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Biochemistry (Moscow)

, Volume 82, Issue 8, pp 887–893 | Cite as

PDX1: A unique pancreatic master regulator constantly changes its functions during embryonic development and progression of pancreatic cancer

  • T. V. VinogradovaEmail author
  • E. D. Sverdlov
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Abstract

Multifunctional activity of the PDX1 gene product is reviewed. The PDX1 protein is unique in that being expressed exclusively in the pancreas it exhibits various functional activities in this organ both during embryonic development and during induction and progression of pancreatic cancer. Hence, PDX1 belongs to the family of master regulators with multiple and often antagonistic functions.

Keywords

dedifferentiation transdifferentiation transcription factors suppressor acinar cell duct cell 

Abbreviations

EMT

epithelial–mesenchymal transition

PDAC

pancreatic ductal adenocarcinoma

PDX1

pancreatic and duodenal homeobox 1

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References

  1. 1.
    Shih, H. P., Seymour, P. A., Patel, N. A., Xie, R., Wang, A., Liu, P. P., Yeo, G. W., Magnuson, M. A., and Sander, M. (2015) A gene regulatory network cooperatively controlled by Pdx1 and Sox9 governs lineage allocation of foregut progenitor cells, Cell Rep., 13, 326–336.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Shih, H. P., Wang, A., and Sander, M. (2013) Pancreas organogenesis: from lineage determination to morphogenesis, Annu. Rev. Cell. Dev. Biol., 29, 81–105.CrossRefPubMedGoogle Scholar
  3. 3.
    Teo, A. K., Tsuneyoshi, N., Hoon, S., Tan, E. K., Stanton, L. W., Wright, C. V., and Dunn, N. R. (2015) PDX1 binds and represses hepatic genes to ensure robust pancreatic commitment in differentiating human embryonic stem cells, Stem Cell Rep., 4, 578–590.CrossRefGoogle Scholar
  4. 4.
    Kondratyeva, L. G., Vinogradova, T. V., Chernov, I. P., and Sverdlov, E. D. (2015) Master transcription regulators specifying cell-lineage fate in development as possible therapeutic targets in oncology, Russ. J. Genet., 51, 1049–1059.CrossRefGoogle Scholar
  5. 5.
    Roy, N., and Hebrok, M. (2015) Regulation of cellular identity in cancer, Dev. Cell, 35, 674–684.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Wang, A., Yue, F., Li, Y., Xie, R., Harper, T., Patel, N. A., Muth, K., Palmer, J., Qiu, Y., Wang, J., Lam, D. K., Raum, J. C., Stoffers, D. A., Ren, B., and Sander, M. (2015) Epigenetic priming of enhancers predicts developmental competence of hESC-derived endodermal lineage intermediates, Cell. Stem. Cell, 16, 386–399.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Stanger, B. Z., and Hebrok, M. (2013) Control of cell identity in pancreas development and regeneration, Gastroenterology, 144, 1170–1179.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Puri, S., Folias, A. E., and Hebrok, M. (2015) Plasticity and dedifferentiation within the pancreas: development, homeostasis, and disease, Cell Stem Cell, 16, 18–31.CrossRefPubMedGoogle Scholar
  9. 9.
    Thompson, N., Gesina, E., Scheinert, P., Bucher, P., and Grapin-Botton, A. (2012) RNA profiling and chromatin immunoprecipitation-sequencing reveal that PTF1a stabilizes pancreas progenitor identity via the control of MNX1/HLXB9 and a network of other transcription factors, Mol. Cell. Biol., 32, 1189–1199.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Hoang, C. Q., Hale, M. A., Azevedo-Pouly, A. C., Elsasser, H. P., Deering, T. G., Willet, S. G., Pan, F. C., Magnuson, M. A., Wright, C. V., Swift, G. H., and MacDonald, R. J. (2016) Transcriptional maintenance of pancreatic acinar identity, differentiation, and homeostasis by PTF1A, Mol. Cell. Biol., 36, 3033–3047.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Dassaye, R., Naidoo, S., and Cerf, M. E. (2016) Transcription factor regulation of pancreatic organogenesis, differentiation and maturation, Islets, 8, 13–34.CrossRefPubMedGoogle Scholar
  12. 12.
    Larsen, H. L., and Grapin-Botton, A. (2017) The molecular and morphogenetic basis of pancreas organogenesis, Semin. Cell Dev. Biol., pii: S1084-9521(17)30007-1.Google Scholar
  13. 13.
    Cano, D. A., Soria, B., Martin, F., and Rojas, A. (2014) Transcriptional control of mammalian pancreas organogenesis, Cell. Mol. Life Sci., 71, 2383–2402.CrossRefPubMedGoogle Scholar
  14. 14.
    Spaeth, J. M., Walker, E. M., and Stein, R. (2016) Impact of Pdx1-associated chromatin modifiers on islet beta-cells, Diabetes Obes. Metab., 18, 123–127.CrossRefPubMedGoogle Scholar
  15. 15.
    Ischenko, I., Petrenko, O., and Hayman, M. J. (2014) Analysis of the tumor-initiating and metastatic capacity of PDX1-positive cells from the adult pancreas, Proc. Natl. Acad. Sci. USA, 111, 3466–3471.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Willmann, S. J., Mueller, N. S., Engert, S., Sterr, M., Burtscher, I., Raducanu, A., Irmler, M., Beckers, J., Sass, S., Theis, F. J., and Lickert, H. (2016) The global gene expression profile of the secondary transition during pancreatic development, Mech. Dev., 139, 51–64.CrossRefPubMedGoogle Scholar
  17. 17.
    Kuzmich, A. I., Tyulkina, D. V., Vinogradova, T. V., and Sverdlov, E. D. (2015) Pioneer transcription factors in normal development and cancerogenesis, Russ. J. Bioorg. Chem., 41, 570–577.CrossRefGoogle Scholar
  18. 18.
    Zinovyeva, M. V., Kuzmich, A. I., Monastyrskaya, G. S., and Sverdlov, E. D. (2016) The role of FOXA subfamily factors in embryonic development and cancerogenesis of the pancreas, Mol. Genet. Microbiol. Virol., 31, 135–142.CrossRefGoogle Scholar
  19. 19.
    Yin, C. (2016) Molecular mechanisms of Sox transcription factors during the development of liver, bile duct, and pancreas, Semin. Cell Dev. Biol., doi: 10.1016/j.semcdb.2016.08.015.Google Scholar
  20. 20.
    Hidalgo, M. (2010) Pancreatic cancer, N. Engl. J. Med., 362, 1605–1617.CrossRefPubMedGoogle Scholar
  21. 21.
    Fokas, E., O’Neill, E., Gordon-Weeks, A., Mukherjee, S., McKenna, W. G., and Muschel, R. J. (2015) Pancreatic ductal adenocarcinoma: from genetics to biology to radiobiology to oncoimmunology and all the way back to the clinic, Biochim. Biophys. Acta, 1855, 61–82.PubMedGoogle Scholar
  22. 22.
    Ying, H., Dey, P., Yao, W., Kimmelman, A. C., Draetta, G. F., Maitra, A., and DePinho, R. A. (2016) Genetics and biology of pancreatic ductal adenocarcinoma, Genes Dev., 30, 355–385.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Gu, D., Schlotman, K. E., and Xie, J. (2016) Deciphering the role of hedgehog signaling in pancreatic cancer, J. Biomed. Res., 30, 353–360.PubMedPubMedCentralGoogle Scholar
  24. 24.
    Bardeesy, N., Aguirre, A. J., Chu, G. C., Cheng, K. H., Lopez, L. V., Hezel, A. F., Feng, B., Brennan, C., Weissleder, R., Mahmood, U., Hanahan, D., Redston, M. S., Chin, L., and Depinho, R. A. (2006) Both p16(Ink4a) and the p19(Arf)-p53 pathway constrain progression of pancreatic adenocarcinoma in the mouse, Proc. Natl. Acad. Sci. USA, 103, 5947–5952.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Gidekel Friedlander, S. Y., Chu, G. C., Snyder, E. L., Girnius, N., Dibelius, G., Crowley, D., Vasile, E., DePinho, R. A., and Jacks, T. (2009) Context-dependent transformation of adult pancreatic cells by oncogenic K-Ras, Cancer Cell, 16, 379–389.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Tanaka, S. (2015) Molecular pathogenesis and targeted therapy of pancreatic cancer, Ann. Surg. Oncol., 23, 197–205.CrossRefGoogle Scholar
  27. 27.
    Norris, A. L., Roberts, N. J., Jones, S., Wheelan, S. J., Papadopoulos, N., Vogelstein, B., Kinzler, K. W., Hruban, R. H., Klein, A. P., and Eshleman, J. R. (2015) Familial and sporadic pancreatic cancer share the same molecular pathogenesis, Fam. Cancer, 14, 95–103.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Brosens, L. A., Hackeng, W. M., Offerhaus, G. J., Hruban, R. H., and Wood, L. D. (2015) Pancreatic adenocarcinoma pathology: changing “landscape”, J. Gastrointest. Oncol., 6, 358–374.PubMedPubMedCentralGoogle Scholar
  29. 29.
    Shah, M., and Allegrucci, C. (2013) Stem cell plasticity in development and cancer: epigenetic origin of cancer stem cells, Subcell. Biochem., 61, 545–565.CrossRefPubMedGoogle Scholar
  30. 30.
    Zinovyeva, M. V., Kostina, M. B., Monastyrskaya, G. S., Sass, A. V., Filyukova, O. B., Vinogradova, T. V., Kopantsev, E. P., and Sverdlov, E. D. (2015) Genetic markers for lung and esophagus common precursor cells in human development, Dokl. Biochem. Biophys., 463, 203–208.CrossRefPubMedGoogle Scholar
  31. 31.
    Roy, N., Takeuchi, K. K., Ruggeri, J. M., Bailey, P., Chang, D., Li, J., Leonhardt, L., Puri, S., Hoffman, M. T., Gao, S., Halbrook, C. J., Song, Y., Ljungman, M., Malik, S., Wright, C. V., Dawson, D. W., Biankin, A. V., Hebrok, M., and Crawford, H. C. (2016) PDX1 dynamically regulates pancreatic ductal adenocarcinoma initiation and maintenance, Genes Dev., 30, 2669–2683.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Blanpain, C. (2013) Tracing the cellular origin of cancer, Nat. Cell. Biol., 15, 126–134.CrossRefPubMedGoogle Scholar
  33. 33.
    Kopp, J. L., von Figura, G., Mayes, E., Liu, F. F., Dubois, C. L., Morris, J. P., Pan, F. C., Akiyama, H., Wright, C. V., Jensen, K., Hebrok, M., and Sander, M. (2012) Identification of Sox9-dependent acinar-to-ductal reprogramming as the principal mechanism for initiation of pancreatic ductal adenocarcinoma, Cancer Cell, 22, 737–750.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Wei, D., Wang, L., Yan, Y., Jia, Z., Gagea, M., Li, Z., Zuo, X., Kong, X., Huang, S., and Xie, K. (2016) KLF4 is essential for induction of cellular identity change and acinar-toductal reprogramming during early pancreatic carcinogenesis, Cancer Cell, 29, 324–338.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Diaferia, G. R., Balestrieri, C., Prosperini, E., Nicoli, P., Spaggiari, P., Zerbi, A., and Natoli, G. (2016) Dissection of transcriptional and cis-regulatory control of differentiation in human pancreatic cancer, EMBO J., 35, 595–617.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Park, J., Hong, S., Klimstra, D., Goggins, M., Maitra, A., and Hruban, R. (2011) Pdx1 expression in pancreatic precursor lesions and neoplasms, Appl. Immunohistochem. Mol. Morphol., 19, 444–449.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Miyazaki, S., Tashiro, F., and Miyazaki, J. (2016) Transgenic expression of a single transcription factor Pdx1 induces transdifferentiation of pancreatic acinar cells to endocrine cells in adult mice, PLoS One, 11, e0161190.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Stepanenko, A. A., Vassetzky, Y. S., and Kavsan, V. M. (2013) Antagonistic functional duality of cancer genes, Gene, 529, 199–207.CrossRefPubMedGoogle Scholar
  39. 39.
    Gao, X., Wang, X., Cai, K., Wang, W., Ju, Q., Yang, X., Wang, H., and Wu, H. (2016) MicroRNA-127 is a tumor suppressor in human esophageal squamous cell carcinoma through the regulation of oncogene FMNL3, Eur. J. Pharmacol., 791, 603–610.CrossRefPubMedGoogle Scholar
  40. 40.
    Wurm, A. A., Tenen, D. G., and Behre, G. (2017) The Janus-faced nature of miR-22 in hematopoiesis: is it an oncogenic tumor suppressor or rather a tumor-suppressive oncogene? PLoS Genet., 13, e1006505.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    David, C. J., Huang, Y. H., Chen, M., Su, J., Zou, Y., Bardeesy, N., Iacobuzio-Donahue, C. A., and Massague, J. (2016) TGF-beta tumor suppression through a lethal EMT, Cell, 164, 1015–1030.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    He, S., and Liang, C. (2015) Frameshift mutation of UVRAG: switching a tumor suppressor to an oncogene in colorectal cancer, Autophagy, 11, 1939–1940.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Pickard, A., and McCance, D. J. (2015) IGF-binding protein 2–oncogene or tumor suppressor? Front. Endocrinol. (Lausanne), 6, 25.Google Scholar
  44. 44.
    Toker, A., and Chin, Y. R. (2014) Akt-ing up on SRPK1: oncogene or tumor suppressor? Mol. Cell, 54, 329–330.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Lobry, C., Oh, P., Mansour, M. R., Look, A. T., and Aifantis, I. (2014) Notch signaling: switching an oncogene to a tumor suppressor, Blood, 123, 2451–2459.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Silipo, M., Gautrey, H., Satam, S., Lennard, T., and Tyson-Capper, A. (2016) How is Herstatin, a tumor suppressor splice variant of the oncogene HER2, regulated? RNA Biol., 9, 1–8.Google Scholar
  47. 47.
    Beaurivage, C., Champagne, A., Tobelaim, W. S., Pomerleau, V., Menendez, A., and Saucier, C. (2016) SOCS1 in cancer: an oncogene and a tumor suppressor, Cytokine, 82, 87–94.CrossRefPubMedGoogle Scholar
  48. 48.
    Liang, J., and Mills, G. B. (2013) AMPK: a contextual oncogene or tumor suppressor? Cancer Res., 73, 2929–2935.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Zinovyeva, M. V., Kostina, M. B., Chernov, I. P., Kodratyeva, L. G., and Sverdlov, E. D. (2016) KLF5, a new player and new target in the permanently changing set of pancreatic cancer molecular drivers, Russ. J. Bioorg. Chem., 42, 606–611.CrossRefGoogle Scholar
  50. 50.
    Ji, Z., and Sharrocks, A. D. (2015) Changing partners: transcription factors form different complexes on and off chromatin, Mol. Syst. Biol., 11, 782.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Cusanovich, D. A., Pavlovic, B., Pritchard, J. K., and Gilad, Y. (2014) The functional consequences of variation in transcription factor binding, PLoS Genet., 10, e1004226.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Pleiades Publishing, Ltd. 2017

Authors and Affiliations

  1. 1.Shemyakin−Ovchinnikov Institute of Bioorganic ChemistryRussian Academy of SciencesMoscowRussia

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