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TWISTing stemness, inflammation and proliferation of epithelial ovarian cancer cells through MIR199A2/214

Oncogene volume 29, pages 3545–3553 (2010)Cite this article

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Abstract

Cancer stem cells are responsible for sustaining the tumor and giving rise to proliferating and progressively differentiating cells. However, the molecular mechanisms regulating the process of cancer stem cell (CSC) differentiation is not clearly understood. Recently, we reported the isolation of the epithelial ovarian cancer (EOC) stem cells (type I/CD44+). In this study, we show that type I/CD44+ cells are characterized by low levels of both miR-199a and miR-214, whereas mature EOC cells (type II/CD44−) have higher levels of miR-199a and miR-214. Moreover, these two micro RNAs (miRNAs) are regulated as a cluster on pri-miR-199a2 within the human Dnm3os gene (GenBank FJ623959). This study identify Twist1 as a regulator of this unique miRNA cluster responsible for the regulation of the IKKβ/NF-κB and PTEN/AKT pathways and its association of ovarian CSC differentiation. Our data suggest that Twist1 may be an important regulator of ‘stemness’ in EOC cells. The regulation of MIR199A2/214 expression may be used as a potential therapeutic approach in EOC patients.

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References

  • Ahmed N, Thompson EW, Quinn MA . (2007). Epithelial-mesenchymal interconversions in normal ovarian surface epithelium and ovarian carcinomas: an exception to the norm. J Cell Physiol 213: 581–588.

    Article  CAS  Google Scholar 

  • Alison MR, Murphy G, Leedham S . (2008). Stem cells and cancer: a deadly mix. Cell Tissue Res 331: 109–124.

    Article  Google Scholar 

  • Alvarez-Garcia I, Miska EA . (2005). MicroRNA functions in animal development and human disease. Development 132: 4653–4662.

    Article  CAS  Google Scholar 

  • Alvero AB, Chen R, Fu HH, Montagna M, Schwartz PE, Rutherford T et al. (2009a). Molecular phenotyping of human ovarian cancer stem cells unravels the mechanisms for repair and chemoresistance. Cell Cycle 8: 158–166.

    Article  CAS  Google Scholar 

  • Alvero AB, Fu HH, Holmberg J, Visintin I, Mor L, Marquina CC et al. (2009b). Stem-like ovarian cancer cells can serve as tumor vascular progenitors. Stem Cells 2009: 2405–2413.

    Article  Google Scholar 

  • Bartel DP . (2004). MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116: 281–297.

    Article  CAS  Google Scholar 

  • Baylies MK, Bate M . (1996). Twist: a myogenic switch in Drosophila. Science 272: 1481–1484.

    CAS  Google Scholar 

  • Bialek P, Kern B, Yang X, Schrock M, Sosic D, Hong N et al. (2004). A twist code determines the onset of osteoblast differentiation. Dev Cell 6: 423–435.

    CAS  Google Scholar 

  • Chen R, Alvero AB, Silasi DA, Kelly MG, Fest S, Visintin I et al. (2008). Regulation of IKKbeta by miR-199a affects NF-kappaB activity in ovarian cancer cells. Oncogene 27: 4712–4723.

    Article  CAS  Google Scholar 

  • Chen R, Alvero AB, Silasi DA, Mor G . (2007). Inflammation, cancer and chemoresistance: taking advantage of the toll-like receptor signaling pathway. Am J Reprod Immunol 57: 93–107.

    Article  CAS  Google Scholar 

  • Cheng GZ, Park S, Shu S, He L, Kong W, Zhang W et al. (2008a). Advances of AKT pathway in human oncogenesis and as a target for anti-cancer drug discovery. Curr Cancer Drug Targets 8: 2–6.

    Article  CAS  Google Scholar 

  • Cheng GZ, Zhang W, Wang LH . (2008b). Regulation of cancer cell survival, migration, and invasion by Twist: AKT2 comes to interplay. Cancer Res 68: 957–960.

    Article  CAS  Google Scholar 

  • Cheng GZ, Zhang WZ, Sun M, Wang Q, Coppola D, Mansour M et al. (2008c). Twist is transcriptionally induced by activation of STAT3 and mediates STAT3 oncogenic function. J Biol Chem 283: 14665–14673.

    Article  CAS  Google Scholar 

  • Clarke MF, Dick JE, Dirks PB, Eaves CJ, Jamieson CH, Jones DL et al. (2006). Cancer stem cells—perspectives on current status and future directions: AACR Workshop on cancer stem cells. Cancer Res 66: 9339–9344.

    Article  CAS  Google Scholar 

  • Clarke MF, Fuller M . (2006). Stem cells and cancer: two faces of eve. Cell 124: 1111–1115.

    Article  CAS  Google Scholar 

  • Clarke-Pearson DL . (2009). Clinical practice. Screening for ovarian cancer. N Engl J Med 361: 170–177.

    Article  CAS  Google Scholar 

  • Entz-Werle N, Stoetzel C, Berard-Marec P, Kalifa C, Brugiere L, Pacquement H et al. (2005). Frequent genomic abnormalities at TWIST in human pediatric osteosarcomas. Int J Cancer 117: 349–355.

    Article  CAS  Google Scholar 

  • Espey DK, Wu XC, Swan J, Wiggins C, Jim MA, Ward E et al. (2007). Annual report to the nation on the status of cancer, 1975–2004, featuring cancer in American Indians and Alaska Natives. Cancer 110: 2119–2152.

    Article  Google Scholar 

  • Jemal A, Siegel R, Ward E, Murray T, Xu J, Smigal C et al. (2006). Cancer statistics, 2006. CA Cancer J Clin 56: 106–130.

    Article  Google Scholar 

  • Kamsteeg M, Rutherford T, Sapi E, Hanczaruk B, Shahabi S, Flick M et al. (2003). Phenoxodiol—an isoflavone analog—induces apoptosis in chemoresistant ovarian cancer cells. Oncogene 22: 2611–2620.

    Article  CAS  Google Scholar 

  • Koga K, Cardenas I, Aldo P, Abrahams VM, Peng B, Fill S et al. (2009). Activation of TLR3 in the trophoblast is associated with preterm delivery. Am J Reprod Immunol 61: 196–212.

    Article  CAS  Google Scholar 

  • Kwok WK, Ling MT, Lee TW, Lau TC, Zhou C, Zhang X et al. (2005). Up-regulation of TWIST in prostate cancer and its implication as a therapeutic target. Cancer Res 65: 5153–5162.

    Article  CAS  Google Scholar 

  • Lee MS, Lowe G, Flanagan S, Kuchler K, Glackin CA . (2000). Human Dermo-1 has attributes similar to twist in early bone development. Bone 27: 591–602.

    Article  CAS  Google Scholar 

  • Lee MS, Lowe GN, Strong DD, Wergedal JE, Glackin CA . (1999). TWIST, a basic helix-loop-helix transcription factor, can regulate the human osteogenic lineage. J Cell Biochem 75: 566–577.

    Article  CAS  Google Scholar 

  • Lee YB, Bantounas I, Lee DY, Phylactou L, Caldwell MA, Uney JB . (2009). Twist-1 regulates the miR-199a/214 cluster during development. Nucleic Acids Res 37: 123–128.

    Article  CAS  Google Scholar 

  • Liu J, Valencia-Sanchez MA, Hannon GJ, Parker R . (2005). MicroRNA-dependent localization of targeted mRNAs to mammalian P-bodies. Nat Cell Biol 7: 719–723.

    Article  CAS  Google Scholar 

  • Loebel DA, O'ourke MP, Steiner KA, Banyer J, Tam PP . (2002). Isolation of differentially expressed genes from wild-type and Twist mutant mouse limb buds. Genesis 33: 103–113.

    Article  CAS  Google Scholar 

  • Mironchik Y, Winnard Jr PT, Vesuna F, Kato Y, Wildes F, Pathak AP et al. (2005). Twist overexpression induces in vivo angiogenesis and correlates with chromosomal instability in breast cancer. Cancer Res 65: 10801–10809.

    Article  CAS  Google Scholar 

  • Miska EA . (2005). How microRNAs control cell division, differentiation and death. Curr Opin Genet Dev 15: 563–568.

    Article  CAS  Google Scholar 

  • O'Dwyer PJ, Moyer JD, Suffness M, Harrison Jr SD, Cysyk RH, Hamilton TC et al. (1994). Antitumor activity and biochemical effects of aphidicolin glycinate (NSC 303812) alone and in combination with cisplatin in vivo. Cancer Res 54: 724–729.

    CAS  Google Scholar 

  • Ota MS, Loebel DA, O'ourke MP, Wong N, Tsoi B, Tam PP . (2004). Twist is required for patterning the cranial nerves and maintaining the viability of mesodermal cells. Dev Dyn 230: 216–228.

    Article  CAS  Google Scholar 

  • Papagiannakopoulos T, Kosik KS . (2008). MicroRNAs: regulators of oncogenesis and stemness. BMC Med 6: 15.

    Article  Google Scholar 

  • Papagiannakopoulos T, Shapiro A, Kosik KS . (2008). MicroRNA-21 targets a network of key tumor-suppressive pathways in glioblastoma cells. Cancer Res 68: 8164–8172.

    Article  CAS  Google Scholar 

  • Salamanca CM, Maines-Bandiera SL, Leung PC, Hu YL, Auersperg N . (2004). Effects of epidermal growth factor/hydrocortisone on the growth and differentiation of human ovarian surface epithelium. J Soc Gynecol Investig 11: 241–251.

    Article  CAS  Google Scholar 

  • Schwartz PE . (2002). Current diagnosis and treatment modalities for ovarian cancer. Cancer Treat Res 107: 99–118.

    Google Scholar 

  • Sosic D, Richardson JA, Yu K, Ornitz DM, Olson EN . (2003). Twist regulates cytokine gene expression through a negative feedback loop that represses NF-kappaB activity. Cell 112: 169–180.

    Article  CAS  Google Scholar 

  • Taylor DD, Gercel-Taylor C . (2008). MicroRNA signatures of tumor-derived exosomes as diagnostic biomarkers of ovarian cancer. Gynecol Oncol 110: 13–21.

    Article  CAS  Google Scholar 

  • Valencia-Sanchez MA, Liu J, Hannon GJ, Parker R . (2006). Control of translation and mRNA degradation by miRNAs and siRNAs. Genes Dev 20: 515–524.

    Article  CAS  Google Scholar 

  • Valsesia-Wittmann S, Magdeleine M, Dupasquier S, Garin E, Jallas AC, Combaret V et al. (2004). Oncogenic cooperation between H-Twist and N-Myc overrides failsafe programs in cancer cells. Cancer Cell 6: 625–630.

    Article  CAS  Google Scholar 

  • Woolas RP, Xu FJ, Jacobs IJ, Yu YH, Daly L, Berchuck A et al. (1993). Elevation of multiple serum markers in patients with stage I ovarian cancer. J Natl Cancer Inst 85: 1748–1751.

    Article  CAS  Google Scholar 

  • Yang H, Kong W, He L, Zhao JJ, O'onnell JD, Wang J et al. (2008). MicroRNA expression profiling in human ovarian cancer: miR-214 induces cell survival and cisplatin resistance by targeting PTEN. Cancer Res 68: 425–433.

    Article  CAS  Google Scholar 

  • Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C et al. (2004). Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 117: 927–939.

    Article  CAS  Google Scholar 

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Acknowledgements

This study was supported in part by grants from NCI/NIH RO1CA127913, RO1CA118678, the Janet Burros Memorial Foundation, the Sands Family Foundation and the Discovery To Cure Research Program.

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Author notes

  1. G Yin and R Chen: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA

    G Yin, R Chen, A B Alvero, H-H Fu, J Holmberg, T Rutherford & G Mor

  2. Neuroscience, Beckman Research Institute of the City of Hope, Duarte, CA, USA

    C Glackin

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  1. G Yin
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  2. R Chen
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  3. A B Alvero
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Correspondence to G Mor.

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Yin, G., Chen, R., Alvero, A. et al. TWISTing stemness, inflammation and proliferation of epithelial ovarian cancer cells through MIR199A2/214. Oncogene 29, 3545–3553 (2010). https://doi.org/10.1038/onc.2010.111

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