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SOX9 as One of the Central Units of Regulation Axis of Pancreas Embryogenesis and Cancer Progression

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Abstract

The embryonic development of all body systems is controlled by coordinated interactions of a group of genes encoding master regulators of development, which determine the fate of cells in the process of differentiation. These genes are often involved in the processes of malignant degeneration of cells. Hence, they are considered as targets of targeted gene therapy in the development of modern approaches to cancer treatment. One of the most aggressive forms of cancer is pancreatic ductal adenocarcinoma (PDAC). Thus, the study of pancreas master regulators genes is a challenging task. This review is devoted to SOX9, which is one of the key master regulators of pancreatic development and is a crucial factor in the induction and progression of PDAC.

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REFERENCES

  1. Antebi, Y.E., Nandagopal, N., and Elowitz, M.B., An operational view of intercellular signaling pathways, Curr. Opin. Syst. Biol., 2017, vol. 1, pp. 16–24.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Perrimon, N., Pitsouli, C., and Shilo, B.-Z., Signaling mechanisms controlling cell fate and embryonic patterning, Cold Spring Harbor Perspect. Biol., 2012, vol. 4, no. 8, p. a005975.

    Article  CAS  Google Scholar 

  3. Neph, S., Stergachis, A.B., Reynolds, A., Sandstrom, R., Borenstein, E., and Stamatoyannopoulos, J.A., Circuitry and dynamics of human transcription factor regulatory networks, Cell, 2012, vol. 150, no. 6, pp. 1274–1286.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Kondratyeva, L.G., Vinogradova, T.V., Chernov, I.P., and Sverdlov, E.D., Master transcription regulators specifying cell-lineage fates in development as possible therapeutic targets in oncology, Russ. J. Genet., 2015, vol. 51, no. 11, pp. 1049–1059.

    Article  CAS  Google Scholar 

  5. Chan, S.S.-K. and Kyba, M., What is a master regulator?, J. Stem Cell Res. Ther., 2013, vol. 3, p. 114.

    PubMed  PubMed Central  Google Scholar 

  6. Ma, Y., Zhang, P., Wang, F., Yang, J., Yang, Z., and Qin, H., The relationship between early embryo development and tumorigenesis, J. Cell. Mol. Med., 2010, vol. 14, no. 12, pp. 2697–2701.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Hadjimichael, C., Chanoumidou, K., Papadopoulou, N., Arampatzi, P., Papamatheakis, J., and Kretsovali, A., Common stemness regulators of embryonic and cancer stem cells, World J. Stem Cells, 2015, vol. 7, no. 9, pp. 1150–1184.

    PubMed  PubMed Central  Google Scholar 

  8. Thiery, J.P., Acloque, H., Huang, R.Y.J., and Nieto, M.A., Epithelial-mesenchymal transitions in development and disease, Cell, 2009, vol. 139, no. 5, pp. 871–890.

    Article  CAS  PubMed  Google Scholar 

  9. Seymour, P.A., Sox9: A master regulator of the pancreatic program, Rev. Diabetic Stud., 2014, vol. 11, no. 1, pp. 51–83.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Bowles, J., Schepers, G., and Koopman, P., Phylogeny of the SOX family of developmental transcription factors based on sequence and structural indicators, Dev. Biol., 2000, vol. 227, no. 2, pp. 239–255.

    Article  CAS  PubMed  Google Scholar 

  11. Reményi, A., Lins, K., Nissen, L.J., Reinbold, R., Schöler, H., and Wilmanns, M., Crystal structure of a POU_HMG_DNA ternary complex suggests differential assembly of Oct4 and Sox2 on two enhancers, Genes Dev., 2003, vol. 17, no. 16, pp. 2048–2059.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. She, Z.Y. and Yang, W.X., SOX family transcription factors involved in diverse cellular events during development, Eur. J. Cell Biol., 2015, vol. 94, no. 12, pp. 547–563.

    Article  CAS  PubMed  Google Scholar 

  13. Kamachi, Y. and Kondoh, H., Sox proteins: regulators of cell fate specification and differentiation, Development, 2013, vol. 140, no. 20, pp. 4129–4144.

    Article  CAS  PubMed  Google Scholar 

  14. Jo, A., Denduluri, S., Zhang, B., Wang, Z., Yin, L., Yan, Z., et al., The versatile functions of Sox9 in development, stem cells, and human diseases, Genes Dis., 2014, vol. 1, no. 2, pp. 149–161.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Malki, S., Boizet-Bonhoure, B., and Poulat, F., Shuttling of SOX proteins, Int. J. Biochem. Cell Biol., 2010, vol. 42, no. 3, pp. 411–416.

    Article  CAS  PubMed  Google Scholar 

  16. Tsuda, M., Takahashi, S., Takahashi, Y., and Asahara, H., Transcriptional co-activators CREB-binding protein and p300 regulate chondrocyte-specific gene expression via association with Sox9, J. Biol. Chem., 2003, vol. 278, no. 29, pp. 27224–27229.

    Article  CAS  PubMed  Google Scholar 

  17. Kawakami, Y., Tsuda, M., Takahashi, S., Taniguchi, N., Esteban, C.R., Zemmyo, M., et al., Transcriptional coactivator PGC-1alpha regulates chondrogenesis via association with Sox9, Proc. Natl. Acad. Sci. U. S. A., 2005, vol. 102, no. 7, pp. 2414–2419.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Hattori, T., Coustry, F., Stephens, S., Eberspaecher, H., Takigawa, M., Yasuda, H., et al., Transcriptional regulation of chondrogenesis by coactivator Tip60 via chromatin association with Sox9 and Sox5, Nucleic Acids Res., 2008, vol. 36, no. 9, pp. 3011–3024.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Bernard, P., Tang, P., Liu, S., Dewing, P., Harley, V.R., and Vilain, E., SOX9 is required for chondrogenesis, but not for sex determination, Hum. Mol. Genet., 2003, vol 12, no. 14, pp. 1755–1765.

    Article  CAS  PubMed  Google Scholar 

  20. Bridgewater, L.C., Walker, M.D., Miller, G.C., Ellison, T.A., Holsinger, L.D., Potter, J.L., et al., Adjacent DNA sequences modulate Sox9 transcriptional activation at paired Sox sites in three chondrocyte-specific enhancer elements, Nucleic Acids Res., 2003, vol. 31, no. 5, pp. 1541–1553.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Huang, Y.H., Jankowski, A., Cheah, K.S.E., Prabhakar, S., and Jauch, R., SOXE transcription factors form selective dimers on non-compact DNA motifs through multifaceted interactions between dimerization and high-mobility group domains., Sci. Rep., 2015, vol. 5, p. 10398.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Kamachi, Y., Uchikawa, M., and Kondoh, H., Pairing SOX off: With partners in the regulation of embryonic development, Trends Genet., 2000, vol. 16, no. 4, pp. 182–187.

    Article  CAS  PubMed  Google Scholar 

  23. Huang, W., Zhou, X., Lefebvre, V., and de Crombrugghe, B., Phosphorylation of SOX9 by cyclic AMP-dependent protein kinase A enhances SOX9’s ability to transactivate a Col2a1 chondrocyte-specific enhancer, Mol. Cell. Biol., 2000, vol. 20, no. 11, pp. 4149–4158.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Oh, H.J., Kido, T., and Lau, Y.F., PIAS1 interacts with and represses SOX9 transactivation activity, Mol. Reprod. Dev., 2007, vol. 74, no. 11, pp. 1446–1455.

    Article  CAS  PubMed  Google Scholar 

  25. Gordon, C.T., Tan, T.Y., Benko, S., FitzPatrick, D., Lyonnet, S., and Farlie, P.G., Long-range regulation at the SOX9 locus in development and disease, J. Med. Genet., 2009, vol. 46, no. 10, pp. 649–656.

    Article  CAS  PubMed  Google Scholar 

  26. Mead, T.J., Wang, Q., Bhattaram, P., Dy, P., Afelik, S., Jensen, J., et al., A far-upstream (–70 kb) enhancer mediates Sox9 auto-regulation in somatic tissues during development and adult regeneration, Nucleic Acids Res., 2013, vol. 41, no. 8, pp. 4459–4469.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Sun, L., Mathews, L.A., Cabarcas, S.M., Zhang, X., Yang, A., Zhang, Y., et al., Epigenetic regulation of SOX9 by the NF-κB signaling pathway in pancreatic cancer stem cells, Stem Cells, 2013, vol. 31, no. 8, pp. 1454–1466.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Larsen, H.L. and Grapin-Botton, A., The molecular and morphogenetic basis of pancreas organogenesis, Semin. Cell Dev. Biol., 2017, vol. 66, pp. 51–68.

    Article  CAS  PubMed  Google Scholar 

  29. Bastidas-Ponce, A., Scheibner, K., Lickert, H., and Bakhti, M., Cellular and molecular mechanisms coordinating pancreas development, Development, 2017, vol. 144, no. 16, pp. 2873–2888.

    Article  CAS  PubMed  Google Scholar 

  30. Jennings, R.E., Berry, A.A., Strutt, J.P., Gerrard, D.T., and Hanley, N.A., Human pancreas development, Development, 2015, vol. 142, no. 18, pp. 3126–3137.

    Article  CAS  PubMed  Google Scholar 

  31. Yin, C., Molecular mechanisms of Sox transcription factors during the development of liver, bile duct, and pancreas, Semin. Cell Dev. Biol., 2017, vol. 63, pp. 68–78.

    Article  CAS  PubMed  Google Scholar 

  32. Seymour, P.A., Freude, K.K., Tran, M.N., Mayes, E.E., Jensen, J., Kist, R., et al., SOX9 is required for maintenance of the pancreatic progenitor cell pool, Proc. Natl. Acad. Sci. U. S. A., 2007, vol. 104, no. 6, pp. 1865–1870.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Piper, K., Ball, S.G., Keeling, J.W., Mansoor, S., Wilson, D.I., and Hanley, N.A., Novel SOX9 expression during human pancreas development correlates to abnormalities in Campomelic dysplasia, Mech. Dev., 2002, vol. 116, nos. 1–2, pp. 223–226.

    Article  CAS  PubMed  Google Scholar 

  34. Shih, H.P., Seymour, P.A., Patel, N.A., Xie, R., Wang, A., Liu, P.P., et al., A gene regulatory network cooperatively controlled by Pdx1 and Sox9 governs lineage allocation of foregut progenitor cells, Cell Rep., 2015, vol. 13, no. 2, pp. 326–336.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Poll, A.V., Pierreux, C.E., Lokmane, L., Haumaitre, C., Achouri, Y., Jacquemin, P., et al., A vHNF1/TCF2-HNF6 cascade regulates the transcription factor network that controls generation of pancreatic precursor cells, Diabetes, 2006, vol. 55, no. 1, pp. 61–69.

    Article  CAS  PubMed  Google Scholar 

  36. Gao, N., LeLay, J., Vatamaniuk, M.Z., Rieck, S., Friedman, J.R., and Kaestner, K.H., Dynamic regulation of Pdx1 enhancers by Foxa1 and Foxa2 is essential for pancreas development, Genes Dev., 2008, vol. 22, pp. 3435–3448.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Kawaguchi, Y., Cooper, B., Gannon, M., Ray, M., MacDonald, R.J., and Wright, C.V.E., The role of the transcriptional regulator Ptf1a in converting intestinal to pancreatic progenitors, Nat. Genet., 2002, vol. 32, no. 1, pp. 128–134.

    Article  CAS  PubMed  Google Scholar 

  38. Cirillo, L.A., Lin, F.R., Cuesta, I., Friedman, D., Jarnik, M., and Zaret, K.S., Opening of compacted chromatin by early developmental transcription factors HNF3 (FoxA) and GATA-4, Mol. Cell, 2002, vol. 9, pp. 279–289.

    Article  CAS  PubMed  Google Scholar 

  39. Kaestner, K.H., The FoxA factors in organogenesis and differentiation, Curr. Opin. Genet. Dev., 2010, vol. 20, no. 5, pp. 527–532.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Zinovyeva, M.V., Kuzmich, A.I., Monastyrskaya, G.S., and Sverdlov, E.D., The role of the FOXA subfamily factors in embryonic development and carcinogenesis of the pancreas, Mol. Genet., Microbiol. Virol., 2016, vol. 31, no. 3, pp. 135–142.

    Article  Google Scholar 

  41. Lee, C.S., Sund, N.J., Vatamaniuk, M.Z., Matschinsky, F.M., Stoffers, D.A., and Kaestner, K.H., Foxa2 controls Pdx1 gene expression in pancreatic beta-cells in vivo, Diabetes, 2002, vol. 51, no. 8, pp. 2546–2551.

    Article  CAS  PubMed  Google Scholar 

  42. Lynn, F.C., Smith, S.B., Wilson, M.E., Yang, K.Y., Nekrep, N., and German, M.S., Sox9 coordinates a transcriptional network in pancreatic progenitor cells, Proc. Natl. Acad. Sci. U. S. A., 2007, vol. 104, no. 25, pp. 10500–10505.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Dubois, C.L., Shih, H.P., Seymour, P.A., Patel, N.A., Behrmann, J.M., Ngo, V., et al., Sox9-haploinsufficiency causes glucose intolerance in mice, PLoS One, 2011, vol. 6, no. 8, p. e23131.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Marshak, S., Benshushan, E., Shoshkes, M., Havin, L., Cerasi, E., and Melloul, D., Functional conservation of regulatory elements in the pdx-1 gene: PDX-1 and hepatocyte nuclear factor 3beta transcription factors mediate beta-cell-specific expression, Mol. Cell. Biol., 2000, vol. 20, no. 20, pp. 7583–7590.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Weedon, M.N., Cebola, I., Patch, A.M., Flanagan, S.E., De Franco, E., Caswell, R., et al., Recessive mutations in a distal PTF1A enhancer cause isolated pancreatic agenesis, Nat. Genet., 2014, vol. 46, no. 1, pp. 61–64.

    Article  CAS  PubMed  Google Scholar 

  46. Seymour, P.A., Shih, H.P., Patel, N.A., Freude, K.K., Xie, R., Lim, C.J., et al., A Sox9/Fgf feed-forward loop maintains pancreatic organ identity, Development, 2012, vol. 139, no. 18, pp. 3363–3372.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Pan, F.C., Bankaitis, E.D., Boyer, D., Xu, X., Van de Casteele, M., Magnuson, M.A., et al., Spatiotemporal patterns of multipotentiality in Ptf1a-expressing cells during pancreas organogenesis and injury-induced facultative restoration, Development, 2013, vol. 140, no. 4, pp. 751–764.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Furuyama, K., Kawaguchi, Y., Akiyama, H., Horiguchi, M., Kodama, S., Kuhara, T., et al., Continuous cell supply from a Sox9-expressing progenitor zone in adult liver, exocrine pancreas and intestine, Nat. Genet., 2011, vol. 43, no. 1, pp. 34–41.

    Article  CAS  PubMed  Google Scholar 

  49. Shroff, S., Rashid, A., Wang, H., Katz, M.H., Abbruzzese, J.L., Fleming, J.B., et al., SOX9: A useful marker for pancreatic ductal lineage of pancreatic neoplasms, Hum. Pathol., 2014, vol. 45, no. 3, pp. 456–463.

    Article  CAS  PubMed  Google Scholar 

  50. Schaffer, A.E., Freude, K.K., Nelson, S.B., and Sander, M., Nkx6 transcription factors and Ptf1a function as antagonistic lineage determinants in multipotent pancreatic progenitors, Dev. Cell, 2010, vol. 18, no. 6, pp. 1022–1029.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Hoang, C.Q., Hale, M.A., Azevedo-Pouly, A., Elsässer, H.P., Deering, T.G., Willet, S.G., et al., Transcriptional maintenance of pancreatic acinar identity, differentiation and homeostasis by PTF1A, Mol. Cell. Biol., 2016, vol. 36, no. 24, pp. 3033–3047.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Seymour, P.A., Freude, K.K., Dubois, C.L., Shih, H.P., Patel, N.A., and Sander, M., A dosage-dependent requirement for Sox9 in pancreatic endocrine cell formation, Dev. Biol., 2008, vol. 323, no. 1, pp. 19–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Shih, H.P., Kopp, J.L., Sandhu, M., Dubois, C.L., Seymour, P.A., Grapin-Botton, A., et al., A Notch-dependent molecular circuitry initiates pancreatic endocrine and ductal cell differentiation, Development, 2012, vol. 139, no. 14, pp. 2488–2499.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. De Vas, M.G., Kopp, J.L., Heliot, C., Sander, M., Cereghini, S., and Haumaitre, C., Hnf1b controls pancreas morphogenesis and the generation of Ngn3+ endocrine progenitors, Development, 2015, vol. 142, no. 5, pp. 871–882.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Jacquemin, P., Durviaux, S.M., Jensen, J., Godfraind, C., Gradwohl, G., Guillemot, F., et al., Transcription factor hepatocyte nuclear factor 6 regulates pancreatic endocrine cell differentiation and controls expression of the proendocrine gene ngn3, Mol. Cell. Biol., 2000, vol. 20, no. 12, pp. 4445–4454.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Maestro, M.A., Boj, S.F., Luco, R.F., Pierreux, C.E., Cabedo, J., Servitja, J.M., et al., Hnf6 and Tcf2 (MODY5) are linked in a gene network operating in a precursor cell domain of the embryonic pancreas, Hum. Mol. Genet., 2003, vol. 12, no. 24, pp. 3307–3314.

    Article  CAS  PubMed  Google Scholar 

  57. Oliver-Krasinski, J.M., Kasner, M.T., Yang, J., Crutchlow, M.F., Rustg, A.K., Kaestne, K.H., et al., The diabetes gene Pdx1 regulates the transcriptional network of pancreatic endocrine progenitor cells in mice, J. Clin. Invest., 2009, vol. 119, no. 7, pp. 1888–1898.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Gouzi, M., Kim, Y.H., Katsumoto, K., Johansson, K., and Grapin-Botton, A., Neurogenin3 initiates stepwise delamination of differentiating endocrine cells during pancreas development, Dev. Dyn., 2011, vol. 240, no. 3, pp. 589–604.

    Article  CAS  PubMed  Google Scholar 

  59. Bastidas-Ponce, A., Roscioni, S.S., Burtscher, I., Bader, E., Sterr, M., Bakhti, M., et al., Foxa2 and Pdx1 cooperatively regulate postnatal maturation of pancreatic β-cells, Mol. Metab., 2017, vol. 6, no. 6, pp. 524–534.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Cancer Facts and Figures 2018, Atlanta, GA: American Cancer Society, 2018, pp. 1–71.

  61. Kopp, J.L., von Figura, G., Mayes, E., Liu, F.F., Dubois, C.L., Morris, J.P., et al., Identification of Sox9-dependent acinar-to-ductal reprogramming as the principal mechanism for initiation of pancreatic ductal adenocarcinoma, Cancer Cell, 2012, vol. 22, no. 6, pp. 737–750.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Reichert, M., Blume, K., Kleger, A., Hartmann, D., and von Figura, G., Developmental pathways direct pancreatic cancer initiation from its cellular origin, Stem Cells Int., 2016, vol. 2016, p. 9298535.

    Article  PubMed  CAS  Google Scholar 

  63. Murtaugh, L.C. and Keefe, M.D., Regeneration and repair of the exocrine pancreas, Annu. Rev. Physiol., 2015, vol. 77, no. 1, pp. 229–249.

    Article  CAS  PubMed  Google Scholar 

  64. Guerra, C., Schuhmacher, A.J., Cañamero, M., Grippo, P.J., Verdaguer, L., Pérez-Galleg, L., et al., Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice, Cancer Cell, 2007, vol. 11, no. 3, pp. 291–302.

    Article  CAS  PubMed  Google Scholar 

  65. Morris, J.P. IV, Cano, D.A., Sekine, S., Wang, S.C., and Hebrok, M., β-Catenin blocks Kras-dependent reprogramming of acini into pancreatic cancer precursor lesions in mice, J. Clin. Invest., 2010, vol. 120, no. 2, pp. 508–520.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Jeannot, P., Callot, C., Baer, R., Duquesnes, N., Guerra, C., Guillermet-Guibert, J., et al., Loss of p27Kip1 promotes metaplasia in the pancreas via the regulation of Sox9 expression, Oncotarget, 2015, vol. 6, no. 34, pp. 35880–35892.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Pinho, A.V., Rooman, I., Reichert, M., De Medts, N., Bouwens, L., Rustgi, A.K., et al., Adult pancreatic acinar cells dedifferentiate to an embryonic progenitor phenotype with concomitant activation of a senescence program that is present in chronic pancreatitis, Gut, 2011, vol. 60, no. 7, pp. 958–966.

    Article  CAS  PubMed  Google Scholar 

  68. Prévot, P.P., Simion, A., Grimont, A., Colletti, M., Khalaileh, A., Van Den Steen, G., et al., Role of the ductal transcription factors HNF6 and Sox9 in pancreatic acinar-to-ductal metaplasia, Gut, 2012, vol. 61, no. 12, pp. 1723–1732.

    Article  PubMed  CAS  Google Scholar 

  69. Wei, D., Wang, L., Yan, Y., Jia, Z., Gagea, M., Li, Z., et al., KLF4 is essential for induction of cellular identity change and acinar-to-ductal reprogramming during early pancreatic carcinogenesis, Cancer Cell, 2016, vol. 29, no. 3, pp. 324–338.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. He, P., Yang, J.W., Yang, V.W., and Bialkowska, A.B., Krüppel-like factor 5, increased in pancreatic ductal adenocarcinoma, promotes proliferation, acinar-to-ductal metaplasia, pancreatic intraepithelial neoplasia, and tumor growth in mice, Gastroenterology, 2018, vol. 154, no. 5, pp. 1494–1508.

    Article  CAS  PubMed  Google Scholar 

  71. Miyatsuka, T., Kaneto, H., Shiraiwa, T., Matsuoka, T.A., Yamamoto, K., Kato, K., et al., Persistent expression of PDX-1 in the pancreas causes acinar-to-ductal metaplasia through Stat3 activation, Genes Dev., 2006, vol. 20, no. 11, pp. 1435–1440.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Vinogradova, T.V. and Sverdlov, E.D., PDX1: A unique pancreatic master regulator constantly changes its functions during embryonic development and progression of pancreatic cancer, Biochemistry (Moscow), 2017, vol. 82, no. 8, pp. 887–893.

    CAS  PubMed  Google Scholar 

  73. Di Magliano, M.P. and Logsdon, C.D., Roles for KRAS in pancreatic tumor development and progression, Gastroenterology, 2013, vol. 144, no. 6, pp. 1220–1229.

    Article  CAS  PubMed  Google Scholar 

  74. Zhou, H., Qin, Y., Ji, S., Ling, J., Fu, J., Zhuang, Z., et al., SOX9 activity is induced by oncogenic Kras to affect MDC1 and MCMs expression in pancreatic cancer, Oncogene, 2018, vol. 37, no. 7, pp. 912–923.

    Article  CAS  PubMed  Google Scholar 

  75. Navas, C., Hernández-Porras, I., Schuhmacher, A.J., Sibilia, M., Guerra, C., and Barbacid, M., EGF receptor signaling is essential for K-Ras oncogene-driven pancreatic ductal adenocarcinoma, Cancer Cell, 2012, vol. 22, no. 3, pp. 318–330.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Hessmann, E., Zhang, J.S., Chen, N.M., Hasselluhn, M., Liou, G.Y., Storz, P., et al., NFATc4 regulates Sox9 gene expression in acinar cell plasticity and pancreatic cancer initiation, Stem Cells Int., 2016, vol. 2016, p. 5272498.

    Article  PubMed  CAS  Google Scholar 

  77. Chen, N.M., Singh, G., Koenig, A., Liou, G.Y., Storz, P., Zhang, J.S., et al., NFATc1 links EGFR signaling to induction of sox9 transcription and acinar-ductal trans-differentiation in the pancreas, Gastroenterology, 2015, vol. 148, no. 5, pp. 1024–1034.

    Article  CAS  PubMed  Google Scholar 

  78. Grimont, A., Pinho, A.V., Cowley, M.J., Augereau, C., Mawson, A., Giry-Laterrière, M., et al., SOX9 regulates ERBB signaling in pancreatic cancer development, Gut, 2015, vol. 64, no. 11, pp. 1790–1799.

    Article  CAS  PubMed  Google Scholar 

  79. Reichert, M., Takano, S., Von Burstin, J., Kim, S.B., Lee, J.S., Ihida-Stansbury, K., et al., The Prrx1 homeodomain transcription factor plays a central role in pancreatic regeneration and carcinogenesis, Genes Dev., 2013, vol. 27, no. 3, pp. 288–300.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Gnoni, A., Licchetta, A., Scarpa, A., Azzariti, A., Brunetti, A.E., Simone, G., et al., Carcinogenesis of pancreatic adenocarcinoma. P. precursor lesions, Int. J. Mol. Sci., 2013, vol. 14, no. 10, pp. 19731–19762.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. von Figura, G., Fukuda, A., Roy, N., Liku, M.E., Morris, J.P. IV, Kim, G.E., et al., The chromatin regulator Brg1 suppresses formation of intraductal papillary mucinous neoplasm and pancreatic ductal adenocarcinoma, Nat. Cell Biol., 2014, vol. 16, no. 3, pp. 255–267.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Roy, N., Malik, S., Villanueva, K.E., Urano, A., Lu, X., Von Figura, G., et al., Brg1 promotes both tumor-suppressive and oncogenic activities at distinct stages of pancreatic cancer formation, Genes Dev., 2015, vol. 29, no. 6, pp. 658–671.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Wei, D., Kanai, M., Jia, Z., Le, X., and Xie, K., Kruppel-like factor 4 induces p27Kip1 expression in and suppresses the growth and metastasis of human pancreatic cancer cells, Cancer Res., 2008, vol. 68, no. 12, pp. 4631–4639.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Benayoun, B.A. and Veitia, R.A., A post-translational modification code for transcription factors: sorting through a sea of signals, Trends Cell Biol., 2009, vol. 19, no. 5, pp. 189–197.

    Article  CAS  PubMed  Google Scholar 

  85. Ji, Z. and Sharrocks, A.D., Changing partners: transcription factors form different complexes on and off chromatin, Mol. Syst. Biol., 2015, vol. 11, no. 1, p. 782.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Taneri, B., Snyder, B., Novoradovsky, A., and Gaasterland, T., Alternative splicing of mouse transcription factors affects their DNA-binding domain architecture and is tissue specific, Genome Biol., 2004, vol. 5, no. 10, p. R75.

    Article  PubMed  PubMed Central  Google Scholar 

  87. Bailey, P., Chang, D.K., Nones, K., Johns, A.L., Patch, A.M., Gingras, M.C., et al., Genomic analyses identify molecular subtypes of pancreatic cancer, Nature, 2016, vol. 531, no. 7592, pp. 47–52.

    Article  CAS  PubMed  Google Scholar 

  88. Roy, N., Takeuchi, K.K., Ruggeri, J.M., Bailey, P., Chang, D., Li, J., et al., PDX1 dynamically regulates pancreatic ductal adenocarcinoma initiation and maintenance, Genes Dev., 2016, vol. 30, no. 24, pp. 2669–2683.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Wu, J., Liu, S., Yu, J., Zhou, G., Rao, D., Jay, C.M., et al., Vertically integrated translational studies of PDX1 as a therapeutic target for pancreatic cancer via a novel bifunctional RNAi platform, Cancer Gene Ther., 2014, vol. 21, no. 2, pp. 48–53.

    Article  PubMed  CAS  Google Scholar 

  90. Song, Y., Washington, M.K., and Crawford, H.C., Loss of FOXA1/2 is essential for the epithelial-to-mesenchymal transition in pancreatic cancer, Cancer Res., 2010 vol. 70, no. 5, pp. 2115–2125.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Russell, R., Perkhofer, L., Liebau, S., Lin, Q., Lechel, A., Feld, F.M., et al., Loss of ATM accelerates pancreatic cancer formation and epithelial-mesenchymal transition, Nat. Commun., 2015, vol. 6, p. 7677.

    Article  CAS  PubMed  Google Scholar 

  92. Huang, J. and Guo, L., Knockdown of SOX9 inhibits the proliferation, invasion, and EMT in thyroid cancer cells, Oncol. Res., 2017, vol. 25, no. 2, pp. 167–176.

    Article  PubMed  PubMed Central  Google Scholar 

  93. Francis, J.C., Capper, A., Ning, J., Knight, E., de Bono, J., and Swain, A., SOX9 is a driver of aggressive prostate cancer by promoting invasion, cell fate and cytoskeleton alterations and epithelial to mesenchymal transition, Oncotarget, 2018, vol. 9, no. 7, pp. 7604–7615.

    Article  PubMed  PubMed Central  Google Scholar 

  94. Zhou, P., Li, B., Liu, F., Zhang, M., Wang, Q., Liu, Y., et al., The epithelial to mesenchymal transition (EMT) and cancer stem cells: Implication for treatment resistance in pancreatic cancer, Mol. Cancer, 2017, vol. 16, no. 1, p. 52.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Kawai, T., Yasuchika, K., Ishii, T., Miyauchi, Y., Kojima, H., Yamaoka, R., et al., SOX9 is a novel cancer stem cell marker surrogated by osteopontin in human hepatocellular carcinoma, Sci. Rep., 2016, vol. 6, p. 30489.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Guo, W., Keckesova, Z., Donaher, J.L., Shibue, T., Tischler, V., Reinhardt, F., et al., Slug and Sox9 cooperatively determine the mammary stem cell state, Cell, 2012, vol. 148, no. 5, pp. 1015–1028.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Higashihara, T., Yoshitomi, H., Nakata, Y., Kagawa, S., Takano, S., Shimizu, H., et al., Sex determining region y Box 9 induces chemoresistance in pancreatic cancer cells by induction of putative cancer stem cell characteristics and its high expression predicts poor prognosis, Pancreas, 2017, vol. 46, no. 10, pp. 1296–1304.

    Article  CAS  PubMed  Google Scholar 

  98. Morgunova, E. and Taipale, J., Structural perspective of cooperative transcription factor binding, Curr. Opin. Struct. Biol., 2017, vol. 47, pp. 1–8.

    Article  CAS  PubMed  Google Scholar 

  99. Girardot, M., Bayet, E., Maurin, J., Fort, P., Roux, P., and Raynaud, P., SOX9 has distinct regulatory roles in alternative splicing and transcription, Nucleic Acids Res., 2018, vol. 46, no. 17, pp. 9106–9118.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

This study was supported by the Russian Science Foundation, project no. 14-50-00131.

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Authors and Affiliations

  1. Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, 117997, Moscow, Russia

    S. S. Bulanenkova, E. V. Snezhkov & S. B. Akopov

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  1. S. S. Bulanenkova
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  2. E. V. Snezhkov
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  3. S. B. Akopov
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Correspondence to S. S. Bulanenkova.

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Translated by M. Novikova

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Bulanenkova, S.S., Snezhkov, E.V. & Akopov, S.B. SOX9 as One of the Central Units of Regulation Axis of Pancreas Embryogenesis and Cancer Progression. Mol. Genet. Microbiol. Virol. 34, 159–169 (2019). https://doi.org/10.3103/S0891416819030030

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  • DOI: https://doi.org/10.3103/S0891416819030030

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