DOI QR코드

DOI QR Code

Peroxiredoxins and the Regulation of Cell Death

  • Hampton, Mark B. (Centre for Free Radical Research, Department of Pathology, University of Otago) ;
  • O'Connor, Karina M. (Centre for Free Radical Research, Department of Pathology, University of Otago)
  • Received : 2015.12.21
  • Accepted : 2015.12.24
  • Published : 2016.01.31

Abstract

Cell death pathways such as apoptosis can be activated in response to oxidative stress, enabling the disposal of damaged cells. In contrast, controlled intracellular redox events are proposed to be a significant event during apoptosis signaling, regardless of the initiating stimulus. In this scenario oxidants act as second messengers, mediating the post-translational modification of specific regulatory proteins. The exact mechanism of this signaling is unclear, but increased understanding offers the potential to promote or inhibit apoptosis through modulating the redox environment of cells. Peroxiredoxins are thiol peroxidases that remove hydroperoxides, and are also emerging as important players in cellular redox signaling. This review discusses the potential role of peroxiredoxins in the regulation of apoptosis, and also their ability to act as biomarkers of redox changes during the initiation and progression of cell death.

References

  1. Adams, J.M., and Cory, S. (1998). The Bcl-2 protein family: arbiters of cell survival. Science 281, 1322-1326. https://doi.org/10.1126/science.281.5381.1322
  2. Bonini, M.G., Rota, C., Tomasi, A., and Mason, R.P. (2006). The oxidation of 2',7'-dichlorofluorescin to reactive oxygen species: a self-fulfilling prophesy? Free Radic. Biol. Med. 40, 968-975. https://doi.org/10.1016/j.freeradbiomed.2005.10.042
  3. Brown, K.K., Eriksson, S.E., Arner, E.S., and Hampton, M.B. (2008). Mitochondrial peroxiredoxin 3 is rapidly oxidized in cells treated with isothiocyanates. Free Radic. Biol. Med. 45, 494-502. https://doi.org/10.1016/j.freeradbiomed.2008.04.030
  4. Burkitt, M.J., and Wardman, P. (2001). Cytochrome C is a potent catalyst of dichlorofluorescin oxidation: implications for the role of reactive oxygen species in apoptosis. Biochem. Biophys. Res. Commun. 282, 329-333. https://doi.org/10.1006/bbrc.2001.4578
  5. Chang, T.S., Cho, C.S., Park, S., Yu, S.Q., Kang, S.W., and Rhee, S.G. (2004). Peroxiredoxin III, a mitochondrion-specific peroxidase, regulates apoptotic signaling by mitochondria. J. Biol. Chem. 279, 41975-41984. https://doi.org/10.1074/jbc.M407707200
  6. Choi, J.H., Kim, T.N., Kim, S., Baek, S.H., Kim, J.H., Lee, S.R., and Kim, J.R. (2002). Overexpression of mitochondrial thioredoxin reductase and peroxiredoxin III in hepatocellular carcinomas. Anticancer Res. 22, 3331-3335.
  7. Cox, A.G., Brown, K.K., Arner, E.S., and Hampton, M.B. (2008a). The thioredoxin reductase inhibitor auranofin triggers apoptosis through a Bax/Bak-dependent process that involves peroxiredoxin 3 oxidation. Biochem. Pharmacol. 76, 1097-1109. https://doi.org/10.1016/j.bcp.2008.08.021
  8. Cox, A.G., Pullar, J.M., Hughes, G., Ledgerwood, E.C., and Hampton, M.B. (2008b). Oxidation of mitochondrial peroxiredoxin 3 during the initiation of receptor-mediated apoptosis. Free Radic. Biol. Med. 44, 1001-1009. https://doi.org/10.1016/j.freeradbiomed.2007.11.017
  9. Cox, A.G., Peskin, A.V., Paton, L.N., Winterbourn, C.C., and Hampton, M.B. (2009). Redox potential and peroxide reactivity of human peroxiredoxin 3. Biochemistry 48, 6495-6501. https://doi.org/10.1021/bi900558g
  10. Cox, A.G., Winterbourn, C.C., and Hampton, M.B. (2010). Mitochondrial peroxiredoxin involvement in antioxidant defence and redox signalling. Biochem. J. 425, 313-325. https://doi.org/10.1042/BJ20091541
  11. Cunniff, B., Newick, K., Nelson, K.J., Wozniak, A.N., Beuschel, S., Leavitt, B., Bhave, A., Butnor, K., Koenig, A., Chouchani, E.T., et al. (2015). Disabling Mitochondrial Peroxide Metabolism via Combinatorial Targeting of Peroxiredoxin 3 as an Effective Therapeutic Approach for Malignant Mesothelioma. PLoS One 10, e0127310. https://doi.org/10.1371/journal.pone.0127310
  12. D'Alessio, M., De Nicola, M., Coppola, S., Gualandi, G., Pugliese, L., Cerella, C., Cristofanon, S., Civitareale, P., Ciriolo, M.R., Bergamaschi, A., et al. (2005). Oxidative Bax dimerization promotes its translocation to mitochondria independently of apoptosis. FASEB J. 19, 1504-1506. https://doi.org/10.1096/fj.04-3329fje
  13. Degterev, A., Huang, Z., Boyce, M., Li, Y., Jagtap, P., Mizushima, N., Cuny, G.D., Mitchison, T.J., Moskowitz, M.A., and Yuan, J. (2005). Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat. Chem. Biol. 1, 112-119. https://doi.org/10.1038/nchembio711
  14. Delaunay, A., Pflieger, D., Barrault, M.B., Vinh, J., and Toledano, M.B. (2002). A thiol peroxidase is an H2O2 receptor and redoxtransducer in gene activation. Cell 111, 471-481. https://doi.org/10.1016/S0092-8674(02)01048-6
  15. Finkel, T. (2000). Redox-dependent signal transduction. FEBS Lett. 476, 52-54. https://doi.org/10.1016/S0014-5793(00)01669-0
  16. Garcia-Perez, C., Roy, S.S., Naghdi, S., Lin, X., Davies, E. and Hajnoczky, G. (2012). Bid-induced mitochondrial membrane permeabilization waves propagated by local reactive oxygen species (ROS) signaling. Proc. Natl. Acad. Sci. USA 109, 4497-4502. https://doi.org/10.1073/pnas.1118244109
  17. Goossens, V., Grooten, J., De Vos, K., and Fiers, W. (1995). Direct evidence for tumor necrosis factor-induced mitochondrial reactive oxygen intermediates and their involvement in cytotoxicity. Proc. Natl. Acad. Sci. USA 92, 8115-8119. https://doi.org/10.1073/pnas.92.18.8115
  18. Hampton, M.B., and Orrenius, S. (1997). Dual regulation of caspase activity by hydrogen peroxide: implications for apoptosis. FEBS Lett. 414, 552-556. https://doi.org/10.1016/S0014-5793(97)01068-5
  19. Hampton, M.B., Stamenkovic, I., and Winterbourn, C.C. (2002). Interaction with substrate sensitises caspase-3 to inactivation by hydrogen peroxide. FEBS Lett. 517, 229-232. https://doi.org/10.1016/S0014-5793(02)02629-7
  20. Han, S., Shen, H., Jung, M., Hahn, B.S., Jin, B.K., Kang, I., Ha, J., and Choe, W. (2012). Expression and prognostic significance of human peroxiredoxin isoforms in endometrial cancer. Oncol. Lett. 3, 1275-1279. https://doi.org/10.3892/ol.2012.648
  21. Hayakawa, M., Miyashita, H., Sakamoto, I., Kitagawa, M., Tanaka, H., Yasuda, H., Karin, M., and Kikugawa, K. (2003). Evidence that reactive oxygen species do not mediate NF-kappaB activation. EMBO J. 22, 3356-3366. https://doi.org/10.1093/emboj/cdg332
  22. Hu, J.X., Gao, Q., and Li, L. (2013). Peroxiredoxin 3 is a novel marker for cell proliferation in cervical cancer. Biomed. Rep. 1, 228-230. https://doi.org/10.3892/br.2012.43
  23. Ichimiya, S., Davis, J.G., O'Rourke, D.M., Katsumata, M., and Greene, M.I. (1997). Murine thioredoxin peroxidase delays neuronal apoptosis and is expressed in areas of the brain most susceptible to hypoxic and ischemic injury. DNA Cell Biol. 16, 311-321. https://doi.org/10.1089/dna.1997.16.311
  24. Jang, H.H., Lee, K.O., Chi, Y.H., Jung, B.G., Park, S.K., Park, J.H., Lee, J.R., Lee, S.S., Moon, J.C., Yun, J.W., et al. (2004). Two enzymes in one; two yeast peroxiredoxins display oxidative stress-dependent switching from a peroxidase to a molecular chaperone function. Cell 117, 625-635. https://doi.org/10.1016/j.cell.2004.05.002
  25. Jarvis, R.M., Hughes, S.M., and Ledgerwood, E.C. (2012). Peroxiredoxin 1 functions as a signal peroxidase to receive, transduce, and transmit peroxide signals in mammalian cells. Free Radic. Biol. Med. 53, 1522-1530. https://doi.org/10.1016/j.freeradbiomed.2012.08.001
  26. Kagan, V.E., Tyurin, V.A., Jiang, J., Tyurina, Y.Y., Ritov, V.B., Amoscato, A.A., Osipov, A.N., Belikova, N.A., Kapralov, A.A., Kini, V., et al. (2005). Cytochrome c acts as a cardiolipin oxygenase required for release of proapoptotic factors. Nat. Chem. Biol. 1, 223-232. https://doi.org/10.1038/nchembio727
  27. Kim, Y.S., Morgan, M.J., Choksi, S., and Liu, Z.G. (2007). TNFinduced activation of the Nox1 NADPH oxidase and its role in the induction of necrotic cell death. Mol. Cell 26, 675-687. https://doi.org/10.1016/j.molcel.2007.04.021
  28. Kinnula, V.L., Lehtonen, S., Sormunen, R., Kaarteenaho-Wiik, R., Kang, S.W., Rhee, S.G., and Soini, Y. (2002). Overexpression of peroxiredoxins I, II, III, V, and VI in malignant mesothelioma. J. Pathol. 196, 316-323. https://doi.org/10.1002/path.1042
  29. Lee, T.H., Kim, S.U., Yu, S.L., Kim, S.H., Park, D.S., Moon, H.B., Dho, S.H., Kwon, K.S., Kwon, H.J., Han, Y.H., et al. (2003). Peroxiredoxin II is essential for sustaining life span of erythrocytes in mice. Blood 101, 5033-5038. https://doi.org/10.1182/blood-2002-08-2548
  30. Li, L., Shoji, W., Takano, H., Nishimura, N., Aoki, Y., Takahashi, R., Goto, S., Kaifu, T., Takai, T., and Obinata, M. (2007). Increased susceptibility of MER5 (peroxiredoxin III) knockout mice to LPS-induced oxidative stress. Biochem. Biophys. Res. Commun. 355, 715-721. https://doi.org/10.1016/j.bbrc.2007.02.022
  31. Li, G., Xie, B., Li, X., Chen, Y., Xu, Y., Xu-Welliver, M., and Zou, L. (2015). Downregulation of peroxiredoxin-1 by beta-elemene enhances the radiosensitivity of lung adenocarcinoma xenografts. Oncol. Rep. 33, 1427-1433. https://doi.org/10.3892/or.2015.3732
  32. Lin, Y., Choksi, S., Shen, H.M., Yang, Q.F., Hur, G.M., Kim, Y.S., Tran, J.H., Nedospasov, S.A., and Liu, Z.G. (2004). Tumor necrosis factor-induced nonapoptotic cell death requires receptorinteracting protein-mediated cellular reactive oxygen species accumulation. J. Biol. Chem. 279, 10822-10828. https://doi.org/10.1074/jbc.M313141200
  33. Liu, C.X., Yin, Q.Q., Zhou, H.C., Wu, Y.L., Pu, J.X., Xia, L., Liu, W., Huang, X., Jiang, T., Wu, M.X., et al. (2012.) Adenanthin targets peroxiredoxin I and II to induce differentiation of leukemic cells. Nat. Chem. Biol. 8, 486-493. https://doi.org/10.1038/nchembio.935
  34. Meng, T.C., Fukada, T., and Tonks, N.K. (2002). Reversible oxidation and inactivation of protein tyrosine phosphatases in vivo. Mol. Cell 9, 387-399. https://doi.org/10.1016/S1097-2765(02)00445-8
  35. Mukhopadhyay, S.S., Leung, K.S., Hicks, M.J., Hastings, P.J., Youssoufian, H., and Plon, S.E. (2006). Defective mitochondrial peroxiredoxin-3 results in sensitivity to oxidative stress in Fanconi anemia. J. Cell Biol. 175, 225-235. https://doi.org/10.1083/jcb.200607061
  36. Murphy, J.M., Czabotar, P.E., Hildebrand, J.M., Lucet, I.S., Zhang, J.G., Alvarez-Diaz, S., Lewis, R., Lalaoui, N., Metcalf, D., Webb, A.I., et al. (2013). The pseudokinase MLKL mediates necroptosis via a molecular switch mechanism. Immunity 39, 443-453. https://doi.org/10.1016/j.immuni.2013.06.018
  37. Myers, C.R. (2015). Enhanced targeting of mitochondrial peroxide defense by the combined use of thiosemicarbazones and inhibitors of thioredoxin reductase. Free Radic. Biol. Med. 91, 81-92.
  38. Neumann, C.A., Krause, D.S., Carman, C.V., Das, S., Dubey, D.P., Abraham, J.L., Bronson, R.T., Fujiwara, Y., Orkin, S.H., and Van Etten, R.A. (2003). Essential role for the peroxiredoxin Prdx1 in erythrocyte antioxidant defence and tumour suppression. Nature 424, 561-565. https://doi.org/10.1038/nature01819
  39. Noh, D.Y., Ahn, S.J., Lee, R.A., Kim, S.W., Park, I.A., and Chae, H.Z. (2001). Overexpression of peroxiredoxin in human breast cancer. Anticancer Res. 21, 2085-2090.
  40. Nonn, L., Berggren, M., and Powis, G. (2003). Increased expression of mitochondrial peroxiredoxin-3 (thioredoxin-peroxidase-2) protects cancer cells against hypoxia and drug-induced hydrogen peroxide-dependent apoptosis. Mol. Cancer Res. 1, 682-689.
  41. Ogusucu, R., Rettori, D., Munhoz, D.C., Netto, L.E., and Augusto, O. (2007). Reactions of yeast thioredoxin peroxidases I and II with hydrogen peroxide and peroxynitrite: rate constants by competitive kinetics. Free Radic. Biol. Med. 42, 326-334. https://doi.org/10.1016/j.freeradbiomed.2006.10.042
  42. Park, J.H., Kim, Y.S., Lee, H.L., Shim, J.Y., Lee, K.S., Oh, Y.J., Shin, S.S., Choi, Y.H., Park, K.J., Park, R.W., et al. (2006). Expression of peroxiredoxin and thioredoxin in human lung cancer and paired normal lung. Respirology 11, 269-275. https://doi.org/10.1111/j.1440-1843.2006.00849.x
  43. Parsonage, D., Youngblood, D.S., Sarma, G.N., Wood, Z.A., Karplus, P.A., and Poole, L.B. (2005). Analysis of the link between enzymatic activity and oligomeric state in AhpC, a bacterial peroxiredoxin. Biochemistry 44, 10583-10592. https://doi.org/10.1021/bi050448i
  44. Peskin, A.V., Low, F.M., Paton, L.N., Maghzal, G.J., Hampton, M.B., and Winterbourn, C.C. (2007). The high reactivity of peroxiredoxin 2 with H(2)O(2) is not reflected in its reaction with other oxidants and thiol reagents. J. Biol. Chem. 282, 11885-11892. https://doi.org/10.1074/jbc.M700339200
  45. Poynton, R.A., and Hampton, M.B. (2014). Peroxiredoxins as biomarkers of oxidative stress. Biochim. Biophys. Acta 1840, 906-912. https://doi.org/10.1016/j.bbagen.2013.08.001
  46. Radjainia, M., Venugopal, H., Desfosses, A., Phillips, A.J., Yewdall, N.A., Hampton, M.B., Gerrard, J.A., and Mitra, A.K. (2015). Cryo-electron microscopy structure of human peroxiredoxin-3 filament reveals the assembly of a putative chaperone. Structure 23, 912-920. https://doi.org/10.1016/j.str.2015.03.019
  47. Rhee, S.G., Chae, H.Z., and Kim, K. (2005). Peroxiredoxins: a historical overview and speculative preview of novel mechanisms and emerging concepts in cell signaling. Free Radic. Biol. Med. 38, 1543-1552. https://doi.org/10.1016/j.freeradbiomed.2005.02.026
  48. Salvesen, G.S., and Dixit, V.M. (1997). Caspases: intracellular signaling by proteolysis. Cell 91, 443-446. https://doi.org/10.1016/S0092-8674(00)80430-4
  49. Schulze-Osthoff, K., Bakker, A.C., Vanhaesebroeck, B., Beyaert, R., Jacob, W.A., and Fiers, W. (1992). Cytotoxic activity of tumor necrosis factor is mediated by early damage of mitochondrial functions. Evidence for the involvement of mitochondrial radical generation. J. Biol. Chem. 267, 5317-5323.
  50. Scotcher, J., Clarke, D.J., Weidt, S.K., Mackay, C.L., Hupp, T.R., Sadler, P.J., and Langridge-Smith, P.R. (2011). Identification of two reactive cysteine residues in the tumor suppressor protein p53 using top-down FTICR mass spectrometry. J. Am. Soc. Mass Spectrom. 22, 888-897. https://doi.org/10.1007/s13361-011-0088-x
  51. Shih, S.F., Wu, Y.H., Hung, C.H., Yang, H.Y., and Lin, J.Y. (2001). Abrin triggers cell death by inactivating a thiol-specific antioxidant protein. J. Biol. Chem. 276, 21870-21877. https://doi.org/10.1074/jbc.M100571200
  52. Sobotta, M.C., Liou, W., Stocker, S., Talwar, D., Oehler, M., Ruppert, T., Scharf, A.N., and Dick, T.P. (2015). Peroxiredoxin-2 and STAT3 form a redox relay for H2O2 signaling. Nat. Chem. Biol. 11, 64-70. https://doi.org/10.1038/nchembio.1695
  53. Sun, L., Wang, H., Wang, Z., He, S., Chen, S., Liao, D., Wang, L., Yan, J., Liu, W., Lei, X., et al. (2012). Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell 148, 213-227. https://doi.org/10.1016/j.cell.2011.11.031
  54. Trzeciecka, A., Klossowski, S., Bajor, M., Zagozdzon, R., Gaj, P., Muchowicz, A., Malinowska, A., Czerwoniec, A., Barankiewicz, J., Domagala, A., et al. (2015). Dimeric peroxiredoxins are druggable targets in human Burkitt lymphoma. Oncotarget [Epub ahead of print]
  55. Vanden Berghe, T., Linkermann, A., Jouan-Lanhouet, S., Walczak, H., and Vandenabeele, P. (2014). Regulated necrosis: the expanding network of non-apoptotic cell death pathways. Nat.Rev. Mol. Cell Biol. 15, 135-147.
  56. Wang, X.Y., Wang, H.J., and Li, X.Q. (2013). Peroxiredoxin III protein expression is associated with platinum resistance in epithelial ovarian cancer. Tumour Biol. 34, 2275-2281. https://doi.org/10.1007/s13277-013-0769-0
  57. Wang, H., Sun, L., Su, L., Rizo, J., Liu, L., Wang, L.F., Wang, F.S., and Wang, X. (2014). Mixed lineage kinase domain-like protein MLKL causes necrotic membrane disruption upon phosphorylation by RIP3. Mol. Cell 54, 133-146. https://doi.org/10.1016/j.molcel.2014.03.003
  58. Whitaker, H.C., Patel, D., Howat, W.J., Warren, A.Y., Kay, J.D., Sangan, T., Marioni, J.C., Mitchell, J., Aldridge, S., Luxton, H.J., et al. (2013). Peroxiredoxin-3 is overexpressed in prostate cancer and promotes cancer cell survival by protecting cells from oxidative stress. Br. J. Cancer 109, 983-993. https://doi.org/10.1038/bjc.2013.396
  59. Winterbourn, C.C. (2008). Reconciling the chemistry and biology of reactive oxygen species. Nat. Chem. Biol. 4, 278-286. https://doi.org/10.1038/nchembio.85
  60. Winterbourn, C.C., and Hampton, M.B. (2008). Thiol chemistry and specificity in redox signaling. Free Radic. Biol. Med. 45, 549-561. https://doi.org/10.1016/j.freeradbiomed.2008.05.004
  61. Wonsey, D.R., Zeller, K.I., and Dang, C.V. (2002). The c-Myc target gene PRDX3 is required for mitochondrial homeostasis and neoplastic transformation. Proc. Natl. Acad. Sci. USA 99, 6649-6654. https://doi.org/10.1073/pnas.102523299
  62. Wood, Z.A., Poole, L.B., Hantgan, R.R. and Karplus, P.A. (2002). Dimers to doughnuts: redox-sensitive oligomerization of 2-cysteine peroxiredoxins. Biochemistry 41, 5493-5504. https://doi.org/10.1021/bi012173m
  63. Wood, Z.A., Poole, L.B., and Karplus, P.A. (2003a). Peroxiredoxin evolution and the regulation of hydrogen peroxide signaling. Science 300, 650-653. https://doi.org/10.1126/science.1080405
  64. Wood, Z.A., Schroder, E., Harris, J.R., and Poole, L.B. (2003b). Structure, mechanism and regulation of peroxiredoxins. Trends Biochem. Sci. 28, 32-40. https://doi.org/10.1016/S0968-0004(02)00003-8
  65. Zhang, P., Liu, B., Kang, S.W., Seo, M.S., Rhee, S.G., and Obeid, L.M. (1997). Thioredoxin peroxidase is a novel inhibitor of apoptosis with a mechanism distinct from that of Bcl-2. J. Biol. Chem. 272, 30615-30618. https://doi.org/10.1074/jbc.272.49.30615
  66. Zhang, H., Go, Y.M., and Jones, D.P. (2007). Mitochondrial thioredoxin-2/peroxiredoxin-3 system functions in parallel with mitochondrial GSH system in protection against oxidative stress. Arch. Biochem. Biophys. 465, 119-126. https://doi.org/10.1016/j.abb.2007.05.001

Cited by

  1. Engineered M13 Nanofiber Accelerates Ischemic Neovascularization by Enhancing Endothelial Progenitor Cells 2017, https://doi.org/10.1007/s13770-017-0074-x
  2. Inhibition of reductase systems by 2-AAPA modulates peroxiredoxin oxidation and mitochondrial function in A172 glioblastoma cells vol.42, 2017, https://doi.org/10.1016/j.tiv.2017.04.028
  3. Mitochondrial peroxiredoxins are essential in regulating the relationship between Drosophila immunity and aging vol.1863, pp.1, 2017, https://doi.org/10.1016/j.bbadis.2016.10.017
  4. Mazes of Nrf2 regulation vol.82, pp.5, 2017, https://doi.org/10.1134/S0006297917050030
  5. Overview on Peroxiredoxin vol.39, pp.1, 2016, https://doi.org/10.14348/molcells.2016.2368
  6. Knockdown of Broad-Complex Gene Expression of Bombyx mori by Oligopyrrole Carboxamides Enhances Silk Production vol.7, pp.1, 2017, https://doi.org/10.1038/s41598-017-00653-3
  7. Silencing peroxiredoxin-2 sensitizes human colorectal cancer cells to ionizing radiation and oxaliplatin vol.388, 2017, https://doi.org/10.1016/j.canlet.2016.12.009
  8. Selenium and redox signaling vol.617, 2017, https://doi.org/10.1016/j.abb.2016.08.003
  9. Probing the conformational changes and peroxidase-like activity of cytochrome c upon interaction with iron nanoparticles vol.35, pp.12, 2017, https://doi.org/10.1080/07391102.2016.1222972
  10. Redox proteomics and amyloid β-peptide: insights into Alzheimer disease pp.00223042, 2018, https://doi.org/10.1111/jnc.14589
  11. Control and dysregulation of redox signalling in the gastrointestinal tract pp.1759-5053, 2018, https://doi.org/10.1038/s41575-018-0079-5
  12. Activation of the apoptotic pathway during prolonged prometaphase blocks daughter cell proliferation vol.29, pp.22, 2018, https://doi.org/10.1091/mbc.E18-01-0026
  13. Reactive Oxygen Species and Oncoprotein Signaling-A Dangerous Liaison vol.29, pp.16, 2018, https://doi.org/10.1089/ars.2017.7441
  14. Peroxiredoxin Involvement in the Initiation and Progression of Human Cancer vol.28, pp.7, 2018, https://doi.org/10.1089/ars.2017.7422