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The role of hypoxia on the acquisition of epithelialmesenchymal transition and cancer stemness: a possible link to epigenetic regulation

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A hypoxic microenvironment leads to cancer progression and increases the metastatic potential of cancer cells within tumors via epithelial-mesenchymal transition(EMT) and cancer stemness acquisition. The hypoxic response pathway can occur under oxygen tensions of < 40 mmHg through hypoxia-inducible factors(HIFs), which are considered key mediators in the adaptation to hypoxia. Previous studies have shown that cellular responses to hypoxia are required for EMT and cancer stemness maintenance through HIF-1α and HIF-2α. The principal transcription factors of EMT include Twist, Snail, Slug, Sip1 (Smad interacting protein 1), and ZEB1 (zinc finger E-box-binding homeobox 1). HIFs bind to hypoxia response elements within the promoter region of these genes and also target cancer stem cell-associated genes and mediate transcriptional responses to hypoxia during stem cell differentiation. Acquisition of stemness characteristics in epithelial cells can be induced by activation of the EMT process. The mechanism of these phenotypic changes includes epigenetic alterations, such as DNA methylation, histone modification, chromatin remodeling, and microRNAs. Increased expression of EMT and pluripotent genes also play a role through demethylation of their promoters. In this review, we summarize the role of hypoxia on the acquisition of EMT and cancer stemness and the possible association with epigenetic regulation, as well as their therapeutic applications.

Abstract

A hypoxic microenvironment leads to cancer progression and increases the metastatic potential of cancer cells within tumors via epithelial-mesenchymal transition(EMT) and cancer stemness acquisition. The hypoxic response pathway can occur under oxygen tensions of < 40 mmHg through hypoxia-inducible factors(HIFs), which are considered key mediators in the adaptation to hypoxia. Previous studies have shown that cellular responses to hypoxia are required for EMT and cancer stemness maintenance through HIF-1α and HIF-2α. The principal transcription factors of EMT include Twist, Snail, Slug, Sip1 (Smad interacting protein 1), and ZEB1 (zinc finger E-box-binding homeobox 1). HIFs bind to hypoxia response elements within the promoter region of these genes and also target cancer stem cell-associated genes and mediate transcriptional responses to hypoxia during stem cell differentiation. Acquisition of stemness characteristics in epithelial cells can be induced by activation of the EMT process. The mechanism of these phenotypic changes includes epigenetic alterations, such as DNA methylation, histone modification, chromatin remodeling, and microRNAs. Increased expression of EMT and pluripotent genes also play a role through demethylation of their promoters. In this review, we summarize the role of hypoxia on the acquisition of EMT and cancer stemness and the possible association with epigenetic regulation, as well as their therapeutic applications.

참고문헌 (79)

  1. Foster JG, "The hypoxic tumor microenvironment:driving the tumorigenesis of non-smallcell lung cancer", Future Oncol, 10, pp.2659~2674 (2014)
  2. Hockel M, "Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects", J Natl Cancer Inst, 93, pp.266~276 (2001)
  3. Gao T, "The mechanism between epithelial mesenchymal transition in breast cancer and hypoxia microenvironment", Biomed Pharmacother, 80, pp.393~405 (2016)
  4. Li M, "Hypoxia inducible factor-1α-dependent epithelial to mesenchymal transition under hypoxic conditions in prostate cancer cells", Oncol Rep, 36, pp.521~527 (2016)
  5. Ye LY, "Hypoxia-induced epithelialto-mesenchymal transition in hepatocellular carcinoma induces an immunosuppressive tumor microenvironment to promote metastasis", Cancer Res, 76, pp.818~830 (2016)
  6. Thiery JP, "Epithelialmesenchymal transitions in development and disease", Cell, 139, pp.871~890 (2009)
  7. Li L, "Epithelial-mesenchymal transition in human cancer: comprehensive reprogramming of metabolism, epigenetics, and differentiation", Pharmacol Ther, 150, pp.33~46 (2015)
  8. Garg M., "Targeting microRNAs in epithelial-to-mesenchymal transition-induced cancer stem cells: therapeutic approaches in cancer", Expert Opin Ther Targets, 19, pp.285~297 (2015)
  9. Reya T, "Stem cells, cancer, and cancer stem cells", Nature, 414, pp.105~111 (2001)
  10. Medema JP., "Cancer stem cells: the challenges ahead", Nat Cell Biol, 15, pp.338~344 (2013)
  11. Mimeault M, "Hypoxia-inducing factors as master regulators of stemness properties and altered metabolism of cancer- and metastasis-initiating cells", J Cell Mol Med, 17, pp.30~54 (2013)
  12. Shukla S, "Epigenetics of cancer stem cells:pathways and therapeutics", Biochim Biophys Acta, 1840, pp.3494~3502 (2014)
  13. Jones PA., "Functions of DNA methylation: islands, start sites, gene bodies and beyond", Nat Rev Genet, 13, pp.484~492 (2012)
  14. Vaupel P, "Detection and characterization of tumor hypoxia using pO2 histography", Antioxid Redox Signal, 9, pp.1221~1235 (2007)
  15. Bertout JA, "The impact of O2 availability on human cancer", Nat Rev Cancer, 8, pp.967~975 (2008)
  16. Myszczyszyn A, "The role of hypoxia and cancer stem cells in renal cell carcinoma pathogenesis", Stem Cell Rev, 11, pp.919~943 (2015)
  17. Yeh KA, "Polarographic needle electrode measurements of oxygen in rat prostate carcinomas:accuracy and reproducibility", Int J Radiat Oncol Biol Phys, 33, pp.111~118 (1995)
  18. Vaupel P, "Hypoxia in cancer: significance and impact on clinical outcome", Cancer Metastasis Rev, 26, pp.225~239 (2007)
  19. Koch CJ, "Optimizing hypoxia detection and treatment strategies", Semin Nucl Med, 45, pp.163~176 (2015)
  20. Shimoda LA, "HIF and the lung: role of hypoxia-inducible factors in pulmonary development and disease", Am J Respir Crit Care Med, 183, pp.152~156 (2011)
  21. Sharp FR, "HIF1 and oxygen sensing in the brain", Nat Rev Neurosci, 5, pp.437~448 (2004)
  22. Harris AL., "Hypoxia: a key regulatory factor in tumour growth", Nat Rev Cancer, 2, pp.38~47 (2002)
  23. Gordan JD, "Hypoxia-inducible factors: central regulators of the tumor phenotype", Curr Opin Genet Dev, 17, pp.71~77 (2007)
  24. Zhao J, "The emerging role of hypoxia-inducible factor-2 involved in chemo", radioresistance in solid tumors, 2015, pp.41, 623~633
  25. Zhang J, "Signal transduction pathways of EMT induced by TGF-beta, SHH, and WNT and their crosstalks", J Clin Med, 5, pp.41~ (2016)[DOI]
  26. Jiang J, "EMT: a new vision of hypoxia promoting cancer progression", Cancer Biol Ther, 11, pp.714~723 (2011)
  27. Imai T, "Hypoxia attenuates the expression of E-cadherin via up-regulation of SNAIL in ovarian carcinoma cells", Am J Pathol, 163, pp.1437~1447 (2003)
  28. Hung JJ, "Prognostic significance of hypoxia-inducible factor-1alpha, TWIST1 and Snail expression in resectable nonsmall cell lung cancer", Thorax, 64, pp.1082~1089 (2009)
  29. Nishi H, "Hypoxia-inducible factor-1 transactivates transforming growth factorbeta3in trophoblast", Endocrinology, 145, pp.4113~4118 (2004)
  30. Sebastian Diecke, "Recent technological updates and clinical applications of induced pluripotent stem cells", The Korean Journal of Internal Medicine, 29(5), pp.547~557 (2014), 대한내과학회[DOI]
  31. 김나연, "Clinical applications of mesenchymal stem cells", The Korean Journal of Internal Medicine, 28(4), pp.387~402 (2013), 대한내과학회[DOI]
  32. Clarke MF, "Cancer stem cells:perspectives on current status and future directions:AACR Workshop on cancer stem cells", Cancer Res, 66, pp.9339~9344 (2006)
  33. Hamburger AW, "Primary bioassay of human tumor stem cells", Science, 197, pp.461~463 (1977)
  34. Sourisseau T, "Lung cancer stem cell: fancy conceptual model of tumor biology or cornerstone of a forthcoming therapeutic breakthrough?", J Thorac Oncol, 9, pp.7~17 (2014)
  35. Giangreco A, "Stem cells are dispensable for lung homeostasis but restore airways after injury", Proc Natl Acad Sci U S A, 106, pp.9286~9291 (2009)
  36. Akunuru S, "Non-small cell lung cancer stem", progenitor cells are enriched in multiple distinct phenotypic subpopulations and exhibit plasticity, 2012, pp.3, e352~
  37. Yang CH, "Identification of CD24as a cancer stem cell marker in human nasopharyngeal carcinoma", PLoS One, 9, pp.e99412~ (2014)
  38. Li Z, "Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells", Cancer Cell, 15, pp.501~513 (2009)
  39. McCord AM, "Physiologic oxygen concentration enhances the stem-like properties of CD133+ human glioblastoma cells in vitro", Mol Cancer Res, 7, pp.489~497 (2009)
  40. Koukourakis MI, "Hypoxia-inducible proteins HIF1α and lactate dehydrogenase LDH5, key markers of anaerobic metabolism, relate with stem cell markers and poor post-radiotherapy outcome in bladder cancer", Int J Radiat Biol, 92, pp.353~363 (2016)
  41. Seidel S, "A hypoxic niche regulates glioblastoma stem cells through hypoxia inducible factor 2 alpha", Brain, 133, pp.983~995 (2010)
  42. Wang Z, "Oncogenic roles and drug target of CXCR4", CXCL12 axis in lung cancer and cancer stem cell, 2016, pp.37, 8515~8528
  43. 조병식, "Targeting the CXCL12", CXCR4 axis in acute myeloid leukemia: from bench to bedside, 2017, pp.32(2), 248~257[DOI]
  44. Nian WQ, "CXCR4 positive cells from Lewis lung carcinoma cell line have cancer metastatic stem cell characteristics", Mol Cell Biochem, 355, pp.241~248 (2011)
  45. Romain B, "Hypoxia differentially regulated CXCR4 and CXCR7 signaling in colon cancer", Mol Cancer, 13, pp.58~ (2014)
  46. Liang Z, "CXCR4", CXCL12 axis promotes VEGF-mediated tumor angiogenesis through Akt signaling pathway, 2007, pp.359, 716~722
  47. Isabel Fabregat, "New Insights into the Crossroads between EMT and Stemness in the Context of Cancer", Journal of Clinical Medicine, 5(3), pp.37~ (2016), MDPI AG[DOI]
  48. Mani SA, "The epithelial-mesenchymal transition generates cells with properties of stem cells", Cell, 133, pp.704~715 (2008)
  49. Morel AP, "Generation of breast cancer stem cells through epithelial-mesenchymal transition", PLoS One, 3, pp.e2888~ (2008)
  50. Rhim AD, "EMT and dissemination precede pancreatic tumor formation", Cell, 148, pp.349~361 (2012)
  51. Kurrey NK, "Snail and slug mediate radioresistance and chemoresistance by antagonizing p53-mediated apoptosis and acquiring a stem-like phenotype in ovarian cancer cells", Stem Cells, 27, pp.2059~2068 (2009)
  52. Wellner U, "The EMT-activator ZEB1 promotes tumorigenicity by repressing stemnessinhibiting microRNAs", Nat Cell Biol, 11, pp.1487~1495 (2009)
  53. Mima K, "CD44s regulates the TGF-beta-mediated mesenchymal phenotype and is associated with poor prognosis in patients with hepatocellular carcinoma", Cancer Res, 72, pp.3414~3423 (2012)
  54. Nomura A, "CD133 initiates tumors, induces epithelial-mesenchymal transition and increases metastasis in pancreatic cancer", Oncotarget, 6, pp.8313~8322 (2015)
  55. Huangyang P, "Epigenetic regulation of epithelial to mesenchymal transition", Curr Cancer Drug Targets, 13, pp.973~985 (2013)
  56. Hennessy BT, "Characterization of a naturally occurring breast cancer subset enriched in epithelial-to-mesenchymal transition and stem cell characteristics", Cancer Res, 69, pp.4116~4124 (2009)
  57. Chen Y, "DNA methylation is associated with transcription of snail and slug genes", Biochem Biophys Res Commun, 430, pp.1083~1090 (2013)
  58. Deneberg S, "Prognostic DNA methylation patterns in cytogenetically normal acute myeloid leukemia are predefined by stem cell chromatin marks", Blood, 118, pp.5573~5582 (2011)
  59. Chang CJ, "p53 regulates epithelial-mesenchymal transition and stem cell properties through modulating miRNAs", Nat Cell Biol, 13, pp.317~323 (2011)
  60. Taube JH, "Epigenetic silencing of microRNA-203 is required for EMT and cancer stem cell properties", Sci Rep, 3, pp.2687~ (2013)
  61. Simonsson S, "DNA demethylation is necessary for the epigenetic reprogramming of somatic cell nuclei", Nat Cell Biol, 6, pp.984~990 (2004)
  62. El Helou R, "Brief reports: a distinct DNA methylation signature defines breast cancer stem cells and predicts cancer outcome", Stem Cells, 32, pp.3031~3036 (2014)
  63. Yamazaki Y, "Gradual DNA demethylation of the Oct4promoter in cloned mouse embryos", Mol Reprod Dev, 73(1), pp.180~188 (2006)
  64. Liu CC, "IL-6 enriched lung cancer stem-like cell population by inhibition of cell cycle regulators via DNMT1 upregulation", Int J Cancer, 136, pp.547~559 (2015)
  65. Suzuki M, "Aberrant methylation of CXCL12 in non-small cell lung cancer is associated with an unfavorable prognosis", Int J Oncol, 33, pp.113~119 (2008)
  66. Zhi Y, "Down-regulation of CXCL12 by DNA hypermethylation and its involvement in gastric cancer metastatic progression", Dig Dis Sci, 57, pp.650~659 (2012)
  67. Fridrichova I, "CXCL12 and ADAM23 hypermethylation are associated with advanced breast cancers", Transl Res, 165, pp.717~730 (2015)
  68. Kubarek L, "Epigenetic up-regulation of CXCR4 and CXCL12 expression by 17 beta-estradiol and tamoxifen is associated with formation of DNA methyltransferase 3B4 splice variant in Ishikawa endometrial adenocarcinoma cells", FEBS Lett, 581, pp.1441~1448 (2007)
  69. Przybylski M, "Increased CXCR4 expression in AsPC1 pancreatic carcinoma cells with RNA interference-mediated knockdown of DNMT1 and DNMT3B", Biomed Pharmacother, 64, pp.254~258 (2010)
  70. Koga C, "Reprogramming using microRNA-302 improves drug sensitivity in hepatocellular carcinoma cells", Ann Surg Oncol, 21(Suppl 4), pp.S591~S600 (2014)
  71. Liu C, "The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44", Nat Med, 17, pp.211~215 (2011)
  72. Shimono Y, "Downregulation of miRNA-200c links breast cancer stem cells with normal stem cells", Cell, 138, pp.592~603 (2009)
  73. Gwak JM, "MicroRNA-9 is associated with epithelial-mesenchymal transition, breast cancer stem cell phenotype, and tumor progression in breast cancer", Breast Cancer Res Treat, 147, pp.39~49 (2014)
  74. Yu T, "MicroRNA-9 inhibits the proliferation of oral squamous cell carcinoma cells by suppressing expression of CXCR4 via the Wnt", beta-catenin signaling pathway, 2014, pp.33, 5017~5027
  75. Yin P, "MiR-451 suppresses cell proliferation and metastasis in A549 lung cancer cells", Mol Biotechnol, 57, pp.1~11 (2015)
  76. Sarvi S, "CD133+ cancer stem-like cells in small cell lung cancer are highly tumorigenic and chemoresistant but sensitive to a novel neuropeptide antagonist", Cancer Res, 74, pp.1554~1565 (2014)
  77. Chen Q, "Promoter methylation regulates cadherin switching in squamous cell carcinoma", Biochem Biophys Res Commun, 315, pp.850~856 (2004)
  78. Peter ME., "Let-7 and miR-200 microRNAs: guardians against pluripotency and cancer progression", Cell Cycle, 8, pp.843~852 (2009)
  79. Chen Y, "CXCR4 inhibition in tumor microenvironment facilitates anti-programmed death receptor-1 immunotherapy in sorafenib-treated hepatocellular carcinoma in mice", Hepatology, 61, pp.1591~1602 (2015)

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