MicroRNAs regulate both epithelial-to-mesenchymal transition and cancer stem cells

Oncogene

Volumn 33, Issue 3, 2014, Pages 269-278

  Ceppi, P ^a   Peter, M E ^a  

^a NORTHWESTERN UNIVERSITY   (United States)

Author keywords

cancer stem cells; epithelial to mesenchymal transition; MiRNAs

Indexed keywords

ANTINEOPLASTIC AGENT; EPIDERMAL GROWTH FACTOR RECEPTOR KINASE INHIBITOR; MICRORNA; MICRORNA 200; MICRORNA 21; TRANSCRIPTION FACTOR; TRANSFORMING GROWTH FACTOR BETA; UVOMORULIN;

BREAST CANCER; CAENORHABDITIS ELEGANS; CANCER CELL; CANCER CELL CULTURE; CANCER CONTROL; CANCER STEM CELL; CARCINOGENESIS; CELL CONTACT; CELL DIFFERENTIATION; CELL FUNCTION; CELL POPULATION; CELL RENEWAL; CHEMORADIOTHERAPY; EPITHELIAL MESENCHYMAL TRANSITION; EUKARYOTIC CELL; GENE EXPRESSION; GENE REPRESSION; HUMAN; NEOPLASM; NONHUMAN; PHENOTYPE; PHENOTYPIC PLASTICITY; PRIORITY JOURNAL; PROTEIN PROCESSING; REGULATORY MECHANISM; REVIEW; TRANSCRIPTION REGULATION; TUMOR DIFFERENTIATION;

EPITHELIAL-MESENCHYMAL TRANSITION; GENE EXPRESSION REGULATION, NEOPLASTIC; HUMANS; MICRORNAS; MODELS, GENETIC; NEOPLASMS; NEOPLASTIC STEM CELLS; TUMOR MARKERS, BIOLOGICAL;

EID: 84892671815     PISSN: 09509232     EISSN: 14765594     Source Type: Journal    
DOI: 10.1038/onc.2013.55     Document Type: Review

References (193)

1. Tiwari N, Gheldof A, Tatari M, Christofori G. EMT as the ultimate survival mechanism of cancer cells. Semin Cancer Biol 2012; 22: 194-207.
2. Magee JA, Piskounova E, Morrison SJ. Cancer stem cells: impact, heterogeneity, and uncertainty. Cancer Cell 2012; 21: 283-296.
3. Singh A, Settleman J. EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene 2010; 29: 4741-4751.
4. Visvader JE, Lindeman GJ. Cancer stem cells: current status and evolving complexities. Cell Stem Cell 2012; 10: 717-728.
5. Iorio MV, Croce CM. MicroRNA dysregulation in cancer: diagnostics, monitoring and therapeutics. A comprehensive review. EMBO Mol Med 2012; 4: 143-159.
6. Peter ME. Let-7 and miR-200 microRNAs: guardians against pluripotency and cancer progression. Cell Cycle 2009; 8: 843-852.
7. Boyer B, Valles AM, Edme N. Induction and regulation of epithelial-mesenchymal transitions. Biochem Pharmacol 2000; 60: 1091-1099.
8. Zavadil J, Bottinger EP. TGF-beta and epithelial-to-mesenchymal transitions. Oncogene 2005; 24: 5764-5774.
9. Savagner P. Leaving the neighborhood: molecular mechanisms involved during epithelial-mesenchymal transition. Bioessays 2001; 23: 912-923.
10. Lien HC, Hsiao YH, Lin YS, Yao YT, Juan HF, Kuo WH et al. Molecular signatures of metaplastic carcinoma of the breast by large-scale transcriptional profiling: identification of genes potentially related to epithelial- mesenchymal transition. Oncogene 2007; 26: 7859-7871.
11. Semb H, Christofori G. The tumor-suppressor function of E-cadherin. Am J Hum Genet 1998; 63: 1588-1593.
12. Inada S, Koto T, Futami K, Arima S, Iwashita A. Evaluation of malignancy and the prognosis of esophageal cancer based on an immunohistochemical study (p53, E-cadherin, epidermal growth factor receptor). Surg Today 1999; 29: 493-503.
13. Sulzer MA, Leers MP, van Noord JA, Bollen EC, Theunissen PH. Reduced E-cadherin expression is associated with increased lymph node metastasis and unfavorable prognosis in non-small cell lung cancer. Am J Respir Crit Care Med 1998; 157: 1319-1323.
14. Siitonen SM, Kononen JT, Helin HJ, Rantala IS, Holli KA, Isola JJ. Reduced E-cadherin expression is associated with invasiveness and unfavorable prognosis in breast cancer. Am J Clin Pathol 1996; 105: 394-402.
15. Umbas R, Isaacs WB, Bringuier PP, Schaafsma HE, Karthaus HF, Oosterhof GO et al. Decreased E-cadherin expression is associated with poor prognosis in patients with prostate cancer. Cancer Res 1994; 54: 3929-3933.
16. Peinado H, Olmeda D, Cano A. Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Cancer 2007; 7: 415-428.
17. Batlle E, Sancho E, Franci C, Dominguez D, Monfar M, Baulida J et al. The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nat Cell Biol 2000; 2: 84-89.
18. Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C et al. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 2004; 117: 927-939.
19. Bolos V, Peinado H, Perez-Moreno MA, Fraga MF, Esteller M, Cano A. The transcription factor Slug represses E-cadherin expression and induces epithelial to mesenchymal transitions: a comparison with Snail and E47 repressors. J Cell Sci 2003; 116: 499-511.
20. Aigner K, Dampier B, Descovich L, Mikula M, Sultan A, Schreiber M et al. The transcription factor ZEB1 (deltaEF1) promotes tumour cell dedifferentiation by repressing master regulators of epithelial polarity. Oncogene 2007; 26: 6979-6988.
21. Bindels S, Mestdagt M, Vandewalle C, Jacobs N, Volders L, Noel A et al. Regulation of vimentin by SIP1 in human epithelial breast tumor cells. Oncogene 2006; 25: 4975-4985.
22. Rosivatz E, Becker I, Specht K, Fricke E, Luber B, Busch R et al. Differential expression of the epithelial-mesenchymal transition regulators snail, SIP1, and twist in gastric cancer. Am J Pathol 2002; 161: 1881-1891.
23. Lombaerts M, van Wezel T, Philippo K, Dierssen JW, Zimmerman RM, Oosting J et al. E-cadherin transcriptional downregulation by promoter methylation but not mutation is related to epithelial-to-mesenchymal transition in breast cancer cell lines. Br J Cancer 2006; 94: 661-671.
24. Kwon O, Jeong SJ, Kim SO, He L, Lee HG, Jang KL et al. Modulation of E-cadherin expression by K-Ras; involvement of DNA methyltransferase-3b. Carcinogenesis 2010; 31: 1194-1201.
25. Ling ZQ, Li P, Ge MH, Zhao X, Hu FJ, Fang XH et al. Hypermethylation- modulated down-regulation of CDH1 expression contributes to the progression of esophageal cancer. Int J Mol Med 2011; 27: 625-635.
26. Aghdassi A, Sendler M, Guenther A, Mayerle J, Behn CO, Heidecke CD et al. Recruitment of histone deacetylases HDAC1 and HDAC2 by the transcriptional repressor ZEB1 downregulates E-cadherin expression in pancreatic cancer. Gut 2012; 61: 439-448.
27. Cao Q, Yu J, Dhanasekaran SM, Kim JH, Mani RS, Tomlins SA et al. Repression of E-cadherin by the polycomb group protein EZH2 in cancer. Oncogene 2008; 27: 7274-7284.
28. Salahshor S, Haixin L, Huo H, Kristensen VN, Loman N, Sjoberg-Margolin S et al. Low frequency of E-cadherin alterations in familial breast cancer. Breast Cancer Res 2001; 3: 199-207.
29. Davies JA. Mesenchyme to epithelium transition during development of the mammalian kidney tubule. Acta Anat (Basel) 1996; 156: 187-201.
30. Yang J, Weinberg RA. Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell 2008; 14: 818-829.
31. Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2002; 2: 442-454.
32. Brabletz T, Jung A, Spaderna S, Hlubek F, Kirchner T. Opinion: migrating cancer stem cells-an integrated concept of malignant tumour progression. Nat Rev Cancer 2005; 5: 744-749.
33. Korpal M, Ell BJ, Buffa FM, Ibrahim T, Blanco MA, Celia-Terrassa T et al. Direct targeting of Sec23a by miR-200 s influences cancer cell secretome and promotes metastatic colonization. Nat Med 2011; 17: 1101-1108.
34. Friedman RC, Farh KK, Burge CB, Bartel DP. Most mammalian mRNAs are conserved targets of microRNAs. Genome Res 2009; 19: 92-105.
35. Lewis BP, Burge CB, Bartel DP. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 2005; 120: 15-20.
36. Cullen BR. Transcription and processing of human microRNA precursors. Mol Cell 2004; 16: 861-865.
37. Zhang L, Huang J, Yang N, Greshock J, Megraw MS, Giannakakis A et al. MicroRNAs exhibit high frequency genomic alterations in human cancer. Proc Natl Acad Sci USA 2006; 103: 9136-9141.
38. Abbott AL, Alvarez-Saavedra E, Miska EA, Lau NC, Bartel DP, Horvitz HR et al. The let-7 MicroRNA family members mir-48, mir-84, and mir-241 function together to regulate developmental timing in Caenorhabditis elegans. Dev Cell 2005; 9: 403-414.
39. Boyerinas B, Park SM, Hau A, Murmann AE, Peter ME. The role of let-7 in cell differentiation and cancer. Endocr Relat Cancer 2010; 17: F19-F36.
40. Boyerinas B, Park SM, Shomron N, Hedegaard MM, Vinther J, Andersen JS et al. Identification of let-7-regulated oncofetal genes. Cancer Res 2008; 68: 2587-2591.
41. Johnson SM, Grosshans H, Shingara J, Byrom M, Jarvis R, Cheng A et al. RAS is regulated by the let-7 microRNA family. Cell 2005; 120: 635-647.
42. Sampson VB, Rong NH, Han J, Yang Q, Aris V, Soteropoulos P et al. MicroRNA let-7a down-regulates MYC and reverts MYC-induced growth in Burkitt lymphoma cells. Cancer Res 2007; 67: 9762-9770.
43. Kim HH, Kuwano Y, Srikantan S, Lee EK, Martindale JL, Gorospe M. HuR recruits let-7/RISC to repress c-Myc expression. Genes Dev 2009; 23: 1743-1748.
44. Viswanathan SR, Powers JT, Einhorn W, Hoshida Y, Ng TL, Toffanin S et al. Lin28 promotes transformation and is associated with advanced human malignancies. Nat Genet 2009; 41: 843-848.
45. Korpal M, Lee ES, Hu G, Kang Y. The miR-200 family inhibits epithelialmesenchymal transition and cancer cell migration by direct targeting of E-cadherin transcriptional repressors ZEB1 and ZEB2. J Biol Chem 2008; 283: 14910-14914.
46. Park SM, Gaur AB, Lengyel E, Peter ME. The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors, ZEB1 and ZEB2. Genes Dev 2008; 22: 894-907.
47. Gregory PA, Bert AG, Paterson EL, Barry SC, Tsykin A, Farshid G et al. The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol 2008; 10: 593-601.
48. Burk U, Schubert J, Wellner U, Schmalhofer O, Vincan E, Spaderna S et al. A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells. EMBO Rep 2008; 9: 582-589.
49. Ceppi P, Mudduluru G, Kumarswamy R, Rapa I, Scagliotti GV, Papotti M et al. Loss of miR-200c expression induces an aggressive, invasive, and chemoresistant phenotype in non-small cell lung cancer. Mol Cancer Res 2010; 8: 1207-1216.
50. Vrba L, Jensen TJ, Garbe JC, Heimark RL, Cress AE, Dickinson S et al. Role for DNA methylation in the regulation of miR-200c and miR-141 expression in normal and cancer cells. PLoS One 2010; 5: e8697.
51. Davalos V, Moutinho C, Villanueva A, Boque R, Silva P, Carneiro F et al. Dynamic epigenetic regulation of the microRNA-200 family mediates epithelial and mesenchymal transitions in human tumorigenesis. Oncogene 2012; 31: 2062-2074.
52. Wiklund ED, Bramsen JB, Hulf T, Dyrskjot L, Ramanathan R, Hansen TB et al. Coordinated epigenetic repression of the miR-200 family and miR-205 in invasive bladder cancer. Int J Cancer 2011; 128: 1327-1334.
53. Yang Y, Ahn YH, Gibbons DL, Zang Y, Lin W, Thilaganathan N et al. The Notch ligand Jagged2 promotes lung adenocarcinoma metastasis through a miR-200-dependent pathway in mice. J Clin Invest 2011; 121: 1373-1385.
54. Kim T, Veronese A, Pichiorri F, Lee TJ, Jeon YJ, Volinia S et al. p53 regulates epithelial-mesenchymal transition through microRNAs targeting ZEB1 and ZEB2. J Exp Med 2011; 208: 875-883.
55. Dykxhoorn DM, Wu Y, Xie H, Yu F, Lal A, Petrocca F et al. miR-200 enhances mouse breast cancer cell colonization to form distant metastases. PLoS One 2009; 4: e7181.
56. Dahiya N, Sherman-Baust CA, Wang TL, Davidson B, Shih IeM, Zhang Y et al. MicroRNA expression and identification of putative miRNA targets in ovarian cancer. PLoS One 2008; 3: e2436.
57. Zhang L, Volinia S, Bonome T, Calin GA, Greshock J, Yang N et al. Genomic and epigenetic alterations deregulate microRNA expression in human epithelial ovarian cancer. Proc Natl Acad Sci USA 2008; 105: 7004-7009.
58. Nam EJ, Yoon H, Kim SW, Kim H, Kim YT, Kim JH et al. MicroRNA expression profiles in serous ovarian carcinoma. Clin Cancer Res 2008; 14: 2690-2695.
59. Iorio MV, Visone R, Di Leva G, Donati V, Petrocca F, Casalini P et al. MicroRNA signatures in human ovarian cancer. Cancer Res 2007; 67: 8699-8707.
60. Kim NH, Kim HS, Li XY, Lee I, Choi HS, Kang SE et al. A p53/miRNA-34 axis regulates Snail1-dependent cancer cell epithelial-mesenchymal transition. J Cell Biol 2011; 195: 417-433.
61. Kumarswamy R, Mudduluru G, Ceppi P, Muppala S, Kozlowski M, Niklinski J et al. MicroRNA-30a inhibits epithelial-to-mesenchymal transition by targeting Snai1 and is downregulated in non-small cell lung cancer. Int J Cancer 2012; 130: 2044-2053.
62. Liu X, Wang C, Chen Z, Jin Y, Wang Y, Kolokythas A et al. MicroRNA-138 suppresses epithelial-mesenchymal transition in squamous cell carcinoma cell lines. Biochem J 2011; 440: 23-31.
63. Ahn YH, Gibbons DL, Chakravarti D, Creighton CJ, Rizvi ZH, Adams HP et al. ZEB1 drives prometastatic actin cytoskeletal remodeling by downregulating miR-34a expression. J Clin Invest 2012; 122: 3170-3183.
64. Kong W, Yang H, He L, Zhao JJ, Coppola D, Dalton WS et al. MicroRNA-155 is regulated by the transforming growth factor beta/Smad pathway and contributes to epithelial cell plasticity by targeting RhoA. Mol Cell Biol 2008; 28: 6773-6784.
65. Merlo LM, Pepper JW, Reid BJ, Maley CC. Cancer as an evolutionary and ecological process. Nat Rev Cancer 2006; 6: 924-935.
66. Campbell LL, Polyak K. Breast tumor heterogeneity: cancer stem cells or clonal evolution? Cell Cycle 2007; 6: 2332-2338.
67. Gupta PB, Chaffer CL, Weinberg RA. Cancer stem cells: mirage or reality? Nat Med 2009; 15: 1010-1012.
68. Li MA, He L. microRNAs as novel regulators of stem cell pluripotency and somatic cell reprogramming. BioEssays 2012; 34: 670-680.
69. Kanellopoulou C, Muljo SA, Kung AL, Ganesan S, Drapkin R, Jenuwein T et al. Dicer-deficient mouse embryonic stem cells are defective in differentiation and centromeric silencing. Genes Dev 2005; 19: 489-501.
70. Choi YJ, Lin CP, Ho JJ, He X, Okada N, Bu P et al. miR-34 miRNAs provide a barrier for somatic cell reprogramming. Nature Cell Biol 2011; 13: 1353-1360.
71. Concepcion CP, Han YC, Mu P, Bonetti C, Yao E, D'Andrea A et al. Intact p53-dependent responses in miR-34-deficient mice. PLoS Genet 2012; 8: e1002797.
72. Ji Q, Hao X, Zhang M, Tang W, Yang M, Li L et al. MicroRNA miR-34 inhibits human pancreatic cancer tumor-initiating cells. PLoS One 2009; 4: e6816.
73. Ibarra I, Erlich Y, Muthuswamy SK, Sachidanandam R, Hannon GJ. A role for microRNAs in maintenance of mouse mammary epithelial progenitor cells. Genes Dev 2007; 21: 3238-3243.
74. Yu F, Yao H, Zhu P, Zhang X, Pan Q, Gong C et al. let-7 regulates self renewal and tumorigenicity of breast cancer cells. Cell 2007; 131: 1109-1123.
75. Shimono Y, Zabala M, Cho RW, Lobo N, Dalerba P, Qian D et al. Downregulation of miRNA-200c links breast cancer stem cells with normal stem cells. Cell 2009; 138: 592-603.
76. Iliopoulos D, Lindahl-Allen M, Polytarchou C, Hirsch HA, Tsichlis PN, Struhl K. Loss of miR-200 inhibition of Suz12 leads to polycomb-mediated repression required for the formation and maintenance of cancer stem cells. Mol Cell 2010; 39: 761-772.
77. Barroso-del Jesus A, Lucena-Aguilar G, Menendez P. The miR-302-367 cluster as a potential stemness regulator in ESCs. Cell Cycle 2009; 8: 394-398.
78. Barroso-delJesus A, Romero-Lopez C, Lucena-Aguilar G, Melen GJ, Sanchez L, Ligero G et al. Embryonic stem cell-specific miR-302-367 cluster: human gene structure and functional characterization of its core promoter. Mol Cell Biol 2008; 28: 6609-6619.
79. Lin SL, Chang DC, Chang-Lin S, Lin CH, Wu DT, Chen DT et al. Mir-302 reprograms human skin cancer cells into a pluripotent ES-cell-like state. RNA 2008; 14: 2115-2124.
80. Wang L, Zhang D, Zhang C, Zhang S, Wang Z, Qu C et al. A microRNA expression signature characterizing the properties of tumor-initiating cells for breast cancer. Oncol Lett 2012; 3: 119-124.
81. Liu C, Kelnar K, Vlassov AV, Brown D, Wang J, Tang DG. Distinct microRNA expression profiles in prostate cancer stem/progenitor cells and tumor-suppressive functions of let-7. Cancer Res 2012; 72: 3393-3404.
82. Nam EJ, Lee M, Yim GW, Kim JH, Kim S, KIM SW et al. MicroRNA profiling of a CD133\+ spheroid-forming subpopulation of the OVCAR3 human ovarian cancer cell line. BMC Med Genomics 2012; 5: 18.
83. Bitarte N, Bandres E, Boni V, Zarate R, Rodriguez J, Gonzalez-Huarriz M et al. MicroRNA-451 is involved in the self-renewal, tumorigenicity, and chemoresistance of colorectal cancer stem cells. Stem Cells 2011; 29: 1661-1671.
84. Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY et al. The epithelialmesenchymal transition generates cells with properties of stem cells. Cell 2008; 133: 704-715.
85. Gupta PB, Fillmore CM, Jiang G, Shapira SD, Tao K, Kuperwasser C et al. Stochastic state transitions give rise to phenotypic equilibrium in populations of cancer cells. Cell 2011; 146: 633-644.
86. Chaffer CL, Brueckmann I, Scheel C, Kaestli AJ, Wiggins PA, Rodrigues LO et al. Normal and neoplastic nonstem cells can spontaneously convert to a stem-like state. Proc Nat Acad Sci USA 2011; 108: 7950-7955.
87. Yang G, Quan Y, Wang W, Fu Q, Wu J, Mei T et al. Dynamic equilibrium between cancer stem cells and non-stem cancer cells in human SW620 and MCF-7 cancer cell populations. Br J Cancer 2012; 106: 1512-1519.
88. Scheel C, Eaton EN, Li SH, Chaffer CL, Reinhardt F, Kah KJ et al. Paracrine and autocrine signals induce and maintain mesenchymal and stem cell states in the breast. Cell 2011; 145: 926-940.
89. Iliopoulos D, Hirsch HA, Wang G, Struhl K. Inducible formation of breast cancer stem cells and their dynamic equilibrium with non-stem cancer cells via IL6 secretion. Proc Natl Acad Sci USA 2011; 108: 1397-1402.
90. Akunuru S, James Zhai Q, Zheng Y. Non-small cell lung cancer stem/progenitor cells are enriched in multiple distinct phenotypic subpopulations and exhibit plasticity. Cell Death Dis 2012; 3: e352.
91. Chen YS, Wu MJ, Huang CY, Lin SC, Chuang TH, Yu CC et al. CD133/Src axis mediates tumor initiating property and epithelial-mesenchymal transition of head and neck cancer. PLoS One 2011; 6: e28053.
92. Yang MH, Hsu DS, Wang HW, Wang HJ, Lan HY, Yang WH et al. Bmi1 is essential in Twist1-induced epithelial-mesenchymal transition. Nature Cell Biol 2010; 12: 982-992.
93. Wang L, Mezencev R, Bowen NJ, Matyunina LV, McDonald JF. Isolation and characterization of stem-like cells from a human ovarian cancer cell line. Mol Cell Biochem 2012; 363: 257-268.
94. Kong D, Banerjee S, Ahmad A, Li Y, Wang Z, Sethi S et al. Epithelial to mesenchymal transition is mechanistically linked with stem cell signatures in prostate cancer cells. PLoS One 2010; 5: e12445.
95. Chang CJ, Chao CH, Xia W, Yang JY, Xiong Y, Li CW et al. p53 regulates epithelialmesenchymal transition and stem cell properties through modulating miRNAs. Nat Cell Biol 2011; 13: 317-323.
96. Guttilla IK, Phoenix KN, Hong X, Tirnauer JS, Claffey KP, White BA. Prolonged mammosphere culture of MCF-7 cells induces an EMT and repression of the estrogen receptor by microRNAs. Breast Cancer Res Treat 2012; 132: 75-85.
97. Qian PX, Banerjee A, Wu ZS, Zhang X, Wang H, Pandey V et al. Loss of SNAIL regulated miR-128-2 on chromosome 3p22.3 targets multiple stem cell factors to promote transformation of mammary epithelial cells. Cancer Res 2012; 72: 6036-6050.
98. Xia H, Ooi LL, Hui KM. MiR-214 targets beta-catenin pathway to suppress invasion, stem-like traits and tecurrence of human hepatocellular carcinoma. PLoS One 2012; 7: e44206.
99. Yang H, Kong W, He L, Zhao JJ, O'Donnell JD, Wang J et al. MicroRNA expression profiling in human ovarian cancer: miR-214 induces cell survival and cisplatin resistance by targeting PTEN. Cancer Res 2008; 68: 425-433.
100. Xu CX, Xu M, Tan L, Yang H, Permuth-Wey J, Kruk PA et al. MiR-214 regulates ovarian cancer cell stemness by targeting p53/nanog. J Biol Chem 2012; 287: 34970-34978.
101. Dong P, Kaneuchi M, Watari H, Hamada J, Sudo S, Ju J et al. MicroRNA-194 inhibits epithelial to mesenchymal transition of endometrial cancer cells by targeting oncogene BMI-1. Mol Cancer 2011; 10: 99.
102. Meng F, Henson R, Wehbe-Janek H, Ghoshal K, Jacob ST, Patel T. MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology 2007; 133: 647-658.
103. Asangani IA, Rasheed SA, Nikolova DA, Leupold JH, Colburn NH, Post S et al. MicroRNA-21 (miR-21) post-transcriptionally downregulates tumor suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in colorectal cancer. Oncogene 2008; 27: 2128-2136.
104. Han M, Liu M, Wang Y, Chen X, Xu J, Sun Y et al. Antagonism of miR-21 reverses epithelial-mesenchymal transition and cancer stem cell phenotype through AKT/ERK1/2 inactivation by targeting PTEN. PLoS One 2012; 7: e39520.
105. Bourguignon LY, Earle C, Wong G, Spevak CC, Krueger K. Stem cell marker (Nanog) and Stat-3 signaling promote MicroRNA-21 expression and chemoresistance in hyaluronan/CD44-activated head and neck squamous cell carcinoma cells. Oncogene 2012; 31: 149-160.
106. Subramanyam D, Lamouille S, Judson RL, Liu JY, Bucay N, Derynck R et al. Multiple targets of miR-302 and miR-372 promote reprogramming of human fibroblasts to induced pluripotent stem cells. Nat Biotechnol 2011; 29: 443-448.
107. Miyoshi N, Ishii H, Nagano H, Haraguchi N, Dewi DL, Kano Y et al. Reprogramming of mouse and human cells to pluripotency using mature microRNAs. Cell Stem Cell 2011; 8: 633-638.
108. Samavarchi-Tehrani P, Golipour A, David L, Sung HK, Beyer TA, Datti A et al. Functional genomics reveals a BMP-driven mesenchymal-to-epithelial transition in the initiation of somatic cell reprogramming. Cell Stem Cell 2010; 7: 64-77.
109. Celia-Terrassa T, Meca-Cortes O, Mateo F, de Paz AM, Rubio N, Arnal-Estape A et al. Epithelial-mesenchymal transition can suppress major attributes of human epithelial tumor-initiating cells. J Clin Invest 2012; 122: 1849-1868.
110. Duong HQ, Hwang JS, Kim HJ, Kang HJ, Seong YS, Bae I. Aldehyde dehydrogenase 1A1 confers intrinsic and acquired resistance to gemcitabine in human pancreatic adenocarcinoma MIA PaCa-2 cells. Int J Oncol 2012; 41: 855-861.
111. Chow EK, Fan LL, Chen X, Bishop JM. Oncogene-specific formation of chemoresistant murine hepatic cancer stem cells. Hepatol 2012; 56: 1331-1341.
112. Ghosh G, Lian X, Kron SJ, Palecek SP. Properties of resistant cells generated from lung cancer cell lines treated with EGFR inhibitors. BMC Cancer 2012; 12: 95.
113. Yi H, Cho HJ, Cho SM, Jo K, Park JA, Lee SH et al. Effect of 5-FU and MTX on the expression of drug-resistance related cancer stem cell markers in non-small cell lung cancer cells. Korean J Physiol Pharmacol 2012; 16: 11-16.
114. Falso MJ, Buchholz BA, White RW. Stem-like cells in bladder cancer cell lines with differential sensitivity to cisplatin. Anticancer Res 2012; 32: 733-738.
115. Tamada M, Nagano O, Tateyama S, Ohmura M, Yae T, Ishimoto T et al. Modulation of glucose metabolism by CD44 contributes to antioxidant status and drug resistance in cancer cells. Cancer Res 2012; 72: 1438-1448.
116. Zhang L, Jiao M, Li L, Wu D, Wu K, Li X et al. Tumorspheres derived from prostate cancer cells possess chemoresistant and cancer stem cell properties. J Cancer Res Clin Onc 2012; 138: 675-686.
117. Steg AD, Bevis KS, Katre AA, Ziebarth A, Dobbin ZC, Alvarez RD et al. Stem cell pathways contribute to clinical chemoresistance in ovarian cancer. Clin Cancer Res 2012; 18: 869-881.
118. Xue Z, Yan H, Li J, Liang S, Cai X, Chen X et al. Identification of cancer stem cells in vincristine preconditioned SGC7901 gastric cancer cell line. J Cell Biochem 2012; 113: 302-312.
119. Achuthan S, Santhoshkumar TR, Prabhakar J, Nair SA, Pillai MR. Drug-induced senescence generates chemoresistant stemlike cells with low reactive oxygen species. J Biol Chem 2011; 286: 37813-37829.
120. Van Phuc P, Nhan PL, Nhung TH, Tam NT, Hoang NM, Tue VG et al. Downregulation of CD44 reduces doxorubicin resistance of CD44CD24 breast cancer cells. Onco Targets Ther 2011; 4: 71-78.
121. Fan X, Ouyang N, Teng H, Yao H. Isolation and characterization of spheroid cells from the HT29 colon cancer cell line. Int J Colorectal Dis 2011; 26: 1279-1285.
122. Tang QL, Liang Y, Xie XB, Yin JQ, Zou CY, Zhao ZQ et al. Enrichment of osteosarcoma stem cells by chemotherapy. Chin J Cancer 2011; 30: 426-432.
123. Latifi A, Abubaker K, Castrechini N, Ward AC, Liongue C, Dobill F et al. Cisplatin treatment of primary and metastatic epithelial ovarian carcinomas generates residual cells with mesenchymal stem cell-like profile. J Cell Biochem 2011; 112: 2850-2864.
124. Kobayashi Y, Seino K, Hosonuma S, Ohara T, Itamochi H, Isonishi S et al. Side population is increased in paclitaxel-resistant ovarian cancer cell lines regardless of resistance to cisplatin. Gynecol Oncol 2011; 121: 390-394.
125. Calcagno AM, Salcido CD, Gillet JP, Wu CP, Fostel JM, Mumau MD et al. Prolonged drug selection of breast cancer cells and enrichment of cancer stem cell characteristics. J Natl Cancer Inst 2010; 102: 1637-1652.
126. Ma L, Lai D, Liu T, Cheng W, Guo L. Cancer stem-like cells can be isolated with drug selection in human ovarian cancer cell line SKOV3. Acta Biochim Biophys Sin (Shanghai) 2010; 42: 593-602.
127. Du Z, Qin R, Wei C, Wang M, Shi C, Tian R et al. Pancreatic cancer cells resistant to chemoradiotherapy rich in "stem-cell-like" tumor cells. Dig Dis Sci 2011; 56: 741-750.
128. Adhikari AS, Agarwal N, Wood BM, Porretta C, Ruiz B, Pochampally RR et al. CD117 and Stro-1 identify osteosarcoma tumor-initiating cells associated with metastasis and drug resistance. Cancer Res 2010; 70: 4602-4612.
129. Sabisz M, Skladanowski A. Cancer stem cells and escape from drug-induced premature senescence in human lung tumor cells: implications for drug resistance and in vitro drug screening models. Cell Cycle 2009; 8: 3208-3217.
130. Hong SP, Wen J, Bang S, Park S, Song SY. CD44-positive cells are responsible for gemcitabine resistance in pancreatic cancer cells. Int J Cancer 2009; 125: 2323-2331.
131. Tanei T, Morimoto K, Shimazu K, Kim SJ, Tanji Y, Taguchi T et al. Association of breast cancer stem cells identified by aldehyde dehydrogenase 1 expression with resistance to sequential Paclitaxel and epirubicin-based chemotherapy for breast cancers. Clin Cancer Res 2009; 15: 4234-4241.
132. Fujii H, Honoki K, Tsujiuchi T, Kido A, Yoshitani K, Takakura Y. Sphere-forming stem-like cell populations with drug resistance in human sarcoma cell lines. Int J Oncol 2009; 34: 1381-1386.
133. Di Fiore R, Santulli A, Ferrante RD, Giuliano M, De Blasio A, Messina C et al. Identification and expansion of human osteosarcoma-cancer-stem cells by longterm 3-aminobenzamide treatment. J Cell Physiol 2009; 219: 301-313.
134. Dylla SJ, Beviglia L, Park IK, Chartier C, Raval J, Ngan L et al. Colorectal cancer stem cells are enriched in xenogeneic tumors following chemotherapy. PLoS One 2008; 3: e2428.
135. Fillmore CM, Kuperwasser C. Human breast cancer cell lines contain stem-like cells that self-renew, give rise to phenotypically diverse progeny and survive chemotherapy. Breast Cancer Res 2008; 10: R25.
136. Uchida Y, Tanaka S, Aihara A, Adikrisna R, Yoshitake K, Matsumura S et al. Analogy between sphere forming ability and stemness of human hepatoma cells. Oncol Rep 2010; 24: 1147-1151.
137. Saigusa S, Tanaka K, Toiyama Y, Yokoe T, Okugawa Y, Ioue Y et al. Correlation of CD133, OCT4, and SOX2 in rectal cancer and their association with distant recurrence after chemoradiotherapy. Ann Surg Oncol 2009; 16: 3488-3498.
138. Sun L, Yao Y, Liu B, Lin Z, Lin L, Yang M et al. MiR-200b and miR-15b regulate chemotherapy-induced epithelial-mesenchymal transition in human tongue cancer cells by targeting BMI1. Oncogene 2012; 31: 432-445.
139. Puhr M, Hoefer J, Schafer G, Erb HH, Oh SJ, Klocker H et al. Epithelial-tomesenchymal transition leads to docetaxel resistance in prostate cancer and is mediated by reduced expression of miR-200c and miR-205. Am J Pathol 2012; 181: 2188-2201.
140. Boyerinas B, Park SM, Murmann AE, Gwin K, Montag AG, Zillardt MR et al. Let-7 modulates acquired resistance of ovarian cancer to Taxanes via IMP-1-mediated stabilization of MDR1. Int J Cancer 2012; 130: 1787-1797.
141. Leskela S, Leandro-Garcia LJ, Mendiola M, Barriuso J, Inglada-Perez L, Munoz I et al. The miR-200 family controls beta-tubulin III expression and is associated with paclitaxel-based treatment response and progression-free survival in ovarian cancer patients. Endocr Relat Cancer 2011; 18: 85-95.
142. Sugimura K, Miyata H, Tanaka K, Hamano R, Takahashi T, Kurokawa Y et al. Let-7 expression is a significant determinant of response to chemotherapy through the regulation of IL-6/STAT3 pathway in esophageal squamous cell carcinoma. Clin Cancer Res 2012; 18: 5133-5153.
143. Adam L, Zhong M, Choi W, Qi W, Nicoloso M, Arora A et al. miR-200 expression regulates epithelial-to-mesenchymal transition in bladder cancer cells and reverses resistance to epidermal growth factor receptor therapy. Clin Cancer Res 2009; 15: 5060-5072.
144. Trang P, Wiggins JF, Daige CL, Cho C, Omotola M, Brown D et al. Systemic delivery of tumor suppressor microRNA mimics using a neutral lipid emulsion inhibits lung tumors in mice. Mol Ther 2011; 19: 1116-1122.
145. Trang P, Medina PP, Wiggins JF, Ruffino L, Kelnar K, Omotola M et al. Regression of murine lung tumors by the let-7 microRNA. Oncogene 2010; 29: 1580-1587.
146. Kota J, Chivukula RR, O'Donnell KA, Wentzel EA, Montgomery CL, Hwang HW et al. Therapeutic microRNA delivery suppresses tumorigenesis in a murine liver cancer model. Cell 2009; 137: 1005-1017.
147. Yang YP, Chien Y, Chiou GY, Cherng JY, Wang ML, Lo WL et al. Inhibition of cancer stem cell-like properties and reduced chemoradioresistance of glioblastoma using microRNA145 with cationic polyurethane-short branch PEI. Biomaterials 2012; 33: 1462-1476.
148. Connelly CM, Thomas M, Deiters A. High-throughput luciferase reporter assay for small-molecule inhibitors of microRNA function. J Biomol Screen 2012; 17: 822-828.
149. Klonisch T, Wiechec E, Hombach-Klonisch S, Ande SR, Wesselborg S, Schulze-Osthoff K et al. Cancer stem cell markers in common cancers-therapeutic implications. Trends Mol Med 2008; 14: 450-460.
150. Vira D, Basak SK, Veena MS, Wang MB, Batra RK, Srivatsan ES. Cancer stem cells, microRNAs, and therapeutic strategies including natural products. Cancer Metast Rev 2012; 31: 733-751.
151. Visvader JE, Lindeman GJ. Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer 2008; 8: 755-768.
152. Wang C, Xie J, Guo J, Manning HC, Gore JC, Guo N. Evaluation of CD44 and CD133 as cancer stem cell markers for colorectal cancer. Oncol Rep 2012; 28: 1301-1308.
153. Charafe-Jauffret E, Ginestier C, Birnbaum D. Breast cancer stem cells: tools and models to rely on. BMC Cancer 2009; 9: 202.
154. Mikhail S, He AR. Liver cancer stem cells. Int J Hepatol 2011; 2011: 486954.
155. Ma S, Chan KW, Lee TK, Tang KH, Wo JY, Zheng BJ et al. Aldehyde dehydrogenase discriminates the CD133 liver cancer stem cell populations. Mol Cancer Res 2008; 6: 1146-1153.
156. Richards M, Tan SP, Tan JH, Chan WK, Bongso A. The transcriptome profile of human embryonic stem cells as defined by SAGE. Stem Cells 2004; 22: 51-64.
157. Silva IA, Bai S, McLean K, Yang K, Griffith K, Thomas D et al. Aldehyde dehydrogenase in combination with CD133 defines angiogenic ovarian cancer stem cells that portend poor patient survival. Cancer Res 2011; 71: 3991-4001.
158. Burgos-Ojeda D, Rueda BR, Buckanovich RJ. Ovarian cancer stem cell markers: prognostic and therapeutic implications. Cancer Lett 2012; 322: 1-7.
159. Chearwae W, Bright JJ. PPARgamma agonists inhibit growth and expansion of CD133\+ brain tumour stem cells. Br J Cancer 2008; 99: 2044-2053.
160. Pestereva E, Kanakasabai S, Bright JJ. PPARgamma agonists regulate the expression of stemness and differentiation genes in brain tumour stem cells. Br J Cancer 2012; 106: 1702-1712.
161. Singh SK, Clarke ID, Hide T, Dirks PB. Cancer stem cells in nervous system tumors. Oncogene 2004; 23: 7267-7273.
162. Eramo A, Lotti F, Sette G, Pilozzi E, Biffoni M, Di Virgilio A et al. Identification and expansion of the tumorigenic lung cancer stem cell population. Cell Death Differ 2008; 15: 504-514.
163. Hurt EM, Kawasaki BT, Klarmann GJ, Thomas SB, Farrar WL. CD44\+ CD24(-) prostate cells are early cancer progenitor/stem cells that provide a model for patients with poor prognosis. Br J Cancer 2008; 98: 756-765.
164. Vlashi E, Kim K, Lagadec C, Donna LD, McDonald JT, Eghbali M et al. In vivo imaging, tracking, and targeting of cancer stem cells. J Natl Cancer Inst 2009; 101: 350-359
165. Wu C, Alman BA. Side population cells in human cancers. Cancer Lett 2008; 268: 1-9.
166. Hirschmann-Jax C, Foster AE, Wulf GG, Nuchtern JG, Jax TW, Gobel U et al. A distinct "side population" of cells with high drug efflux capacity in human tumor cells. Proc Natl Acad Sci USA 2004; 101: 14228-14233.
167. Wu Y, Wu PY. CD133 as a marker for cancer stem cells: progresses and concerns. Stem Cells Dev 2009; 18: 1127-1134.
168. Jaggupilli A, Elkord E. Significance of CD44 and CD24 as cancer stem cell markers: an enduring ambiguity. Clin Dev Immunol 2012; 2012: 708036.
169. Shmelkov SV, Butler JM, Hooper AT, Hormigo A, Kushner J, Milde T et al. CD133 expression is not restricted to stem cells, and both CD133\+ and CD133-metastatic colon cancer cells initiate tumors. J Clin Invest 2008; 118: 2111-2120.
170. Stuelten CH, Mertins SD, Busch JI, Gowens M, Scudiero DA, Burkett MW et al. Complex display of putative tumor stem cell markers in the NCI60 tumor cell line panel. Stem Cells 2010; 28: 649-660.
171. Brown BD, Gentner B, Cantore A, Colleoni S, Amendola M, Zingale A et al. Endogenous microRNA can be broadly exploited to regulate transgene expression according to tissue, lineage and differentiation state. Nat Biotechnol 2007; 25: 1457-1467.
172. De Pietri Tonelli D, Calegari F, Fei JF, Nomura T, Osumi N, Heisenberg CP et al. Single-cell detection of microRNAs in developing vertebrate embryos after acute administration of a dual-fluorescence reporter/sensor plasmid. Biotechniques 2006; 41: 727-732.
173. Mansfield JH, Harfe BD, Nissen R, Obenauer J, Srineel J, Chaudhuri A et al. MicroRNA-responsive 'sensor' transgenes uncover Hox-like and other developmentally regulated patterns of vertebrate microRNA expression. Nat Genet 2004; 36: 1079-1083.
174. Di Stefano B, Maffioletti SM, Gentner B, Ungaro F, Schira G, Naldini L et al. A microRNA-based system for selecting and maintaining the pluripotent state in human induced pluripotent stem cells. Stem Cells 2011; 29: 1684-1695.
175. Kamata M, Liang M, Liu S, Nagaoka Y, Chen IS. Live cell monitoring of hiPSC generation and differentiation using differential expression of endogenous microRNAs. PLoS One 2010; 5: e11834.
176. Beillard E, Ong SC, Giannakakis A, Guccione E, Vardy LA, Voorhoeve PM. miRSens-a retroviral dual-luciferase reporter to detect microRNA activity in primary cells. RNA 2012; 18: 1091-1100.
177. Gentner B, Visigalli I, Hiramatsu H, Lechman E, Ungari S, Giustacchini A et al. Identification of hematopoietic stem cell-specific miRNAs enables gene therapy of globoid cell leukodystrophy. Sci Transl Med 2010; 2: 58ra84.
178. Chang CJ, Hsu CC, Chang CH, Tsai LL, Chang YC, Lu SW et al. Let-7d functions as novel regulator of epithelial-mesenchymal transition and chemoresistant property in oral cancer. Oncol Rep 2011; 26: 1003-1010.
179. Xia H, Cheung WK, Sze J, Lu G, Jiang S, Yao H et al. miR-200a regulates epithelialmesenchymal to stem-like transition via ZEB2 and beta-catenin signaling. J Biol Chem 2010; 285: 36995-37004.
180. Han M, Wang Y, Liu M, Bi X, Bao J, Zeng N et al. MiR-21 regulates epithelialmesenchymal transition phenotype and hypoxia-inducible factor-1alpha expression in third-sphere forming breast cancer stem cell-like cells. Cancer Sci 2012; 103: 1058-1064.
181. Iliopoulos D, Polytarchou C, Hatziapostolou M, Kottakis F, Maroulakou IG, Struhl K et al. MicroRNAs differentially regulated by Akt isoforms control EMT and stem cell renewal in cancer cells. Sci Signal 2009; 2: ra62.
182. Smith AL, Iwanaga R, Drasin DJ, Micalizzi DS, Vartuli RL, Tan AC et al. The miR-106b-25 cluster targets Smad7, activates TGF-beta signaling, and induces EMT and tumor initiating cell characteristics downstream of Six1 in human breast cancer. Oncogene 2012; 31: 5162-5171.
183. Chiou GY, Cherng JY, Hsu HS, Wang ML, Tsai CM, Lu KH et al. Cationic polyurethanes-short branch PEI-mediated delivery of Mir145 inhibited epithelialmesenchymal transdifferentiation and cancer stem-like properties and in lung adenocarcinoma. J Control Release 2012; 159: 240-250.
184. Tellez CS, Juri DE, Do K, Bernauer AM, Thomas CL, Damiani LA et al. EMT and stem cell-like properties associated with miR-205 and miR-200 epigenetic silencing are early manifestations during carcinogen-induced transformation of human lung epithelial cells. Cancer Res 2011; 71: 3087-3097.
185. Nalls D, Tang SN, Rodova M, Srivastava RK, Shankar S. Targeting epigenetic regulation of miR-34a for treatment of pancreatic cancer by inhibition of pancreatic cancer stem cells. PLoS One 2011; 6: e24099.
186. Bao B, Wang Z, Ali S, Kong D, Banerjee S, Ahmad A et al. Over-expression of FoxM1 leads to epithelial-mesenchymal transition and cancer stem cell phenotype in pancreatic cancer cells. J Cell Biochem 2011; 112: 2296-2306.
187. Wellner U, Schubert J, Burk UC, Schmalhofer O, Zhu F, Sonntag A et al. The EMTactivator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs. Nat Cell Biol 2009; 11: 1487-1495.
188. Garibaldi F, Cicchini C, Conigliaro A, Santangelo L, Cozzolino AM, Grassi G et al. An epistatic mini-circuitry between the transcription factors Snail and HNF4alpha controls liver stem cell and hepatocyte features exhorting opposite regulation on stemness-inhibiting microRNAs. Cell Death Differ 2012; 19: 937-946.
189. Bao B, Ahmad A, Kong D, Ali S, Azmi AS, Li Y et al. Hypoxia induced aggressiveness of prostate cancer cells is linked with deregulated expression of VEGF, IL-6 and miRNAs that are attenuated by CDF. PLoS One 2012; 7: e43726.
190. Wu N, Xiao L, Zhao X, Zhao J, Wang J, Wang F et al. miR-125b regulates the proliferation of glioblastoma stem cells by targeting E2F2. FEBS Lett 2012; 586: 3831-3839.
191. Lang MF, Yang S, Zhao C, Sun G, Murai K, Wu X et al. Genome-wide profiling identified a set of miRNAs that are differentially expressed in glioblastoma stem cells and normal neural stem cells. PLoS One 2012; 7: e36248.
192. Jung DE, Wen J, Oh T, Song SY. Differentially expressed microRNAs in pancreatic cancer stem cells. Pancreas 2011; 40: 1180-1187.
193. Xu XT, Xu Q, Tong JL, Zhu MM, Nie F, Chen X et al. MicroRNA expression profiling identifies miR-328 regulates cancer stem cell-like SP cells in colorectal cancer. Br J Cancer 2012; 106: 1320-1330.