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Oxidative Medicine and Cellular Longevity
Volume 2017 (2017), Article ID 4386947, 16 pages
https://doi.org/10.1155/2017/4386947
Research Article

Hypoxia Downregulates MAPK/ERK but Not STAT3 Signaling in ROS-Dependent and HIF-1-Independent Manners in Mouse Embryonic Stem Cells

1Institute of Experimental Biology, Faculty of Science, Masaryk University, Kotlářská 267/2, 61137 Brno, Czech Republic
2Institute of Biophysics, Academy of Sciences of the Czech Republic, Královopolská 2590/135, 61200 Brno, Czech Republic
3International Clinical Research Center, Centre of Biomolecular and Cellular Engineering, St. Anne’s University Hospital, Pekařská 53, 65691 Brno, Czech Republic

Correspondence should be addressed to Jiří Pacherník

Received 18 January 2017; Revised 27 April 2017; Accepted 15 May 2017; Published 27 July 2017

Academic Editor: Magdalena Skonieczna

Copyright © 2017 Jan Kučera et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. Q. Lin, Y. Kim, R. M. Alarcon, and Z. Yun, “Oxygen and cell fate decisions,” Gene Regulation and Systems Biology, vol. 2, pp. 43–51, 2008. View at Google Scholar
  2. T. Ezashi, P. Das, and R. M. Roberts, “Low O2 tensions and the prevention of differentiation of hES cells,” Proceedings of the National Academy of Sciences, vol. 102, no. 13, pp. 4783–4788, 2005. View at Publisher · View at Google Scholar · View at Scopus
  3. C.-H. Jeong, H.-J. Lee, J.-H. Cha, J. H. J.-H. Kim, K.-W. K. R. Kim, and D.-K. Yoon, “Hypoxia-inducible factor-1 alpha inhibits self-renewal of mouse embryonic stem cells in vitro via negative regulation of the leukemia inhibitory factor-STAT3 pathway,” The Journal of Biological Chemistry, vol. 282, no. 18, pp. 13672–13679, 2007. View at Publisher · View at Google Scholar · View at Scopus
  4. S. Prado-Lopez, A. Conesa, A. Armiñán et al., “Hypoxia promotes efficient differentiation of human embryonic stem cells to functional endothelium,” Stem Cells, vol. 28, no. 3, pp. 407–418, 2010. View at Publisher · View at Google Scholar · View at Scopus
  5. J. Mathieu, Z. Zhang, A. Nelson et al., “Hypoxia induces re-entry of committed cells into pluripotency,” Stem Cells, vol. 31, no. 9, pp. 1737–1748, 2013. View at Publisher · View at Google Scholar · View at Scopus
  6. G. L. Wang, B. H. Jiang, E. A. Rue, and G. L. Semenza, “Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension,” Proceedings of the National Academy of Sciences of the United States of America, vol. 92, no. 12, pp. 5510–5514, 1995. View at Google Scholar
  7. Y. Z. Gu, S. M. Moran, J. B. Hogenesch, L. Wartman, and C. A. Bradfield, “Molecular characterization and chromosomal localization of a third alpha-class hypoxia inducible factor subunit, HIF3alpha,” Gene Expression, vol. 7, no. 3, pp. 205–213, 1998. View at Google Scholar
  8. L. E. Huang, J. Gu, M. Schau, and H. F. Bunn, “Regulation of hypoxia-inducible factor 1alpha is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 14, pp. 7987–7992, 1998. View at Google Scholar
  9. P. H. Maxwell, M. S. Wiesener, G. W. Chang et al., “The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis,” Nature, vol. 399, no. 6733, pp. 271–275, 1999. View at Publisher · View at Google Scholar · View at Scopus
  10. P. Jaakkola, D. R. Mole, Y. M. Tian et al., “Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation,” Science, vol. 292, no. 5516, pp. 468–472, 2001. View at Publisher · View at Google Scholar
  11. R. H. Wenger, “Mammalian oxygen sensing, signalling and gene regulation,” The Journal of Experimental Biology, vol. 203, Part 8, pp. 1253–1263, 2000. View at Google Scholar
  12. K. Bedard and K. Krause, “The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology,” Physiological Reviews, vol. 87, no. 1, pp. 245–313, 2007. View at Publisher · View at Google Scholar · View at Scopus
  13. N. S. Chandel and G. R. S. Budinger, “The cellular basis for diverse responses to oxygen,” Free Radical Biology & Medicine, vol. 42, no. 2, pp. 165–174, 2007. View at Publisher · View at Google Scholar · View at Scopus
  14. H. Niwa, T. Burdon, I. Chambers, and A. Smith, “Self-renewal of pluripotent embryonic stem cells is mediated via activation of STAT3,” Genes & Development, vol. 12, no. 13, pp. 2048–2060, 1998. View at Publisher · View at Google Scholar
  15. M. P. Storm, H. K. Bone, C. G. Beck et al., “Regulation of Nanog expression by phosphoinositide 3-kinase-dependent signaling in murine embryonic stem cells,” The Journal of Biological Chemistry, vol. 282, no. 9, pp. 6265–6273, 2007. View at Publisher · View at Google Scholar · View at Scopus
  16. T. Burdon, C. Stracey, I. Chambers, J. Nichols, and A. Smith, “Suppression of SHP-2 and ERK signalling promotes self-renewal of mouse embryonic stem cells,” Developmental Biology, vol. 210, no. 1, pp. 30–43, 1999. View at Publisher · View at Google Scholar · View at Scopus
  17. C. Liu, Y. Shi, Y. Du et al., “Dual-specificity phosphatase DUSP1 protects overactivation of hypoxia-inducible factor 1 through inactivating ERK MAPK,” Experimental Cell Research, vol. 309, no. 2, pp. 410–418, 2005. View at Publisher · View at Google Scholar · View at Scopus
  18. O. Bermudez, P. Jouandin, J. Rottier, C. Bourcier, G. Pagès, and C. Gimond, “Post-transcriptional regulation of the DUSP6/MKP-3 phosphatase by MEK/ERK signaling and hypoxia,” Journal of Cellular Physiology, vol. 226, no. 1, pp. 276–284, 2011. View at Publisher · View at Google Scholar · View at Scopus
  19. P. T. Heikkinen, M. Nummela, S.-K. Leivonen et al., “Hypoxia-activated Smad3-specific dephosphorylation by PP2A,” The Journal of Biological Chemistry, vol. 285, no. 6, pp. 3740–3749, 2010. View at Publisher · View at Google Scholar · View at Scopus
  20. C. P. Hofstetter, J.-K. Burkhardt, B. J. Shin et al., “Protein phosphatase 2A mediates dormancy of glioblastoma multiforme-derived tumor stem-like cells during hypoxia,” PloS One, vol. 7, no. 1, article e30059, 2012. View at Google Scholar
  21. H. S. C. Barbosa, T. G. Fernandes, T. P. Dias, M. M. Diogo, and J. M. S. Cabral, “New insights into the mechanisms of embryonic stem cell self-renewal under hypoxia: a multifactorial analysis approach,” PloS One, vol. 7, no. 6, article e38963, 2012. View at Google Scholar
  22. L. Binó, J. Kučera, K. Štefková et al., “The stabilization of hypoxia inducible factor modulates differentiation status and inhibits the proliferation of mouse embryonic stem cells,” Chemico-Biological Interactions, vol. 244, pp. 204–214, 2016. View at Publisher · View at Google Scholar · View at Scopus
  23. D. E. Powers, J. R. Millman, R. B. Huang, and C. K. Colton, “Effects of oxygen on mouse embryonic stem cell growth, phenotype retention, and cellular energetics,” Biotechnology and Bioengineering, vol. 101, no. 2, pp. 241–254, 2008. View at Publisher · View at Google Scholar · View at Scopus
  24. P. Carmeliet, Y. Dor, J. M. Herbert et al., “Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis,” Nature, vol. 394, no. 6692, pp. 485–490, 1998. View at Publisher · View at Google Scholar · View at Scopus
  25. J. Kučera, L. Binó, K. Štefková et al., “Apocynin and Diphenyleneiodonium induce oxidative stress and modulate PI3K/Akt and MAPK/Erk activity in mouse embryonic stem cells,” Oxidative Medicine and Cellular Longevity, vol. 2016, Article ID 7409196, 14 pages, 2016. View at Publisher · View at Google Scholar · View at Scopus
  26. P. Carrero, K. Okamoto, P. Coumailleau, S. O’Brien, H. Tanaka, and L. Poellinger, “Redox-regulated recruitment of the transcriptional coactivators CREB-binding protein and SRC-1 to hypoxia-inducible factor 1alpha,” Molecular and Cellular Biology, vol. 20, no. 1, pp. 402–415, 2000. View at Publisher · View at Google Scholar
  27. T. Matsui, T. Kinoshita, T. Hirano, T. Yokota, and A. Miyajima, “STAT3 down-regulates the expression of cyclin D during liver development,” The Journal of Biological Chemistry, vol. 277, no. 39, pp. 36167–36173, 2002. View at Publisher · View at Google Scholar · View at Scopus
  28. H. Kotasová, I. Veselá, J. Kučera et al., “Phosphoinositide 3-kinase inhibition enables retinoic acid-induced neurogenesis in monolayer culture of embryonic stem cells,” Journal of Cellular Biochemistry, vol. 113, no. 2, pp. 563–570, 2012. View at Publisher · View at Google Scholar · View at Scopus
  29. H. Zhao, J. Joseph, H. M. Fales et al., “Detection and characterization of the product of hydroethidine and intracellular superoxide by HPLC and limitations of fluorescence,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 16, pp. 5727–5732, 2005. View at Google Scholar
  30. J. Zielonka, J. Vasquez-Vivar, and B. Kalyanaraman, “Detection of 2-hydroxyethidium in cellular systems: a unique marker product of superoxide and hydroethidine,” Nature Protocols, vol. 3, no. 1, pp. 8–21, 2008. View at Publisher · View at Google Scholar · View at Scopus
  31. M. Kovarikova, J. Pachernik, J. Hofmanova, Z. Zadak, and A. Kozubik, “TNF-alpha modulates the differentiation induced by butyrate in the HT-29 human colon adenocarcinoma cell line,” European Journal of Cancer, vol. 36, no. 14, pp. 1844–1852, 2000. View at Publisher · View at Google Scholar · View at Scopus
  32. K. Stefkova, J. Prochazkova, and J. Pachernik, “Alkaline phosphatase in stem cells,” Stem Cells International, vol. 2015, Article ID 628368, 11 pages, 2015. View at Publisher · View at Google Scholar · View at Scopus
  33. N. R. D. Paling, H. Wheadon, H. K. Bone, and M. J. Welham, “Regulation of embryonic stem cell self-renewal by phosphoinositide 3-kinase-dependent signaling,” The Journal of Biological Chemistry, vol. 279, no. 46, pp. 48063–48070, 2004. View at Publisher · View at Google Scholar · View at Scopus
  34. J. Mazumdar, V. Dondeti, and M. C. Simon, “Hypoxia-inducible factors in stem cells and cancer,” Journal of Cellular and Molecular Medicine, vol. 13, no. 11-12, pp. 4319–4328, 2009. View at Publisher · View at Google Scholar · View at Scopus
  35. M. Albertoni, P. H. Shaw, M. Nozaki et al., “Anoxia induces macrophage inhibitory cytokine-1 (MIC-1) in glioblastoma cells independently of p53 and HIF-1,” Oncogene, vol. 21, no. 27, pp. 4212–4219, 2002. View at Publisher · View at Google Scholar · View at Scopus
  36. P. Vaňhara, A. Hampl, A. Kozubík, and K. Souček, “Growth/differentiation factor-15: prostate cancer suppressor or promoter?” Prostate Cancer and Prostatic Diseases, vol. 15, no. 4, pp. 320–328, 2012. View at Publisher · View at Google Scholar · View at Scopus
  37. K. J. Woo, T.-J. Lee, J.-W. Park, and T. K. Kwon, “Desferrioxamine, an iron chelator, enhances HIF-1alpha accumulation via cyclooxygenase-2 signaling pathway,” Biochemical and Biophysical Research Communications, vol. 343, no. 1, pp. 8–14, 2006. View at Publisher · View at Google Scholar · View at Scopus
  38. T. D. Barrett, H. L. Palomino, T. I. Brondstetter et al., “Pharmacological characterization of 1-(5-chloro-6-(trifluoromethoxy)-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid (JNJ-42041935), a potent and selective hypoxia-inducible factor prolyl hydroxylase inhibitor,” Molecular Pharmacology, vol. 79, no. 6, pp. 910–920, 2011. View at Publisher · View at Google Scholar · View at Scopus
  39. H. J. Kim, S.-J. Yang, Y. S. Kim, and T. U. Kim, “Cobalt chloride-induced apoptosis and extracellular signal-regulated protein kinase activation in human cervical cancer HeLa cells,” Journal of Biochemistry and Molecular Biology, vol. 36, no. 5, pp. 468–474, 2003. View at Google Scholar
  40. S.-J. Yang, J. Pyen, I. Lee, H. Lee, Y. Kim, and T. Kim, “Cobalt chloride-induced apoptosis and extracellular signal-regulated protein kinase 1/2 activation in rat C6 glioma cells,” Journal of Biochemistry and Molecular Biology, vol. 37, no. 4, pp. 480–486, 2004. View at Google Scholar
  41. S.-K. Lee, H.-J. Jang, H.-J. Lee et al., “p38 and ERK MAP kinase mediates iron chelator-induced apoptosis and -suppressed differentiation of immortalized and malignant human oral keratinocytes,” Life Sciences, vol. 79, no. 15, pp. 1419–1427, 2006. View at Publisher · View at Google Scholar · View at Scopus
  42. A. Triantafyllou, P. Liakos, A. Tsakalof, E. Georgatsou, G. Simos, and S. Bonanou, “Cobalt induces hypoxia-inducible factor-1alpha (HIF-1alpha) in HeLa cells by an iron-independent, but ROS-, PI-3K- and MAPK-dependent mechanism,” Free Radical Research, vol. 40, no. 8, pp. 847–856, 2006. View at Google Scholar
  43. X. Huang, J. Dai, C. Huang, Q. Zhang, O. Bhanot, and E. Pelle, “Deferoxamine synergistically enhances iron-mediated AP-1 activation: a showcase of the interplay between extracellular-signal-regulated kinase and tyrosine phosphatase,” Free Radical Research, vol. 41, no. 10, pp. 1135–1142, 2007. View at Google Scholar
  44. M. Torres and H. J. Forman, “Redox signaling and the MAP kinase pathways,” BioFactors, vol. 17, no. 1–4, pp. 287–296, 2003. View at Google Scholar
  45. D. Trachootham, W. Lu, M. A. Ogasawara, R.-D. V. Nilsa, and P. Huang, “Redox regulation of cell survival,” Antioxidants & Redox Signaling, vol. 10, no. 8, pp. 1343–1374, 2008. View at Publisher · View at Google Scholar · View at Scopus
  46. N. S. Chandel, D. S. McClintock, C. E. Feliciano et al., “Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1alpha during hypoxia: a mechanism of O2 sensing,” The Journal of Biological Chemistry, vol. 275, no. 33, pp. 25130–25138, 2000. View at Publisher · View at Google Scholar · View at Scopus
  47. Y. Liu, Y. Cui, M. Shi, Q. Zhang, Q. Wang, and X. Chen, “Deferoxamine promotes MDA-MB-231 cell migration and invasion through increased ROS-dependent HIF-1α accumulation,” Cellular Physiology and Biochemistry, vol. 33, no. 4, pp. 1036–1046, 2014. View at Publisher · View at Google Scholar · View at Scopus
  48. C. Liu, Y. Shi, Z. Han et al., “Suppression of the dual-specificity phosphatase MKP-1 enhances HIF-1 trans-activation and increases expression of EPO,” Biochemical and Biophysical Research Communications, vol. 312, no. 3, pp. 780–786, 2003. View at Publisher · View at Google Scholar · View at Scopus
  49. D. N. Slack, O. M. Seternes, M. Gabrielsen, and S. M. Keyse, “Distinct binding determinants for ERK2/p38alpha and JNK map kinases mediate catalytic activation and substrate selectivity of map kinase phosphatase-1,” The Journal of Biological Chemistry, vol. 276, no. 19, pp. 16491–16500, 2001. View at Publisher · View at Google Scholar · View at Scopus
  50. A. Kucharska, L. K. Rushworth, C. Staples, N. A. Morrice, and S. M. Keyse, “Regulation of the inducible nuclear dual-specificity phosphatase DUSP5 by ERK MAPK,” Cellular Signalling, vol. 21, no. 12, pp. 1794–1805, 2009. View at Publisher · View at Google Scholar · View at Scopus
  51. K. R. Laderoute, H. L. Mendonca, J. M. Calaoagan, A. M. Knapp, A. J. Giaccia, and P. J. Stork, “Mitogen-activated protein kinase phosphatase-1 (MKP-1) expression is induced by low oxygen conditions found in solid tumor microenvironments. A candidate MKP for the inactivation of hypoxia-inducible stress-activated protein kinase/c-Jun N-terminal protein kinase activity,” The Journal of Biological Chemistry, vol. 274, no. 18, pp. 12890–12897, 1999. View at Publisher · View at Google Scholar · View at Scopus
  52. K. A. Seta, R. Kim, H. W. Kim, D. E. Millhorn, and D. Beitner-Johnson, “Hypoxia-induced regulation of MAPK phosphatase-1 as identified by subtractive suppression hybridization and cDNA microarray analysis,” The Journal of Biological Chemistry, vol. 276, no. 48, pp. 44405–44412, 2001. View at Publisher · View at Google Scholar · View at Scopus
  53. S. Marchetti, C. Gimond, J.-C. Chambard et al., “Extracellular signal-regulated kinases phosphorylate mitogen-activated protein kinase phosphatase 3/DUSP6 at serines 159 and 197, two sites critical for its proteasomal degradation,” Molecular and Cellular Biology, vol. 25, no. 2, pp. 854–864, 2005. View at Publisher · View at Google Scholar · View at Scopus
  54. O. Bermudez, G. Pages, and C. Gimond, “The dual-specificity MAP kinase phosphatases: critical roles in development and cancer,” American Journal of Physiology Cell Physiology, vol. 299, no. 2, pp. C189–C202, 2010. View at Google Scholar
  55. D. A. Wassarman, N. M. Solomon, H. C. Chang, F. D. Karim, M. Therrien, and G. M. Rubin, “Protein phosphatase 2A positively and negatively regulates Ras1-mediated photoreceptor development in Drosophila,” Genes & Development, vol. 10, no. 3, pp. 272–278, 1996. View at Publisher · View at Google Scholar
  56. Y.-C. Kuo, K.-Y. Huang, C.-H. Yang, Y.-S. Yang, W.-Y. Lee, and C.-W. Chiang, “Regulation of phosphorylation of Thr-308 of Akt, cell proliferation, and survival by the B55alpha regulatory subunit targeting of the protein phosphatase 2A holoenzyme to Akt,” The Journal of Biological Chemistry, vol. 283, no. 4, pp. 1882–1892, 2008. View at Publisher · View at Google Scholar · View at Scopus
  57. E. Sontag, S. Fedorov, C. Kamibayashi, D. Robbins, M. Cobb, and M. Mumby, “The interaction of SV40 small tumor antigen with protein phosphatase 2A stimulates the map kinase pathway and induces cell proliferation,” Cell, vol. 75, no. 5, pp. 887–897, 1993. View at Publisher · View at Google Scholar · View at Scopus
  58. D. R. Alessi, N. Gomez, G. Moorhead, T. Lewis, S. M. Keyse, and P. Cohen, “Inactivation of p42 MAP kinase by protein phosphatase 2A and a protein tyrosine phosphatase, but not CL100, in various cell lines,” Current Biology, vol. 5, no. 3, pp. 283–295, 1995. View at Publisher · View at Google Scholar · View at Scopus
  59. T. Sawa, T. Sasaoka, H. Hirai et al., “Intracellular signalling pathways of okadaic acid leading to mitogenesis in rat1 fibroblast overexpressing insulin receptors: okadaic acid regulates Shc phosphorylation by mechanisms independent of insulin,” Cellular Signalling, vol. 11, no. 11, pp. 797–803, 1999. View at Publisher · View at Google Scholar · View at Scopus
  60. S. M. Hernández-Sotomayor, M. Mumby, and G. Carpenter, “Okadaic acid-induced hyperphosphorylation of the epidermal growth factor receptor. Comparison with receptor phosphorylation and functions affected by another tumor promoter, 12-O-tetradecanoylphorbol-13-acetate,” The Journal of Biological Chemistry, vol. 266, no. 31, pp. 21281–21286, 1991. View at Google Scholar
  61. S. Ory, M. Zhou, T. P. Conrads, T. D. Veenstra, and D. K. Morrison, “Protein phosphatase 2A positively regulates Ras signaling by dephosphorylating KSR1 and Raf-1 on critical 14-3-3 binding sites,” Current Biology, vol. 13, no. 16, pp. 1356–1364, 2003. View at Publisher · View at Google Scholar · View at Scopus
  62. S. Zimmermann, “Phosphorylation and regulation of Raf by Akt (protein kinase B),” Science, vol. 286, no. 5445, pp. 1741–1744, 1999. View at Publisher · View at Google Scholar · View at Scopus
  63. J. Zhang, X. Wang, V. Vikash et al., “ROS and ROS-mediated cellular signaling,” Oxidative Medicine and Cellular Longevity, vol. 2016, Article ID 4350965, 18 pages, 2016. View at Publisher · View at Google Scholar · View at Scopus
  64. Y. Son, Y. Cheong, N. Kim, H. Chung, D. G. Kang, and H. Pae, “Mitogen-activated protein kinases and reactive oxygen species: how can ROS activate MAPK pathways?” Journal of Signal Transduction, vol. 2011, Article ID 792639, 6 pages, 2011. View at Publisher · View at Google Scholar
  65. S. Di Meo, T. T. Reed, P. Venditti, and V. M. Victor, “Role of ROS and RNS sources in physiological and pathological conditions,” Oxidative Medicine and Cellular Longevity, vol. 2016, Article ID 1245049, 44 pages, 2016. View at Publisher · View at Google Scholar · View at Scopus
  66. B. Marengo, M. Nitti, A. L. Furfaro et al., “Redox homeostasis and cellular antioxidant systems: crucial players in cancer growth and therapy,” Oxidative Medicine and Cellular Longevity, vol. 2016, Article ID 6235641, 16 pages, 2016. View at Publisher · View at Google Scholar · View at Scopus
  67. R. Roskoski, “ERK1/2 MAP kinases: structure, function, and regulation,” Pharmacological Research, vol. 66, no. 2, pp. 105–143, 2012. View at Publisher · View at Google Scholar · View at Scopus
  68. M. Á. Ramírez, E. Pericuesta, M. Yáñez-Mó, A. Palasz, and A. Gutiérrez-Adán, “Effect of long-term culture of mouse embryonic stem cells under low oxygen concentration as well as on glycosaminoglycan hyaluronan on cell proliferation and differentiation,” Cell Proliferation, vol. 44, no. 1, pp. 75–85, 2011. View at Publisher · View at Google Scholar · View at Scopus
  69. H. F. Chen, H. C. Kuo, W. Chen, F. C. Wu, Y. S. Yang, and H. N. Ho, “A reduced oxygen tension (5%) is not beneficial for maintaining human embryonic stem cells in the undifferentiated state with short splitting intervals,” Human Reproduction, vol. 24, no. 1, pp. 71–80, 2009. View at Publisher · View at Google Scholar · View at Scopus
  70. T. Matsuda, T. Nakamura, K. Nakao et al., “STAT3 activation is sufficient to maintain an undifferentiated state of mouse embryonic stem cells,” The EMBO Journal, vol. 18, no. 15, pp. 4261–4269, 1999. View at Publisher · View at Google Scholar · View at Scopus
  71. P. Wu, D. Wu, L. Zhao, L. Huang, G. Shen, and J. Huang, “Prognostic role of STAT3 in solid tumors: a systematic review and meta-analysis,” Oncotarget, vol. 7, no. 15, pp. 19863–19883, 2016. View at Publisher · View at Google Scholar · View at Scopus
  72. J. Yuan, F. Zhang, and R. Niu, “Multiple regulation pathways and pivotal biological functions of STAT3 in cancer,” Scientific Reports, vol. 5, article 17663, 2015. View at Publisher · View at Google Scholar · View at Scopus