Abstract
The zinc finger transcription factor ZFX functions as an important regulator of self-renewal in multiple stem cell types, as well as a sex determinant of mammals. Moreover, ZFX expression is abnormally elevated in several cancers, and correlates with malignancy grade. To investigate its role in the pathogenesis of gliomas, we used lentivirus-mediated RNA interference (RNAi) to knockdown ZFX expression in human glioma cell lines. Our results demonstrate that ZFX plays a crucial role in glioma proliferation and survival, confirming recent reports. We also show for the first time that ZFX knockdown decreases the in vivo growth potential of U87 glioma xenografts in both subcutaneous and intracranial models in nude mice. We conclude that lentivirus-mediated RNAi targeting of ZFX may serve as a promising strategy for glioma therapy.
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References
Park DM, Rich JN (2009) Biology of glioma cancer stem cells. Mol Cells 28:7–12
Young RA (2011) Control of the embryonic stem cell state. Cell 144:940–954
Palmer MS, Berta P, Sinclair AH et al (1990) Comparison of human ZFY and ZFX transcripts. Proc Natl Acad Sci U S A 87:1681–1685
Schneider-Gadicke A, Beer-Romero P, Brown LG et al (1989) Putative transcription activator with alternative isoforms encoded by human ZFX gene. Nature 342:708–711
Harel S, Tu EY, Weisberg S et al (2012) ZFX Controls the Self-Renewal of Human Embryonic Stem Cells. PLoS ONE. doi:10.1371/journal.pone.0042302
Galan-Caridad JM, Harel S, Arenzana TL et al (2007) Zfx controls the self-renewal of embryonic and hematopoietic stem cells. Cell 129:345–357
Lu J, Li XP, Dong Q et al (2010) TBX2 and TBX3: the special value for anticancer drug targets. Biochim Biophys Acta 1806:268–274
Teitell MA (2005) The TCL1 family of oncoproteins: co-activators of transformation. Nat Rev Cancer 5:640–648
Hu G, Kim J, Xu Q et al (2009) A genome-wide RNAi screen identifies a new transcriptional module required for self-renewal. Genes Dev 23:837–848
Huang D, Gao Q, Guo L (2009) Isolation and identification of cancer stem-like cells in esophageal carcinoma cell lines. Stem Cells Dev 18:465–473
Akiyoshi S, Fukagawa T, Ueo H et al (2012) Clinical significance of miR-144-ZFX axis in disseminated tumour cells in bone marrow in gastric cancer cases. Br J Cancer 107:1345–1353
Ramalho-Santos M, Yoon S, Matsuzaki Y et al (2002) “Stemness” transcriptional profiling of embryonic and adult stem cells. Science 298:597–600
Fang J, Yu Z, Lian M et al (2012) Knockdown of zinc finger protein, X-linked (ZFX) inhibits cell proliferation and induces apoptosis in human laryngeal squamous cell carcinoma. Mol Cell Biochem 360:301–307
Zhou Y, Su Z, Huang Y et al (2011) The Zfx gene is expressed in human gliomas and is important in the proliferation and apoptosis of the human malignant glioma cell line U251. J Exp Clin Cancer Res 30:114
Jiang H, Zhang L, Liu J et al (2012) Knockdown of zinc finger protein X-linked inhibits prostate cancer cell proliferation and induces apoptosis by activating caspase-3 and caspase-9. Cancer Gene Ther 19:684–689
Martin SJ, Henry CM, Cullen SP (2012) A perspective on Mammalian caspases as positive and negative regulators of inflammation. Mol Cell 46:387–397
Ramljak D, Coticchia CM, Nishanian TG et al (2003) Epidermal growth factor inhibition of c-Myc-mediated apoptosis through Akt and Erk involves Bcl-xL upregulation in mammary epithelial cells. Exp Cell Res 287:397–410
Jeong JC, Kim MS, Kim TH et al (2009) Kaempferol induces cell death through ERK and Akt-dependent down-regulation of XIAP and survivin in human glioma cells. Neurochem Res 34:991–1001
Gopinath S, Alapati K, Malla RR et al (2011) Mechanism of p27 upregulation induced by downregulation of cathepsin B and uPAR in glioma. Mol Oncol 5:426–437
Brayer KJ, Segal DJ (2008) Keep your fingers off my DNA: protein-protein interactions mediated by C2H2 zinc finger domains. Cell Biochem Biophys 50:111–131
Gazin C (1999) ZFX transactivation of the HIV-1 LTR is cell specific and depends on core enhancer and TATA box sequences. Nucleic Acids Res 27:2156–2164
Pervouchine DD, Khrameeva EE, Pichugina MY et al (2012) Evidence for widespread association of mammalian splicing and conserved long-range RNA structures. RNA 18:1–15
Lau YF, Chan KM (1989) The putative testis-determining factor and related genes are expressed as discrete-sized transcripts in adult gonadal and somatic tissues. Am J Hum Genet 45:942–952
Kraljević Pavelić S, Marjanović M, Poznić M et al (2009) Adenovirally mediated p53 overexpression diversely influence the cell cycle of HEp-2 and CAL 27 cell lines upon cisplatin and methotrexate treatment. J Cancer Res Clin Oncol 135:1747–1761
Ishii N, Maier D, Merlo A et al (1999) Frequent co-alterations of TP53, p16/CDKN2A, p14ARF, PTEN tumor suppressor genes in human glioma cell lines. Brain Pathol 9:469–479
Zou Z, Gao C, Nagaich AK et al (2000) p53 regulates the expression of the tumor suppressor gene maspin. J Biol Chem 275:6051–6054
Wang J, Wang H, Li Z et al (2008) c-Myc is required for maintenance of glioma cancer stem cells. PLoS ONE. doi:10.1371/journal.pone.0003769
Hendruschk S, Wiedemuth R, Aigner A et al (2011) RNA interference targeting survivin exerts antitumoral effects in vitro and in established glioma xenografts in vivo. Neuro Oncol 13:1074–1089
Komata T, Kanzawa T, Takeuchi H et al (2003) Antitumour effect of cyclin-dependent kinase inhibitors (p16(INK4A), p18(INK4C), p19(INK4D), p21(WAF1/CIP1) and p27(KIP1)) on malignant glioma cells. Br J Cancer 88:1277–1280
Acknowledgments
This work was supported by grants from the National Natural Science Foundation of China (No.31000474, No.30872675 and No. 30901549), by Science and Technology Commission of Shanghai Municipality (No. 08411965100 and No.12JC1401800), by the China Postdoctoral Science Special Foundation (201003259) to Jing Zheng, and by the Shanghai Committee of Science and Technology (Grant 11DZ2260600) and the 111 Project (B07023).
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The authors declare that they have no conflict of interest.
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Zhu, Z., Li, K., Xu, D. et al. ZFX regulates glioma cell proliferation and survival in vitro and in vivo. J Neurooncol 112, 17–25 (2013). https://doi.org/10.1007/s11060-012-1032-z
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DOI: https://doi.org/10.1007/s11060-012-1032-z