Open Access

Regulating glioma stem cells by hypoxia through the Notch1 and Oct3/4 signaling pathway

  • Authors:
    • Fei Zeng
    • Hong Chen
    • Zhaohui Zhang
    • Tao Yao
    • Guan Wang
    • Qingxing Zeng
    • Shenhan Duan
    • Yanqiang Zhan
  • View Affiliations

  • Published online on: September 17, 2018     https://doi.org/10.3892/ol.2018.9442
  • Pages: 6315-6322
  • Copyright: © Zeng et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

To investigate the effects of hypoxia on the features of cancer stem cells in the glioma cancer U87 cell line and underlying mechanism, stem cell markers and features in U87 were studied under the hypoxic and normoxic culture conditions by reverse transcription‑quantitative polymerase chain reaction, western blot analysis, MTT, a colony formation test and flow cytometry. Compared to the normoxic group, the cluster of differentiation 133+ phenotype, clone formation rate and cell vitality were significantly elevated in U87 cells cultured in a hypoxic microenvironment. Also, the mRNA and protein expression of neurogenic locus notch homolog protein 1 (Notch1) and Oct3/4 were significantly elevated in U87 cells cultured in a hypoxic microenvironment, however, transcription factor SOX‑2 expression was not significantly changed. These results indicate that hypoxia can promote the proliferation of glioma stem cells and maintain the characteristics of stem cells through the activation of Notch1 and Oct3/4 or Notch1 activation, affecting the biological characteristics of glioma cells.

References

1 

Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, Ohgaki H, Wiestler OD, Kleihues P and Ellison DW: The 2016 world health organization classification of tumors of the central nervous system: A summary. Acta Neuropathol. 131:803–820. 2016. View Article : Google Scholar : PubMed/NCBI

2 

Davis ME: Glioblastoma: Overview of disease and treatment. Clin J Oncol Nurs. 20 Suppl 5:S2–S8. 2016. View Article : Google Scholar : PubMed/NCBI

3 

Ostrom QT, Gittleman H, Fulop J, Liu M, Blanda R, Kromer C, Wolinsky Y, Kruchko C and Barnholtz-Sloan JS: Central brain tumor registry of the united States (CBTRUS) statistical report: Primary brain and central nervous system tumors diagnosed in the united states in 2008–2012. Neuro Oncol. 17 Suppl 4:iv1–iv62. 2015. View Article : Google Scholar : PubMed/NCBI

4 

Clarke MF, Dick JE, Dirks PB, Eaves CJ, Jamieson CH, Jones DL, Visvader J, Weissman IL and Wahl GM: Cancer stem cells-perspectives on current status and future directions: AACR Workshop on cancer stem cells. Cancer Res. 66:9339–9344. 2006. View Article : Google Scholar : PubMed/NCBI

5 

Soltanian S and Matin MM: Cancer stem cells and cancer therapy. Tumour Biol. 32:425–440. 2011. View Article : Google Scholar : PubMed/NCBI

6 

Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J and Dirks PB: Identification of a cancer stem cell in human brain tumors. Cancer Res. 63:5821–5828. 2003.PubMed/NCBI

7 

Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD and Dirks PB: Identification of human brain tumour initiating cells. Nature. 432:396–401. 2004. View Article : Google Scholar : PubMed/NCBI

8 

Uchida N, Buck DW, He D, Reitsma MJ, Masek M, Phan TV, Tsukamoto AS, Gage FH and Weissman IL: Direct isolation of human central nervous system stem cells. Proc Natl Acad Sci USA. 97:14720–14725. 2000. View Article : Google Scholar : PubMed/NCBI

9 

Galli R, Binda E, Orfanelli U, Cipelletti B, Gritti A, De Vitis S, Fiocco R, Foroni C, Dimeco F and Vescovi A: Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res. 64:7011–7021. 2004. View Article : Google Scholar : PubMed/NCBI

10 

Vescovi AL, Galli R and Reynolds BA: Brain tumour stem cells. Nat Rev Cancer. 6:425–436. 2006. View Article : Google Scholar : PubMed/NCBI

11 

Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, Dewhirst MW, Bigner DD and Rich JN: Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 444:756–760. 2006. View Article : Google Scholar : PubMed/NCBI

12 

Costa FF, Seftor EA, Bischof JM, Kirschmann DA, Strizzi L, Arndt K, Bonaldo Mde F, Soares MB and Hendrix MJ: Epigenetically reprogramming metastatic tumor cells with an embryonic microenvironment. Epigenomics. 1:387–398. 2009. View Article : Google Scholar : PubMed/NCBI

13 

Eales KL, Hollinshead KE and Tennant DA: Hypoxia and metabolic adaptation of cancer cells. Oncogenesis. 5:e1902016. View Article : Google Scholar : PubMed/NCBI

14 

Jensen RL: Brain tumor hypoxia: Tumorigenesis, angiogenesis, imaging, pseudoprogression, and as a therapeutic target. J Neurooncol. 92:317–335. 2009. View Article : Google Scholar : PubMed/NCBI

15 

Birner P, Piribauer M, Fischer I, Gatterbauer B, Marosi C, Ambros PF, Ambros IM, Bredel M, Oberhuber G, Rössler K, et al: Vascular patterns in glioblastoma influence clinical outcome and associate with variable expression of angiogenic proteins: Evidence for distinct angiogenic subtypes. Brain Pathol. 13:133–143. 2003. View Article : Google Scholar : PubMed/NCBI

16 

Chi JT, Wang Z, Nuyten DS, Rodriguez EH, Schaner ME, Salim A, Wang Y, Kristensen GB, Helland A, Børresen-Dale AL, et al: Gene expression programs in response to hypoxia: Cell type specificity and prognostic significance in human cancers. PLoS Med. 3:e472006. View Article : Google Scholar : PubMed/NCBI

17 

Sathornsumetee S, Cao Y, Marcello JE, Herndon JE II, McLendon RE, Desjardins A, Friedman HS, Dewhirst MW, Vredenburgh JJ and Rich JN: Tumor angiogenic and hypoxic profiles predict radiographic response and survival in malignant astrocytoma patients treated with bevacizumab and irinotecan. J Clin Oncol. 26:271–278. 2008. View Article : Google Scholar : PubMed/NCBI

18 

Semenza GL: Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 3:721–732. 2003. View Article : Google Scholar : PubMed/NCBI

19 

Semenza GL: Intratumoral hypoxia, radiation resistance, and HIF-1. Cancer Cell. 5:405–406. 2004. View Article : Google Scholar : PubMed/NCBI

20 

Vaupel P and Mayer A: Hypoxia in cancer: Significance and impact on clinical outcome. Cancer Metastasis Rev. 26:225–239. 2007. View Article : Google Scholar : PubMed/NCBI

21 

Ludwig K and Kornblum HI: Molecular markers in glioma. J Neurooncol. 134:505–512. 2017. View Article : Google Scholar : PubMed/NCBI

22 

Gonzalez F and Huangfu D: Mechanisms underlying the formation of induced pluripotent stem cells. Wiley Interdiscip Rev Dev Biol. 5:39–65. 2016. View Article : Google Scholar : PubMed/NCBI

23 

Takahashi K and Yamanaka S: Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 126:663–673. 2006. View Article : Google Scholar : PubMed/NCBI

24 

Fazio C and Ricciardiello L: Inflammation and notch signaling: A crosstalk with opposite effects on tumorigenesis. Cell Death Dis. 7:e25152016. View Article : Google Scholar : PubMed/NCBI

25 

Jundt F, Pröbsting KS, Anagnostopoulos I, Muehlinghaus G, Chatterjee M, Mathas S, Bargou RC, Manz R, Stein H and Dörken B: Jagged1-induced Notch signaling drives proliferation of multiple myeloma cells. Blood. 103:3511–3515. 2004. View Article : Google Scholar : PubMed/NCBI

26 

Weijzen S, Rizzo P, Braid M, Vaishnav R, Jonkheer SM, Zlobin A, Osborne BA, Gottipati S, Aster JC, Hahn WC, et al: Activation of Notch-1 signaling maintains the neoplastic phenotype in human ras-transformed cells. Nat Med. 8:979–986. 2002. View Article : Google Scholar : PubMed/NCBI

27 

Balint K, Xiao M, Pinnix CC, Soma A, Veres I, Juhasz I, Brown EJ, Capobianco AJ, Herlyn M and Liu ZJ: Activation of Notch1 signaling is required for beta-catenin-mediated human primary melanoma progression. J Clin Invest. 115:3166–3176. 2005. View Article : Google Scholar : PubMed/NCBI

28 

Amaya-Chanaga CI and Rassenti LZ: Biomarkers in chronic lymphocytic leukemia: Clinical applications and prognostic markers. Best Pract Res Clin Haematol. 29:79–89. 2016. View Article : Google Scholar : PubMed/NCBI

29 

Allen M, Bjerke M, Edlund H, Nelander S and Westermark B: Origin of the U87MG glioma cell line: Good news and bad news. Sci Transl Med. 8:354re32016. View Article : Google Scholar : PubMed/NCBI

30 

Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI

31 

Evers P, Lee PP, DeMarco J, Agazaryan N, Sayre JW, Selch M and Pajonk F: Irradiation of the potential cancer stem cell niches in the adult brain improves progression-free survival of patients with malignant glioma. BMC Cancer. 10:3842010. View Article : Google Scholar : PubMed/NCBI

32 

Yin AH, Miraglia S, Zanjani ED, Almeida-Porada G, Ogawa M, Leary AG, Olweus J, Kearney J and Buck DW: AC133, a novel marker for human hematopoietic stem and progenitor cells. Blood. 90:5002–5012. 1997.PubMed/NCBI

33 

Wu Y and Wu PY: CD133 as a marker for cancer stem cells: Progresses and concerns. Stem Cells Dev. 18:1127–1134. 2009. View Article : Google Scholar : PubMed/NCBI

34 

Li Z: CD133: A stem cell biomarker and beyond. Exp Hematol Oncol. 2:172013. View Article : Google Scholar : PubMed/NCBI

35 

Denko NC: Hypoxia, HIF1 and glucose metabolism in the solid tumour. Nat Rev Cancer. 8:705–713. 2008. View Article : Google Scholar : PubMed/NCBI

36 

Muz B, de la Puente P, Azab F and Azab AK: The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy. Hypoxia (Auckl). 3:83–92. 2015. View Article : Google Scholar : PubMed/NCBI

37 

Gustafsson MV, Zheng X, Pereira T, Gradin K, Jin S, Lundkvist J, Ruas JL, Poellinger L, Lendahl U and Bondesson M: Hypoxia requires notch signaling to maintain the undifferentiated cell state. Dev Cell. 9:617–628. 2005. View Article : Google Scholar : PubMed/NCBI

38 

Bar EE, Lin A, Mahairaki V, Matsui W and Eberhart CG: Eberhart, hypoxia increases the expression of stem-cell markers and promotes clonogenicity in glioblastoma neurospheres. Am J Pathol. 177:1491–1502. 2010. View Article : Google Scholar : PubMed/NCBI

39 

Rizzino A: Concise review: The Sox2-Oct4 connection: Critical players in a much larger interdependent network integrated at multiple levels. Stem Cells. 31:1033–1039. 2013. View Article : Google Scholar : PubMed/NCBI

40 

Niwa H, Miyazaki J and Smith AG: Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells. Nat Genet. 24:372–376. 2000. View Article : Google Scholar : PubMed/NCBI

41 

Tai MH, Chang CC, Kiupel M, Webster JD, Olson LK and Trosko JE: Oct4 expression in adult human stem cells: Evidence in support of the stem cell theory of carcinogenesis. Carcinogenesis. 26:495–502. 2005. View Article : Google Scholar : PubMed/NCBI

42 

Liu J, Sato C, Cerletti M and Wagers A: Notch signaling in the regulation of stem cell self-renewal and differentiation. Curr Top Dev Biol. 92:367–409. 2010. View Article : Google Scholar : PubMed/NCBI

43 

Li JL and Harris AL: Notch signaling from tumor cells: A new mechanism of angiogenesis. Cancer Cell. 8:1–3. 2005. View Article : Google Scholar : PubMed/NCBI

44 

Politi K, Feirt N and Kitajewski J: Notch in mammary gland development and breast cancer. Semin Cancer Biol. 14:341–347. 2004. View Article : Google Scholar : PubMed/NCBI

45 

Jiang L, Wu J, Chen Q, Hu X, Li W and Hu G: Notch1 expression is upregulated in glioma and is associated with tumor progression. J Clin Neurosci. 18:387–390. 2011. View Article : Google Scholar : PubMed/NCBI

46 

Zhang X, Chen T, Zhang J, Mao Q, Li S, Xiong W, Qiu Y, Xie Q and Ge J: Notch1 promotes glioma cell migration and invasion by stimulating β-catenin and NF-κB signaling via AKT activation. Cancer Sci. 103:181–190. 2012. View Article : Google Scholar : PubMed/NCBI

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November 2018
Volume 16 Issue 5

Print ISSN: 1792-1074
Online ISSN:1792-1082

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Copy and paste a formatted citation
APA
Zeng, F., Chen, H., Zhang, Z., Yao, T., Wang, G., Zeng, Q. ... Zhan, Y. (2018). Regulating glioma stem cells by hypoxia through the Notch1 and Oct3/4 signaling pathway. Oncology Letters, 16, 6315-6322. https://doi.org/10.3892/ol.2018.9442
MLA
Zeng, F., Chen, H., Zhang, Z., Yao, T., Wang, G., Zeng, Q., Duan, S., Zhan, Y."Regulating glioma stem cells by hypoxia through the Notch1 and Oct3/4 signaling pathway". Oncology Letters 16.5 (2018): 6315-6322.
Chicago
Zeng, F., Chen, H., Zhang, Z., Yao, T., Wang, G., Zeng, Q., Duan, S., Zhan, Y."Regulating glioma stem cells by hypoxia through the Notch1 and Oct3/4 signaling pathway". Oncology Letters 16, no. 5 (2018): 6315-6322. https://doi.org/10.3892/ol.2018.9442