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Investigating the Role of the Embryonic Stem Cell Self-Renewal Gene NANOG in Neoplastic Processes

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Stem Cells and Cancer Stem Cells, Volume 11

Part of the book series: Stem Cells and Cancer Stem Cells ((STEM,volume 11))

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Abstract

Embryonic stem cell transcription factors are among the myriad of stem cell (SC)-related genes implicated in neoplastic disease processes. NANOG, a homeobox domain transcription factor essential to embryogenesis promotes proliferation and self-renewal integral to both normal and tumor development. NANOG mRNA species and protein have been detected in numerous types of tumor cells ranging from malignant pluripotent teratocarcinoma to somatic tumors of the brain, liver, breast and prostate, among others. Functionally, NANOG has been implicated as an important mediator of tumor cell clonogenic growth, cellular proliferation and tumor development. Further, NANOG has been shown to promote cancer progression, such as the manifestation of resistance to conventional chemotherapeutic drugs. However, it remains unclear how NANOG affects these biological responses at the cellular and molecular level. In this chapter, we shall review some of the evidence supporting the notion that NANOG is an important pro-tumorigenic molecule and consider the upstream regulatory mechanisms and downstream effectors integrating NANOG into cancer cell molecular circuitry.

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References

  • Alldridge L, Metodieva G, Greenwood C, Al-Janabi K, Thwaites L, Sauven P, Metodiev M (2008) Proteome profiling of breast tumors by gel electrophoresis and nanoscale electrospray ionization mass spectrometry. J Proteome Res 7:1458–1469

    Article  PubMed  CAS  Google Scholar 

  • Becker KA, Ghule PN, Therrien JA, Lian JB, Stein JL, van Wijnen AJ, Stein GS (2006) Self-renewal of human embryonic stem cells is supported by a shortened G1 cell cycle phase. J Cell Physiol 209:883–893

    Article  PubMed  CAS  Google Scholar 

  • Ben-Porath I, Thomson MW, Carey VJ, Ge R, Bell GW, Regev A, Weinberg RA (2008) An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nat Genet 40:499–507

    Article  PubMed  CAS  Google Scholar 

  • Booth HA, Holland PW (2004) Eleven daughters of NANOG. Genomics 84:229–238

    Article  PubMed  CAS  Google Scholar 

  • Bourguignon LY, Peyrollier K, Xia W, Gilad E (2008) 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 283:17635–17651

    Article  PubMed  CAS  Google Scholar 

  • Bourguignon LY, Spevak CC, Wong G, Xia W, Gilad E (2009) 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 284:26533–26546

    Article  PubMed  CAS  Google Scholar 

  • Bourguignon LY, Earle C, Wong G, Spevak CC, Krueger K (2012a) 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 31:149–160

    Article  PubMed  CAS  Google Scholar 

  • Bourguignon LY, Wong G, Earle C, Chen L (2012b) 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 287:32800–32824

    Article  PubMed  CAS  Google Scholar 

  • Chambers I, Tomlinson SR (2009) The transcriptional foundation of pluripotency. Development 136:2311–2322

    Article  PubMed  CAS  Google Scholar 

  • Chambers I, Colby D, Robertson M, Nichols J, Lee S, Tweedie S, Smith A (2003) Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells. Cell 113:643–655

    Article  PubMed  CAS  Google Scholar 

  • Chiou SH, Yu CC, Huang CY, Lin SC, Liu CJ, Tsai TH, Chou SH, Chien CS, Ku HH, Lo JF (2008) Positive correlations of Oct-4 and Nanog in oral cancer stem-like cells and high-grade oral squamous cell carcinoma. Clin Cancer Res 14:4085–4095

    Article  PubMed  CAS  Google Scholar 

  • Chiou SH, Wang ML, Chou YT, Chen CJ, Hong CF, Hsieh WJ, Chang HT, Chen YS, Lin TW, Hsu HS, Wu CW (2010) Coexpression of Oct4 and Nanog enhances malignancy in lung adenocarcinoma by inducing cancer stem cell-like properties and epithelial-mesenchymal transdifferentiation. Cancer Res 70:10433–10444

    Article  PubMed  CAS  Google Scholar 

  • Das S, Jena S, Levasseur DN (2011) Alternative splicing produces Nanog protein variants with different capacities for self-renewal and pluripotency in embryonic stem cells. J Biol Chem 286:42690–42703

    Article  PubMed  CAS  Google Scholar 

  • Ezeh UI, Turek PJ, Reijo RA, Clark AT (2005) Human embryonic stem cell genes OCT4, NANOG, STELLAR, and GDF3 are expressed in both seminoma and breast carcinoma. Cancer 104:2255–2265

    Article  PubMed  CAS  Google Scholar 

  • Gibbs CP, Kukekov VG, Reith JD, Tchigrinova O, Suslov ON, Scott EW, Ghivizzani SC, Ignatova TN, Steindler DA (2005) Stem-like cells in bone sarcomas: implications for tumorigenesis. Neoplasia 7:967–976

    Article  PubMed  CAS  Google Scholar 

  • Giuliano CJ, Kerley-Hamilton JS, Bee T, Freemantle SJ, Manickaratnam R, Dmitrovsky E, Spinella MJ (2005) Retinoic acid represses a cassette of candidate pluripotency chromosome 12p genes during induced loss of human embryonal carcinoma tumorigenicity. Biochim Biophys Acta 1731:48–56

    Article  PubMed  CAS  Google Scholar 

  • Han J, Zhang F, Yu M, Zhao P, Ji W, Zhang H, Wu B, Wang Y, Niu R (2012) RNA interference-mediated silencing of NANOG reduces cell proliferation and induces G0/G1 cell cycle arrest in breast cancer cells. Cancer Lett 321:80–88

    Article  PubMed  CAS  Google Scholar 

  • Hasmim M, Noman MZ, Lauriol J, Benlalam H, Mallavialle A, Rosselli F, Mami-Chouaib F, Alcaide-Loridan C, Chouaib S (2011) Hypoxia-dependent inhibition of tumor cell susceptibility to CTL-mediated lysis involves NANOG induction in target cells. J Immunol 187:4031–4039

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Ibrahim EE, Babaei-Jadidi R, Saadeddin A, Spencer-Dene B, Hossaini S, Abuzinadah M, Li N, Fadhil W, Ilyas M, Bonnet D, Nateri AS (2012) Embryonic NANOG activity defines colorectal cancer stem cells and modulates through AP1- and TCF-dependent mechanisms. Stem Cells 30:2076–2087

    Article  PubMed  CAS  Google Scholar 

  • Jeter CR, Badeaux M, Choy G, Chandra D, Patrawala L, Liu C, Calhoun-Davis T, Zaehres H, Daley GQ, Tang DG (2009) Functional evidence that the self-renewal gene NANOG regulates human tumor development. Stem Cells 27:993–1005

    Article  PubMed  CAS  Google Scholar 

  • Jeter CR, Liu B, Liu X, Chen X, Liu C, Calhoun-Davis T, Repass J, Zaehres H, Shen JJ, Tang DG (2011) NANOG promotes cancer stem cell characteristics and prostate cancer resistance to androgen deprivation. Oncogene 30:3833–3845

    Article  PubMed  CAS  Google Scholar 

  • Ji J, Werbowetski-Ogilvie TE, Zhong B, Hong SH, Bhatia M (2009) Pluripotent transcription factors possess distinct roles in normal versus transformed human stem cells. PLoS One 4:e8065

    Article  PubMed  Google Scholar 

  • Kong D, Banerjee S, Ahmad A, Li Y, Wang Z, Sethi S, Sarkar FH (2010) Epithelial to mesenchymal transition is mechanistically linked with stem cell signatures in prostate cancer cells. PLoS One 5:e12445

    Article  PubMed  Google Scholar 

  • Kong D, Li Y, Wang Z, Sarkar FH (2011) Cancer stem cells and Epithelial-to-Mesenchymal Transition (EMT)-phenotypic cells: are they cousins or twins? Cancers 3:716–729

    Article  PubMed  Google Scholar 

  • Korkola JE, Houldsworth J, Chadalavada RS, Olshen AB, Dobrzynski D, Reuter VE, Bosl GJ, Chaganti RS (2006) Down-regulation of stem cell genes, including those in a 200-kb gene cluster at 12p13.31, is associated with in vivo differentiation of human male germ cell tumors. Cancer Res 66:820–827

    Article  PubMed  CAS  Google Scholar 

  • Lee TK, Castilho A, Cheung VC, Tang KH, Ma S, Ng IO (2011) CD24(+) liver tumor-initiating cells drive self-renewal and tumor initiation through STAT3-mediated NANOG regulation. Cell Stem Cell 9:50–63

    Article  PubMed  CAS  Google Scholar 

  • Lin YL, Han ZB, Xiong FY, Tian LY, Wu XJ, Xue SW, Zhou YR, Deng JX, Chen HX (2011) Malignant transformation of 293 cells induced by ectopic expression of human Nanog. Mol Cell Biochem 351:109–116

    Article  PubMed  CAS  Google Scholar 

  • Liu Y, Clem B, Zuba-Surma EK, El-Naggar S, Telang S, Jenson AB, Wang Y, Shao H, Ratajczak MZ, Chesney J, Dean DC (2009) Mouse fibroblasts lacking RB1 function form spheres and undergo reprogramming to a cancer stem cell phenotype. Cell Stem Cell 4:336–347

    Article  PubMed  CAS  Google Scholar 

  • Ma Y, Liang D, Liu J, Axcrona K, Kvalheim G, Stokke T, Nesland JM, Suo Z (2011) Prostate cancer cell lines under hypoxia exhibit greater stem-like properties. PLoS One 6:e29170

    Article  PubMed  CAS  Google Scholar 

  • Machida K, Tsukamoto H, Mkrtchyan H, Duan L, Dynnyk A, Liu HM, Asahina K, Govindarajan S, Ray R, Ou JH, Seki E, Deshaies R, Miyake K, Lai MM (2009) Toll-like receptor 4 mediates synergism between alcohol and HCV in hepatic oncogenesis involving stem cell marker Nanog. Proc Natl Acad Sci USA 106:1548–1553

    Article  PubMed  CAS  Google Scholar 

  • Mathieu J, Zhang Z, Zhou W, Wang AJ, Heddleston JM, Pinna CM, Hubaud A, Stadler B, Choi M, Bar M, Tewari M, Liu A, Vessella R, Rostomily R, Born D, Horwitz M, Ware C, Blau CA, Cleary MA, Rich JN, Ruohola-Baker H (2011) HIF induces human embryonic stem cell markers in cancer cells. Cancer Res 71:4640–4652

    Article  PubMed  CAS  Google Scholar 

  • Meng HM, Zheng P, Wang XY, Liu C, Sui HM, Wu SJ, Zhou J, Ding YQ, Li JM (2010) Overexpression of nanog predicts tumor progression and poor prognosis in colorectal cancer. Cancer Biol Ther 9:295–302

    Article  CAS  Google Scholar 

  • Mitsui K, Tokuzawa Y, Itoh H, Segawa K, Murakami M, Takahashi K, Maruyama M, Maeda M, Yamanaka S (2003) The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells. Cell 113:631–642

    Article  PubMed  CAS  Google Scholar 

  • Niu CS, Li DX, Liu YH, Fu XM, Tang SF, Li J (2011) Expression of NANOG in human gliomas and its relationship with undifferentiated glioma cells. Oncol Rep 26:593–601

    PubMed  CAS  Google Scholar 

  • Noh KH, Kim BW, Song KH, Cho H, Lee YH, Kim JH, Chung JY, Hewitt SM, Seong SY, Mao CP, Wu TC, Kim TW (2012a) Nanog signaling in cancer promotes stem-like phenotype and immune evasion. J Clin Invest 122:4077–4093

    Article  PubMed  CAS  Google Scholar 

  • Noh KH, Lee YH, Jeon JH, Kang TH, Mao CP, Wu TC, Kim TW (2012b) Cancer vaccination drives Nanog-dependent evolution of tumor cells toward an immune-resistant and stem-like phenotype. Cancer Res 72:1717–1727

    Article  PubMed  CAS  Google Scholar 

  • Piestun D, Kochupurakkal BS, Jacob-Hirsch J, Zeligson S, Koudritsky M, Domany E, Amariglio N, Rechavi G, Givol D (2006) Nanog transforms NIH3T3 cells and targets cell-type restricted genes. Biochem Biophys Res Commun 343:279–285

    Article  PubMed  CAS  Google Scholar 

  • Po A, Ferretti E, Miele E, De Smaele E, Paganelli A, Canettieri G, Coni S, Di Marcotullio L, Biffoni M, Massimi L, Di Rocco C, Screpanti I, Gulino A (2010) Hedgehog controls neural stem cells through p53-independent regulation of Nanog. EMBO J 29:2646–2658

    Article  PubMed  CAS  Google Scholar 

  • Qin J, Liu X, Laffin B, Chen X, Choy G, Jeter CR, Calhoun-Davis T, Li H, Palapattu GS, Pang S, Lin K, Huang J, Ivanov I, Li W, Suraneni MV, Tang DG (2012) The PSA(−/lo) prostate cancer cell population harbors self-renewing long-term tumor-propagating cells that resist castration. Cell Stem Cell 10:556–569

    Article  PubMed  CAS  Google Scholar 

  • Santini R, Vinci MC, Pandolfi S, Penachioni JY, Montagnani V, Olivito B, Gattai R, Pimpinelli N, Gerlini G, Borgognoni L, Stecca B (2012) Hedgehog-GLI signaling drives self-renewal and tumorigenicity of human melanoma-initiating cells. Stem Cells 30:1808–1818

    Article  PubMed  CAS  Google Scholar 

  • Silva J, Smith A (2008) Capturing pluripotency. Cell 132:532–536

    Article  PubMed  CAS  Google Scholar 

  • Singh A, Settleman J (2010) EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene 29:4741–4751

    Article  PubMed  CAS  Google Scholar 

  • Siu MK, Wong ES, Kong DS, Chan HY, Jiang L, Wong OG, Lam EW, Chan KK, Ngan HY, Le XF, Cheung AN (2012) Stem cell transcription factor NANOG controls cell migration and invasion via dysregulation of E-cadherin and FoxJ1 and contributes to adverse clinical outcome in ovarian cancers. Oncogene (in press). doi:10.1038/onc2012.363

  • Tanaka Y, Era T, Nishikawa S, Kawamata S (2007) Forced expression of Nanog in hematopoietic stem cells results in a gammadeltaT-cell disorder. Blood 110:107–115

    Article  PubMed  CAS  Google Scholar 

  • Tang DG, Patrawala L, Calhoun T, Bhatia B, Choy G, Schneider-Broussard R, Jeter C (2007) Prostate cancer stem/progenitor cells: identification, characterization, and implications. Mol Carcinog 46:1–14

    Article  PubMed  CAS  Google Scholar 

  • Visvader JE (2011) Cells of origin in cancer. Nature 469:314–322

    Article  PubMed  CAS  Google Scholar 

  • Visvader JE, Lindeman GJ (2008) Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer 8:755–768

    Article  PubMed  CAS  Google Scholar 

  • Wong DJ, Liu H, Ridky TW, Cassarino D, Segal E, Chang HY (2008) Module map of stem cell genes guides creation of epithelial cancer stem cells. Cell Stem Cell 2:333–344

    Article  PubMed  CAS  Google Scholar 

  • Young RA (2011) Control of the embryonic stem cell state. Cell 144:940–954

    Article  PubMed  CAS  Google Scholar 

  • Zbinden M, Duquet A, Lorente-Trigos A, Ngwabyt SN, Borges I, Ruiz i Altaba A (2010) NANOG regulates glioma stem cells and is essential in vivo acting in a cross-functional network with GLI1 and p53. EMBO J 29:2659–2674

    Article  PubMed  CAS  Google Scholar 

  • Zhang J, Wang X, Chen B, Suo G, Zhao Y, Duan Z, Dai J (2005) Expression of Nanog gene promotes NIH3T3 cell proliferation. Biochem Biophys Res Commun 338:1098–1102

    Article  PubMed  CAS  Google Scholar 

  • Zhang J, Wang X, Li M, Han J, Chen B, Wang B, Dai J (2006) NANOGP8 is a retrogene expressed in cancers. FEBS J 273:1723–1730

    Article  PubMed  CAS  Google Scholar 

  • Zhang S, Balch C, Chan MW, Lai HC, Matei D, Schilder JM, Yan PS, Huang TH, Nephew KP (2008) Identification and characterization of ovarian cancer-initiating cells from primary human tumors. Cancer Res 68:4311–4320

    Article  PubMed  CAS  Google Scholar 

  • Zhang X, Neganova I, Przyborski S, Yang C, Cooke M, Atkinson SP, Anyfantis G, Fenyk S, Keith WN, Hoare SF, Hughes O, Strachan T, Stojkovic M, Hinds PW, Armstrong L, Lako M (2009) A role for NANOG in G1 to S transition in human embryonic stem cells through direct binding of CDK6 and CDC25A. J Cell Biol 184:67–82

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

The work in the author’s lab was supported in part by a grant from the Cancer Prevention Research Institute of Texas, RP120394.

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  1. Department of Molecular Carcinogenesis, University of Texas, MD Anderson Cancer Center, 1808 Park Rd, 1C, 389, 78957, Smithville, TX, USA

    Collene R. Jeter

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  1. Collene R. Jeter
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Correspondence to Collene R. Jeter .

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  1. Department of Biological Sciences, Kean university, Room 213, Library Building, Union, New Jersey, USA

    M.A. Hayat

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Jeter, C.R. (2014). Investigating the Role of the Embryonic Stem Cell Self-Renewal Gene NANOG in Neoplastic Processes. In: Hayat, M. (eds) Stem Cells and Cancer Stem Cells, Volume 11. Stem Cells and Cancer Stem Cells, vol 11. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-7329-5_2

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