.K., Blanchard, J., Lam, K., Son, E.Y., Chung, J.E., Egli, D., Loh, K.M., Carter, A.C., Di Giorgio, F.P., Koszka, K., et al. (2009). A small-molecule inhibitor of tgf-Beta signaling replaces sox2 in reprogramming by inducing nanog. Cell stem cell 5, 491-503.
    連結：
61. Iyer, N.V., Kotch, L.E., Agani, F., Leung, S.W., Laughner, E., Wenger, R.H., Gassmann, M., Gearhart, J.D., Lawler, A.M., Yu, A.Y., et al. (1998). Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha. Genes & development 12, 149-162.
    連結：
62. Jeong, C.H., Cho, Y.Y., Kim, M.O., Kim, S.H., Cho, E.J., Lee, S.Y., Jeon, Y.J., Lee, K.Y., Yao, K., Keum, Y.S., et al. (2010). Phosphorylation of Sox2 cooperates in reprogramming to pluripotent stem cells. Stem cells 28, 2141-2150.
    連結：
63. Kaji, K., Norrby, K., Paca, A., Mileikovsky, M., Mohseni, P., and Woltjen, K. (2009). Virus-free induction of pluripotency and subsequent excision of reprogramming factors. Nature 458, 771-775.
    連結：
64. Keller, G. (2005). Embryonic stem cell differentiation: emergence of a new era in biology and medicine. Genes & development 19, 1129-1155.
    連結：
65. Kelly, K.F., Ng, D.Y., Jayakumaran, G., Wood, G.A., Koide, H., and Doble, B.W. (2011). beta-catenin enhances Oct-4 activity and reinforces pluripotency through a TCF-independent mechanism. Cell stem cell 8, 214-227.
    連結：
66. Kidder, B.L., Yang, J., and Palmer, S. (2008). Stat3 and c-Myc genome-wide promoter occupancy in embryonic stem cells. PloS one 3, e3932.
    連結：
67. Kim, D., Kim, C.H., Moon, J.I., Chung, Y.G., Chang, M.Y., Han, B.S., Ko, S., Yang, E., Cha, K.Y., Lanza, R., et al. (2009a). Generation of human induced pluripotent stem cells by direct delivery of reprogramming proteins. Cell stem cell 4, 472-476.
    連結：
68. Kim, H., Jang, H., Kim, T.W., Kang, B.H., Lee, S.E., Jeon, Y.K., Chung, D.H., Choi, J., Shin, J., Cho, E.J., et al. (2015). Core Pluripotency Factors Directly Regulate Metabolism in Embryonic Stem Cell to Maintain Pluripotency. Stem cells 33, 2699-2711.
    連結：
69. Kim, J.B., Greber, B., Arauzo-Bravo, M.J., Meyer, J., Park, K.I., Zaehres, H., and Scholer, H.R. (2009b). Direct reprogramming of human neural stem cells by OCT4. Nature 461, 649-643.
    連結：
70. Kim, J.B., Zaehres, H., Wu, G., Gentile, L., Ko, K., Sebastiano, V., Arauzo-Bravo, M.J., Ruau, D., Han, D.W., Zenke, M., et al. (2008). Pluripotent stem cells induced from adult neural stem cells by reprogramming with two factors. Nature 454, 646-650.
    連結：
71. Klincumhom, N., Pirity, M.K., Berzsenyi, S., Ujhelly, O., Muenthaisong, S., Rungarunlert, S., Tharasanit, T., Techakumphu, M., and Dinnyes, A. (2012). Generation of neuronal progenitor cells and neurons from mouse sleeping beauty transposon-generated induced pluripotent stem cells. Cellular reprogramming 14, 390-397.
    連結：
72. Kolle, G., Ho, M., Zhou, Q., Chy, H.S., Krishnan, K., Cloonan, N., Bertoncello, I., Laslett, A.L., and Grimmond, S.M. (2009). Identification of human embryonic stem cell surface markers by combined membrane-polysome translation state array analysis and immunotranscriptional profiling. Stem cells 27, 2446-2456.
    連結：
73. Lal, M., and Caplan, M. (2011). Regulated intramembrane proteolysis: signaling pathways and biological functions. Physiology 26, 34-44.
    連結：
74. Leeb, C., Jurga, M., McGuckin, C., Moriggl, R., and Kenner, L. (2010). Promising new sources for pluripotent stem cells. Stem cell reviews 6, 15-26.
    連結：
75. Li, Z., Bao, S., Wu, Q., Wang, H., Eyler, C., Sathornsumetee, S., Shi, Q., Cao, Y., Lathia, J., McLendon, R.E., et al. (2009). Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells. Cancer cell 15, 501-513.
    連結：
76. Lichtenthaler, S.F., Haass, C., and Steiner, H. (2011). Regulated intramembrane proteolysis--lessons from amyloid precursor protein processing. Journal of neurochemistry 117, 779-796.
    連結：
77. Lin, C.W., Liao, M.Y., Lin, W.W., Wang, Y.P., Lu, T.Y., and Wu, H.C. (2012). Epithelial cell adhesion molecule regulates tumor initiation and tumorigenesis via activating reprogramming factors and epithelial-mesenchymal transition gene expression in colon cancer. The Journal of biological chemistry 287, 39449-39459.
    連結：
78. Litvinov, S.V., Balzar, M., Winter, M.J., Bakker, H.A., Briaire-de Bruijn, I.H., Prins, F., Fleuren, G.J., and Warnaar, S.O. (1997). Epithelial cell adhesion molecule modulates (EpCAM) cell-cell interactions mediated by classic cadherins. The Journal of cell biology 139, 1337-1348.
    連結：
79. Litvinov, S.V., Velders, M.P., Bakker, H.A., Fleuren, G.J., and Warnaar, S.O. (1994). Ep-CAM: a human epithelial antigen is a homophilic cell-cell adhesion molecule. The Journal of cell biology 125, 437-446.
    連結：
80. Lu, T.Y., Lu, R.M., Liao, M.Y., Yu, J., Chung, C.H., Kao, C.F., and Wu, H.C. (2010a). Epithelial cell adhesion molecule regulation is associated with the maintenance of the undifferentiated phenotype of human embryonic stem cells. The Journal of biological chemistry 285, 8719-8732.
    連結：
81. Lu, T.Y., Lu, R.M., Liao, M.Y., Yu, J., Chung, C.H., Kao, C.F., and Wu, H.C. (2010b). Epithelial cell adhesion molecule regulation is associated with the maintenance of the undifferentiated phenotype of human embryonic stem cells. Journal of Biological Chemistry 285, 8719-8732.
    連結：
82. Maghzal, N., Kayali, H.A., Rohani, N., Kajava, A.V., and Fagotto, F. (2013). EpCAM controls actomyosin contractility and cell adhesion by direct inhibition of PKC. Developmental cell 27, 263-277.
    連結：
83. Maghzal, N., Vogt, E., Reintsch, W., Fraser, J.S., and Fagotto, F. (2010). The tumor-associated EpCAM regulates morphogenetic movements through intracellular signaling. Journal of Cell Biology 191, 645-659.
    連結：
84. Mathieu, J., Zhang, Z., Nelson, A., Lamba, D.A., Reh, T.A., Ware, C., and Ruohola-Baker, H. (2013). Hypoxia induces re-entry of committed cells into pluripotency. Stem cells 31, 1737-1748.
    連結：
85. Matsuda, T., Nakamura, T., Nakao, K., Arai, T., Katsuki, M., Heike, T., and Yokota, T. (1999). STAT3 activation is sufficient to maintain an undifferentiated state of mouse embryonic stem cells. The EMBO journal 18, 4261-4269.
    連結：
86. Medvedev, S.P., Shevchenko, A.I., and Zakian, S.M. (2010). Molecular basis of Mammalian embryonic stem cell pluripotency and self-renewal. Acta naturae 2, 30-46.
    連結：
87. Meh, P., Pavsic, M., Turk, V., Baici, A., and Lenarcic, B. (2005). Dual concentration-dependent activity of thyroglobulin type-1 domain of testican: specific inhibitor and substrate of cathepsin L. Biological chemistry 386, 75-83.
    連結：
88. Meir, Y.J., Lin, A., Huang, M.F., Lin, J.R., Weirauch, M.T., Chou, H.C., Lin, S.J., and Wu, S.C. (2013). A versatile, highly efficient, and potentially safer piggyBac transposon system for mammalian genome manipulations. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 27, 4429-4443.
    連結：
89. Mitsui, K., Tokuzawa, Y., Itoh, H., Segawa, K., Murakami, M., Takahashi, K., Maruyama, M., Maeda, M., and Yamanaka, S. (2003). The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells. Cell 113, 631-642.
    連結：
90. Mohyeldin, A., Garzon-Muvdi, T., and Quinones-Hinojosa, A. (2010). Oxygen in stem cell biology: a critical component of the stem cell niche. Cell stem cell 7, 150-161.
    連結：
91. Molina, F., Bouanani, M., Pau, B., and Granier, C. (1996). Characterization of the type-1 repeat from thyroglobulin, a cysteine-rich module found in proteins from different families. European journal of biochemistry / FEBS 240, 125-133.
    連結：
92. Montserrat, N., Nivet, E., Sancho-Martinez, I., Hishida, T., Kumar, S., Miquel, L., Cortina, C., Hishida, Y., Xia, Y., Esteban, C.R., et al. (2013). Reprogramming of human fibroblasts to pluripotency with lineage specifiers. Cell stem cell 13, 341-350.
    連結：
93. Morrison, S.J., Csete, M., Groves, A.K., Melega, W., Wold, B., and Anderson, D.J. (2000). Culture in reduced levels of oxygen promotes clonogenic sympathoadrenal differentiation by isolated neural crest stem cells. The Journal of neuroscience : the official journal of the Society for Neuroscience 20, 7370-7376.
    連結：
94. Muenthaisong, S., Ujhelly, O., Polgar, Z., Varga, E., Ivics, Z., Pirity, M.K., and Dinnyes, A. (2012). Generation of mouse induced pluripotent stem cells from different genetic backgrounds using Sleeping beauty transposon mediated gene transfer. Experimental cell research 318, 2482-2489.
    連結：
95. Munz, M., Baeuerle, P.A., and Gires, O. (2009). The emerging role of EpCAM in cancer and stem cell signaling. Cancer research 69, 5627-5629.
    連結：
96. Munz, M., Fellinger, K., Hofmann, T., Schmitt, B., and Gires, O. (2008). Glycosylation is crucial for stability of tumour and cancer stem cell antigen EpCAM. Frontiers in bioscience : a journal and virtual library 13, 5195-5201.
    連結：
97. Munz, M., Kieu, C., Mack, B., Schmitt, B., Zeidler, R., and Gires, O. (2004). The carcinoma-associated antigen EpCAM upregulates c-myc and induces cell proliferation. Oncogene 23, 5748-5758.
    連結：
98. Munz, M., Murr, A., Kvesic, M., Rau, D., Mangold, S., Pflanz, S., Lumsden, J., Volkland, J., Fagerberg, J., Riethmuller, G., et al. (2010). Side-by-side analysis of five clinically tested anti-EpCAM monoclonal antibodies. Cancer cell international 10, 44.
    連結：
99. Mutskov, V., and Felsenfeld, G. (2004). Silencing of transgene transcription precedes methylation of promoter DNA and histone H3 lysine 9. The EMBO journal 23, 138-149.
    連結：
100. Ng, V.Y., Ang, S.N., Chan, J.X., and Choo, A.B. (2010). Characterization of epithelial cell adhesion molecule as a surface marker on undifferentiated human embryonic stem cells. Stem cells 28, 29-35.
     連結：
101. Niwa, H., Burdon, T., Chambers, I., and Smith, A. (1998). Self-renewal of pluripotent embryonic stem cells is mediated via activation of STAT3. Genes & development 12, 2048-2060.
     連結：
102. Niwa, H., Ogawa, K., Shimosato, D., and Adachi, K. (2009). A parallel circuit of LIF signalling pathways maintains pluripotency of mouse ES cells. Nature 460, 118-122.
     連結：
103. Nubel, T., Preobraschenski, J., Tuncay, H., Weiss, T., Kuhn, S., Ladwein, M., Langbein, L., and Zoller, M. (2009). Claudin-7 regulates EpCAM-mediated functions in tumor progression. Molecular cancer research : MCR 7, 285-299.
     連結：
104. Okita, K., Nakagawa, M., Hyenjong, H., Ichisaka, T., and Yamanaka, S. (2008). Generation of mouse induced pluripotent stem cells without viral vectors. Science 322, 949-953.
     連結：
105. Onishi, K., and Zandstra, P.W. (2015). LIF signaling in stem cells and development. Development 142, 2230-2236.
     連結：
106. Panopoulos, A.D., Yanes, O., Ruiz, S., Kida, Y.S., Diep, D., Tautenhahn, R., Herrerias, A., Batchelder, E.M., Plongthongkum, N., Lutz, M., et al. (2012). The metabolome of induced pluripotent stem cells reveals metabolic changes occurring in somatic cell reprogramming. Cell research 22, 168-177.
     連結：
107. Park, I.H., Zhao, R., West, J.A., Yabuuchi, A., Huo, H., Ince, T.A., Lerou, P.H., Lensch, M.W., and Daley, G.Q. (2008). Reprogramming of human somatic cells to pluripotency with defined factors. Nature 451, 141-146.
     連結：
108. Park, J., Kim, S.Y., Kim, H.J., Kim, K.M., Choi, E.Y., and Kang, M.S. (2016). A reciprocal regulatory circuit between CD44 and FGFR2 via c-myc controls gastric cancer cell growth. Oncotarget.
     連結：
109. Patel, M., and Yang, S. (2010). Advances in reprogramming somatic cells to induced pluripotent stem cells. Stem cell reviews 6, 367-380.
     連結：
110. Paukku, K., Valgeirsdottir, S., Saharinen, P., Bergman, M., Heldin, C.H., and Silvennoinen, O. (2000). Platelet-derived growth factor (PDGF)-induced activation of signal transducer and activator of transcription (Stat) 5 is mediated by PDGF beta-receptor and is not dependent on c-src, fyn, jak1 or jak2 kinases. The Biochemical journal 345 Pt 3, 759-766.
     連結：
111. Pauli, C., Munz, M., Kieu, C., Mack, B., Breinl, P., Wollenberg, B., Lang, S., Zeidler, R., and Gires, O. (2003). Tumor-specific glycosylation of the carcinoma-associated epithelial cell adhesion molecule EpCAM in head and neck carcinomas. Cancer letters 193, 25-32.
     連結：
112. Pawlus, M.R., Wang, L., and Hu, C.J. (2014). STAT3 and HIF1alpha cooperatively activate HIF1 target genes in MDA-MB-231 and RCC4 cells. Oncogene 33, 1670-1679.
     連結：
113. Peng, G.H., and Chen, S. (2013). Double chromatin immunoprecipitation: analysis of target co-occupancy of retinal transcription factors. Methods in molecular biology 935, 311-328.
     連結：
114. Petruzzelli, R., Christensen, D.R., Parry, K.L., Sanchez-Elsner, T., and Houghton, F.D. (2014). HIF-2alpha regulates NANOG expression in human embryonic stem cells following hypoxia and reoxygenation through the interaction with an Oct-Sox cis regulatory element. PloS one 9, e108309.
     連結：
115. Pinho, S.S., Seruca, R., Gartner, F., Yamaguchi, Y., Gu, J., Taniguchi, N., and Reis, C.A. (2011). Modulation of E-cadherin function and dysfunction by N-glycosylation. Cellular and molecular life sciences : CMLS 68, 1011-1020.
     連結：
116. Pouyssegur, J., Dayan, F., and Mazure, N.M. (2006). Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature 441, 437-443.
     連結：
117. Prigione, A., and Adjaye, J. (2010). Modulation of mitochondrial biogenesis and bioenergetic metabolism upon in vitro and in vivo differentiation of human ES and iPS cells. The International journal of developmental biology 54, 1729-1741.
     連結：
118. Rafalski, V.A., Mancini, E., and Brunet, A. (2012). Energy metabolism and energy-sensing pathways in mammalian embryonic and adult stem cell fate. Journal of cell science 125, 5597-5608.
     連結：
119. Rawson, R.B. (2002). Regulated intramembrane proteolysis: from the endoplasmic reticulum to the nucleus. Essays in biochemistry 38, 155-168.
     連結：
120. Redmer, T., Diecke, S., Grigoryan, T., Quiroga-Negreira, A., Birchmeier, W., and Besser, D. (2011). E-cadherin is crucial for embryonic stem cell pluripotency and can replace OCT4 during somatic cell reprogramming. EMBO reports 12, 720-726.
     連結：
121. Ryan, H.E., Lo, J., and Johnson, R.S. (1998). HIF-1 alpha is required for solid tumor formation and embryonic vascularization. The EMBO journal 17, 3005-3015.
     連結：
122. Sato, T., Joyner, A.L., and Nakamura, H. (2004). How does Fgf signaling from the isthmic organizer induce midbrain and cerebellum development? Development, growth & differentiation 46, 487-494.
     連結：
123. Schmelzer, E., Wauthier, E., and Reid, L.M. (2006). The phenotypes of pluripotent human hepatic progenitors. Stem cells 24, 1852-1858.
     連結：
124. Schon, M.P., Schon, M., Mattes, M.J., Stein, R., Weber, L., Alberti, S., and Klein, C.E. (1993). Biochemical and immunological characterization of the human carcinoma-associated antigen MH 99/KS 1/4. International journal of cancer 55, 988-995.
     連結：
125. Semenza, G.L. (2003). Targeting HIF-1 for cancer therapy. Nature reviews Cancer 3, 721-732.
     連結：
126. Shu, J., Wu, C., Wu, Y., Li, Z., Shao, S., Zhao, W., Tang, X., Yang, H., Shen, L., Zuo, X., et al. (2013). Induction of pluripotency in mouse somatic cells with lineage specifiers. Cell 153, 963-975.
     連結：
127. Simon, B., Podolsky, D.K., Moldenhauer, G., Isselbacher, K.J., Gattoni-Celli, S., and Brand, S.J. (1990). Epithelial glycoprotein is a member of a family of epithelial cell surface antigens homologous to nidogen, a matrix adhesion protein. Proceedings of the National Academy of Sciences of the United States of America 87, 2755-2759.
     連結：
128. Simsek, T., Kocabas, F., Zheng, J., Deberardinis, R.J., Mahmoud, A.I., Olson, E.N., Schneider, J.W., Zhang, C.C., and Sadek, H.A. (2010). The distinct metabolic profile of hematopoietic stem cells reflects their location in a hypoxic niche. Cell stem cell 7, 380-390.
     連結：
129. Sivagnanam, M., Mueller, J.L., Lee, H., Chen, Z., Nelson, S.F., Turner, D., Zlotkin, S.H., Pencharz, P.B., Ngan, B.Y., Libiger, O., et al. (2008). Identification of EpCAM as the gene for congenital tufting enteropathy. Gastroenterology 135, 429-437.
     連結：
130. Slanchev, K., Carney, T.J., Stemmler, M.P., Koschorz, B., Amsterdam, A., Schwarz, H., and Hammerschmidt, M. (2009). The epithelial cell adhesion molecule EpCAM is required for epithelial morphogenesis and integrity during zebrafish epiboly and skin development. PLoS genetics 5, e1000563.
     連結：
131. Snyder, M., Huang, X.Y., and Zhang, J.J. (2008). Identification of novel direct Stat3 target genes for control of growth and differentiation. The Journal of biological chemistry 283, 3791-3798.
     連結：
132. Spizzo, G., Went, P., Dirnhofer, S., Obrist, P., Simon, R., Spichtin, H., Maurer, R., Metzger, U., von Castelberg, B., Bart, R., et al. (2004). High Ep-CAM expression is associated with poor prognosis in node-positive breast cancer. Breast cancer research and treatment 86, 207-213.
     連結：
133. Stadtfeld, M., Brennand, K., and Hochedlinger, K. (2008a). Reprogramming of pancreatic beta cells into induced pluripotent stem cells. Current biology : CB 18, 890-894.
     連結：
134. Stadtfeld, M., Nagaya, M., Utikal, J., Weir, G., and Hochedlinger, K. (2008b). Induced pluripotent stem cells generated without viral integration. Science 322, 945-949.
     連結：
135. Stingl, J., Raouf, A., Emerman, J.T., and Eaves, C.J. (2005). Epithelial progenitors in the normal human mammary gland. Journal of mammary gland biology and neoplasia 10, 49-59.
     連結：
136. Strooper, B.D., and Annaert, W. (2001). Presenilins and the intramembrane proteolysis of proteins: facts and fiction. Nature cell biology 3, E221-225.
     連結：
137. Studer, L., Csete, M., Lee, S.H., Kabbani, N., Walikonis, J., Wold, B., and McKay, R. (2000). Enhanced proliferation, survival, and dopaminergic differentiation of CNS precursors in lowered oxygen. The Journal of neuroscience : the official journal of the Society for Neuroscience 20, 7377-7383.
     連結：
138. Suhr, S.T., Chang, E.A., Tjong, J., Alcasid, N., Perkins, G.A., Goissis, M.D., Ellisman, M.H., Perez, G.I., and Cibelli, J.B. (2010). Mitochondrial rejuvenation after induced pluripotency. PloS one 5, e14095.
     連結：
139. Sundberg, M., Jansson, L., Ketolainen, J., Pihlajamaki, H., Suuronen, R., Skottman, H., Inzunza, J., Hovatta, O., and Narkilahti, S. (2009). CD marker expression profiles of human embryonic stem cells and their neural derivatives, determined using flow-cytometric analysis, reveal a novel CD marker for exclusion of pluripotent stem cells. Stem cell research 2, 113-124.
     連結：
140. Szala, S., Kasai, Y., Steplewski, Z., Rodeck, U., Koprowski, H., and Linnenbach, A.J. (1990). Molecular cloning of cDNA for the human tumor-associated antigen CO-029 and identification of related transmembrane antigens. Proceedings of the National Academy of Sciences of the United States of America 87, 6833-6837.
     連結：
141. Takahashi, K., Mitsui, K., and Yamanaka, S. (2003). Role of ERas in promoting tumour-like properties in mouse embryonic stem cells. Nature 423, 541-545.
     連結：
142. Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., and Yamanaka, S. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861-872.
     連結：
143. Takahashi, K., and Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663-676.
     連結：
144. Takubo, K., Goda, N., Yamada, W., Iriuchishima, H., Ikeda, E., Kubota, Y., Shima, H., Johnson, R.S., Hirao, A., Suematsu, M., et al. (2010). Regulation of the HIF-1alpha level is essential for hematopoietic stem cells. Cell stem cell 7, 391-402.
     連結：
145. Takubo, K., and Suda, T. (2012). Roles of the hypoxia response system in hematopoietic and leukemic stem cells. International journal of hematology 95, 478-483.
     連結：
146. Tang, Y., Luo, Y., Jiang, Z., Ma, Y., Lin, C.J., Kim, C., Carter, M.G., Amano, T., Park, J., Kish, S., et al. (2012). Jak/Stat3 signaling promotes somatic cell reprogramming by epigenetic regulation. Stem cells 30, 2645-2656.
     連結：
147. Tang, Y., and Tian, X.C. (2013). JAK-STAT3 and somatic cell reprogramming. Jak-Stat 2, e24935.
     連結：
148. Thampoe, I.J., Ng, J.S., and Lloyd, K.O. (1988). Biochemical analysis of a human epithelial surface antigen: differential cell expression and processing. Archives of biochemistry and biophysics 267, 342-352.
     連結：
149. Turk, V., Stoka, V., Vasiljeva, O., Renko, M., Sun, T., Turk, B., and Turk, D. (2012). Cysteine cathepsins: from structure, function and regulation to new frontiers. Biochimica et biophysica acta 1824, 68-88.
     連結：
150. Varga, M., Obrist, P., Schneeberger, S., Muhlmann, G., Felgel-Farnholz, C., Fong, D., Zitt, M., Brunhuber, T., Schafer, G., Gastl, G., et al. (2004). Overexpression of epithelial cell adhesion molecule antigen in gallbladder carcinoma is an independent marker for poor survival. Clinical cancer research : an official journal of the American Association for Cancer Research 10, 3131-3136.
     連結：
151. Varum, S., Rodrigues, A.S., Moura, M.B., Momcilovic, O., Easley, C.A.t., Ramalho-Santos, J., Van Houten, B., and Schatten, G. (2011). Energy metabolism in human pluripotent stem cells and their differentiated counterparts. PloS one 6, e20914.
     連結：
152. Vignais, M.L., and Gilman, M. (1999). Distinct mechanisms of activation of Stat1 and Stat3 by platelet-derived growth factor receptor in a cell-free system. Molecular and cellular biology 19, 3727-3735.
     連結：
153. Vignais, M.L., Sadowski, H.B., Watling, D., Rogers, N.C., and Gilman, M. (1996). Platelet-derived growth factor induces phosphorylation of multiple JAK family kinases and STAT proteins. Molecular and cellular biology 16, 1759-1769.
     連結：
154. Wang, X., Sun, W., Shen, W., Xia, M., Chen, C., Xiang, D., Ning, B., Cui, X., Li, H., Li, X., et al. (2016). Long non-coding RNA DILC regulates liver cancer stem cells via IL-6/STAT3 axis. Journal of hepatology.
     連結：
155. Wang, Y., Liu, Y., Malek, S.N., Zheng, P., and Liu, Y. (2011). Targeting HIF1alpha eliminates cancer stem cells in hematological malignancies. Cell stem cell 8, 399-411.
     連結：
156. Wang, Y., van Boxel-Dezaire, A.H., Cheon, H., Yang, J., and Stark, G.R. (2013). STAT3 activation in response to IL-6 is prolonged by the binding of IL-6 receptor to EGF receptor. Proceedings of the National Academy of Sciences of the United States of America 110, 16975-16980.
     連結：
157. Warren, L., Manos, P.D., Ahfeldt, T., Loh, Y.H., Li, H., Lau, F., Ebina, W., Mandal, P.K., Smith, Z.D., Meissner, A., et al. (2010). Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell stem cell 7, 618-630.
     連結：
158. Wernig, M., Lengner, C.J., Hanna, J., Lodato, M.A., Steine, E., Foreman, R., Staerk, J., Markoulaki, S., and Jaenisch, R. (2008). A drug-inducible transgenic system for direct reprogramming of multiple somatic cell types. Nature biotechnology 26, 916-924.
     連結：
159. Wernig, M., Meissner, A., Foreman, R., Brambrink, T., Ku, M., Hochedlinger, K., Bernstein, B.E., and Jaenisch, R. (2007). In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature 448, 318-324.
     連結：
160. Woltjen, K., Michael, I.P., Mohseni, P., Desai, R., Mileikovsky, M., Hamalainen, R., Cowling, R., Wang, W., Liu, P., Gertsenstein, M., et al. (2009). piggyBac transposition reprograms fibroblasts to induced pluripotent stem cells. Nature 458, 766-770.
     連結：
161. Yang, W., Zheng, Y., Xia, Y., Ji, H., Chen, X., Guo, F., Lyssiotis, C.A., Aldape, K., Cantley, L.C., and Lu, Z. (2012). ERK1/2-dependent phosphorylation and nuclear translocation of PKM2 promotes the Warburg effect. Nature cell biology 14, 1295-1304.
     連結：
162. Yoshida, Y., Takahashi, K., Okita, K., Ichisaka, T., and Yamanaka, S. (2009). Hypoxia enhances the generation of induced pluripotent stem cells. Cell stem cell 5, 237-241.
     連結：
163. Zhang, H., Ma, Y., Gu, J., Liao, B., Li, J., Wong, J., and Jin, Y. (2012). Reprogramming of somatic cells via TAT-mediated protein transduction of recombinant factors. Biomaterials 33, 5047-5055.
     連結：
164. Zhang, J., Khvorostov, I., Hong, J.S., Oktay, Y., Vergnes, L., Nuebel, E., Wahjudi, P.N., Setoguchi, K., Wang, G., Do, A., et al. (2011). UCP2 regulates energy metabolism and differentiation potential of human pluripotent stem cells. The EMBO journal 30, 4860-4873.
     連結：
165. Zhao, J., Jiang, W.J., Sun, C., Hou, C.Z., Yang, X.M., and Gao, J.G. (2013). Induced pluripotent stem cells: origins, applications, and future perspectives. Journal of Zhejiang University Science B 14, 1059-1069.
     連結：
166. Zhou, W., Choi, M., Margineantu, D., Margaretha, L., Hesson, J., Cavanaugh, C., Blau, C.A., Horwitz, M.S., Hockenbery, D., Ware, C., et al. (2012). HIF1alpha induced switch from bivalent to exclusively glycolytic metabolism during ESC-to-EpiSC/hESC transition. The EMBO journal 31, 2103-2116.
     連結：
167. Zhou, W., and Freed, C.R. (2009). Adenoviral gene delivery can reprogram human fibroblasts to induced pluripotent stem cells. Stem cells 27, 2667-2674.
     連結：
168. Zhou, X.D., and Agazie, Y.M. (2008). Inhibition of SHP2 leads to mesenchymal to epithelial transition in breast cancer cells. Cell death and differentiation 15, 988-996.
     連結：
169. Zhu, S., Li, W., Zhou, H., Wei, W., Ambasudhan, R., Lin, T., Kim, J., Zhang, K., and Ding, S. (2010). Reprogramming of human primary somatic cells by OCT4 and chemical compounds. Cell stem cell 7, 651-655.
     連結：
170. Al-Hajj, M., Wicha, M.S., Benito-Hernandez, A., Morrison, S.J., and Clarke, M.F. (2003). Prospective identification of tumorigenic breast cancer cells. Proceedings of the National Academy of Sciences of the United States of America 100, 3983-3988.
171. Anglesio, M.S., George, J., Kulbe, H., Friedlander, M., Rischin, D., Lemech, C., Power, J., Coward, J., Cowin, P.A., House, C.M., et al. (2011). IL6-STAT3-HIF signaling and therapeutic response to the angiogenesis inhibitor sunitinib in ovarian clear cell cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 17, 2538-2548.
172. Auersperg, N., Pan, J., Grove, B.D., Peterson, T., Fisher, J., Maines-Bandiera, S., Somasiri, A., and Roskelley, C.D. (1999). E-cadherin induces mesenchymal-to-epithelial transition in human ovarian surface epithelium. Proceedings of the National Academy of Sciences of the United States of America 96, 6249-6254.
173. Balzar, M., Winter, M.J., de Boer, C.J., and Litvinov, S.V. (1999). The biology of the 17-1A antigen (Ep-CAM). Journal of molecular medicine 77, 699-712.
174. Ban, H., Nishishita, N., Fusaki, N., Tabata, T., Saeki, K., Shikamura, M., Takada, N., Inoue, M., Hasegawa, M., Kawamata, S., et al. (2011). Efficient generation of transgene-free human induced pluripotent stem cells (iPSCs) by temperature-sensitive Sendai virus vectors. Proceedings of the National Academy of Sciences of the United States of America 108, 14234-14239.
175. Bellin, M., Marchetto, M.C., Gage, F.H., and Mummery, C.L. (2012). Induced pluripotent stem cells: the new patient? Nature reviews Molecular cell biology 13, 713-726.
176. Brown, M.S., Ye, J., Rawson, R.B., and Goldstein, J.L. (2000). Regulated intramembrane proteolysis: a control mechanism conserved from bacteria to humans. Cell 100, 391-398.
177. Brunner, A., Schaefer, G., Veits, L., Brunner, B., Prelog, M., and Ensinger, C. (2008). EpCAM overexpression is associated with high-grade urothelial carcinoma in the renal pelvis. Anticancer research 28, 125-128.
178. Christiansen, M.N., Chik, J., Lee, L., Anugraham, M., Abrahams, J.L., and Packer, N.H. (2014). Cell surface protein glycosylation in cancer. Proteomics 14, 525-546.
179. Dalerba, P., Dylla, S.J., Park, I.K., Liu, R., Wang, X., Cho, R.W., Hoey, T., Gurney, A., Huang, E.H., Simeone, D.M., et al. (2007). Phenotypic characterization of human colorectal cancer stem cells. Proceedings of the National Academy of Sciences of the United States of America 104, 10158-10163.
180. Ezashi, T., Das, P., and Roberts, R.M. (2005). Low O2 tensions and the prevention of differentiation of hES cells. Proceedings of the National Academy of Sciences of the United States of America 102, 4783-4788.
181. Franovic, A., Holterman, C.E., Payette, J., and Lee, S. (2009). Human cancers converge at the HIF-2alpha oncogenic axis. Proceedings of the National Academy of Sciences of the United States of America 106, 21306-21311.
182. Groeneveld, G.J., Veldink, J.H., van der Tweel, I., Kalmijn, S., Beijer, C., de Visser, M., Wokke, J.H., Franssen, H., and van den Berg, L.H. (2003). A randomized sequential trial of creatine in amyotrophic lateral sclerosis. Annals of neurology 53, 437-445.
183. Hakomori, S. (1996). Tumor malignancy defined by aberrant glycosylation and sphingo(glyco)lipid metabolism. Cancer research 56, 5309-5318.
184. Kerns, W.D., Pavkov, K.L., Donofrio, D.J., Gralla, E.J., and Swenberg, J.A. (1983). Carcinogenicity of formaldehyde in rats and mice after long-term inhalation exposure. Cancer research 43, 4382-4392.
185. Kim, J.B., Sebastiano, V., Wu, G., Arauzo-Bravo, M.J., Sasse, P., Gentile, L., Ko, K., Ruau, D., Ehrich, M., van den Boom, D., et al. (2009c). Oct4-induced pluripotency in adult neural stem cells. Cell 136, 411-419.
186. Linnenbach, A.J., Wojcierowski, J., Wu, S.A., Pyrc, J.J., Ross, A.H., Dietzschold, B., Speicher, D., and Koprowski, H. (1989). Sequence investigation of the major gastrointestinal tumor-associated antigen gene family, GA733. Proceedings of the National Academy of Sciences of the United States of America 86, 27-31.
187. Litvinov, S.V., van Driel, W., van Rhijn, C.M., Bakker, H.A., van Krieken, H., Fleuren, G.J., and Warnaar, S.O. (1996). Expression of Ep-CAM in cervical squamous epithelia correlates with an increased proliferation and the disappearance of markers for terminal differentiation. The American journal of pathology 148, 865-875.
188. Maetzel, D., Denzel, S., Mack, B., Canis, M., Went, P., Benk, M., Kieu, C., Papior, P., Baeuerle, P.A., Munz, M., et al. (2009). Nuclear signalling by tumour-associated antigen EpCAM. Nature cell biology 11, 162-171.
189. Mathieu, J., Zhang, Z., Zhou, W., Wang, A.J., Heddleston, J.M., Pinna, C.M., Hubaud, A., Stadler, B., Choi, M., Bar, M., et al. (2011). HIF induces human embryonic stem cell markers in cancer cells. Cancer research 71, 4640-4652.
190. Momburg, F., Moldenhauer, G., Hammerling, G.J., and Moller, P. (1987). Immunohistochemical study of the expression of a Mr 34,000 human epithelium-specific surface glycoprotein in normal and malignant tissues. Cancer research 47, 2883-2891.
191. Scheunemann, P., Stoecklein, N.H., Rehders, A., Bidde, M., Metz, S., Peiper, M., Eisenberger, C.F., Schulte Am Esch, J., Knoefel, W.T., and Hosch, S.B. (2008). Occult tumor cells in lymph nodes as a predictor for tumor relapse in pancreatic adenocarcinoma. Langenbeck's archives of surgery / Deutsche Gesellschaft fur Chirurgie 393, 359-365.
192. Schmelzer, E., Zhang, L., Bruce, A., Wauthier, E., Ludlow, J., Yao, H.L., Moss, N., Melhem, A., McClelland, R., Turner, W., et al. (2007). Human hepatic stem cells from fetal and postnatal donors. The Journal of experimental medicine 204, 1973-1987.
193. Sekkai, D., Gruel, G., Herry, M., Moucadel, V., Constantinescu, S.N., Albagli, O., Tronik-Le Roux, D., Vainchenker, W., and Bennaceur-Griscelli, A. (2005). Microarray analysis of LIF/Stat3 transcriptional targets in embryonic stem cells. Stem cells 23, 1634-1642.
194. Strnad, J., Hamilton, A.E., Beavers, L.S., Gamboa, G.C., Apelgren, L.D., Taber, L.D., Sportsman, J.R., Bumol, T.F., Sharp, J.D., and Gadski, R.A. (1989). Molecular cloning and characterization of a human adenocarcinoma/epithelial cell surface antigen complementary DNA. Cancer research 49, 314-317.
195. Sugii, S., Kida, Y., Kawamura, T., Suzuki, J., Vassena, R., Yin, Y.Q., Lutz, M.K., Berggren, W.T., Izpisua Belmonte, J.C., and Evans, R.M. (2010). Human and mouse adipose-derived cells support feeder-independent induction of pluripotent stem cells. Proceedings of the National Academy of Sciences of the United States of America 107, 3558-3563.
196. Takeda, K., Noguchi, K., Shi, W., Tanaka, T., Matsumoto, M., Yoshida, N., Kishimoto, T., and Akira, S. (1997). Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality. Proceedings of the National Academy of Sciences of the United States of America 94, 3801-3804.
197. Yanes, O., Clark, J., Wong, D.M., Patti, G.J., Sanchez-Ruiz, A., Benton, H.P., Trauger, S.A., Desponts, C., Ding, S., and Siuzdak, G. (2010). Metabolic oxidation regulates embryonic stem cell differentiation. Nature chemical biology 6, 411-417.
198. Yi, D., Kuo, S.Z., Zheng, H., Abhold, E.L., Brown, C.M., Doherty, J.K., Wang-Rodriguez, J., Harris, J.P., and Ongkeko, W.M. (2012). Activation of PDGFR and EGFR promotes the acquisition of a stem cell-like phenotype in schwannomas. Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology 33, 1640-1647.
199. Yu, J., Vodyanik, M.A., Smuga-Otto, K., Antosiewicz-Bourget, J., Frane, J.L., Tian, S., Nie, J., Jonsdottir, G.A., Ruotti, V., Stewart, R., et al. (2007). Induced pluripotent stem cell lines derived from human somatic cells. Science 318, 1917-1920.