User menu

Accès à distance ? S'identifier sur le proxy UCLouvain

A model for the epigenetic switch linking inflammation to cell transformation: deterministic and stochastic approaches

Primary tabs

download
  • Open access
  • PDF
  • 7.09 M
Gérard, Claude Gonze, Didier Lemaigre, Frédéric [UCL] Novák, Béla

Recently, a molecular pathway linking inflammation to cell transformation has been discovered. This molecular pathway rests on a positive inflammatory feedback loop between NF-κB, Lin28, Let-7 microRNA and IL6, which leads to an epigenetic switch allowing cell transformation. A transient activation of an inflammatory signal, mediated by the oncoprotein Src, activates NF-κB, which elicits the expression of Lin28. Lin28 decreases the expression of Let-7 microRNA, which results in higher level of IL6 than achieved directly by NF-κB. In turn, IL6 can promote NF-κB activation. Finally, IL6 also elicits the synthesis of STAT3, which is a crucial activator for cell transformation. Here, we propose a computational model to account for the dynamical behavior of this positive inflammatory feedback loop. By means of a deterministic model, we show that an irreversible bistable switch between a transformed and a non-transformed state of the cell is at the core of the dynamical behavior of the positive feedback loop linking inflammation to cell transformation. The model indicates that inhibitors (tumor suppressors) or activators (oncogenes) of this positive feedback loop regulate the occurrence of the epigenetic switch by modulating the threshold of inflammatory signal (Src) needed to promote cell transformation. Both stochastic simulations and deterministic simulations of a heterogeneous cell population suggest that random fluctuations (due to molecular noise or cell-to-cell variability) are able to trigger cell transformation. Moreover, the model predicts that oncogenes/tumor suppressors respectively decrease/increase the robustness of the non-transformed state of the cell towards random fluctuations. Finally, the model accounts for the potential effect of competing endogenous RNAs, ceRNAs, on the dynamics of the epigenetic switch. Depending on their microRNA targets, the model predicts that ceRNAs could act as oncogenes or tumor suppressors by regulating the occurrence of cell transformation.

Document type Article de périodique (Journal article) – Article de recherche
Access type Accès libre
Publication date 2014
Language Anglais
Journal information "PLoS Computational Biology" - Vol. 10, no. 1, p. e1003455 (2014)
Peer reviewed yes
Publisher Public Library of Science
issn 1553-734X
e-issn 1553-7358
Publication status Publié
Affiliation UCL - SSS/DDUV - Institut de Duve
Links
  1. Hanahan Douglas, Weinberg Robert A., Hallmarks of Cancer: The Next Generation, 10.1016/j.cell.2011.02.013
  2. Chiba Tsutomu, Marusawa Hiroyuki, Ushijima Toshikazu, Inflammation-Associated Cancer Development in Digestive Organs: Mechanisms and Roles for Genetic and Epigenetic Modulation, 10.1053/j.gastro.2012.07.009
  3. Sun Beicheng, Karin Michael, Obesity, inflammation, and liver cancer, 10.1016/j.jhep.2011.09.020
  4. Martin Marion, Herceg Zdenko, From hepatitis to hepatocellular carcinoma: a proposed model for cross-talk between inflammation and epigenetic mechanisms, 10.1186/gm307
  5. Balkwill Fran, Mantovani Alberto, Inflammation and cancer: back to Virchow?, 10.1016/s0140-6736(00)04046-0
  6. Balkwill Fran, Coussens Lisa M., Cancer: An inflammatory link, 10.1038/431405a
  7. Iliopoulos Dimitrios, Hirsch Heather A., Struhl Kevin, An Epigenetic Switch Involving NF-κB, Lin28, Let-7 MicroRNA, and IL6 Links Inflammation to Cell Transformation, 10.1016/j.cell.2009.10.014
  8. Carthew Richard W., Sontheimer Erik J., Origins and Mechanisms of miRNAs and siRNAs, 10.1016/j.cell.2009.01.035
  9. Mukherji Shankar, Ebert Margaret S, Zheng Grace X Y, Tsang John S, Sharp Phillip A, van Oudenaarden Alexander, MicroRNAs can generate thresholds in target gene expression, 10.1038/ng.905
  10. Selbach Matthias, Schwanhäusser Björn, Thierfelder Nadine, Fang Zhuo, Khanin Raya, Rajewsky Nikolaus, Widespread changes in protein synthesis induced by microRNAs, 10.1038/nature07228
  11. Tsang John, Zhu Jun, van Oudenaarden Alexander, MicroRNA-Mediated Feedback and Feedforward Loops Are Recurrent Network Motifs in Mammals, 10.1016/j.molcel.2007.05.018
  12. Herranz H., Cohen S. M., MicroRNAs and gene regulatory networks: managing the impact of noise in biological systems, 10.1101/gad.1937010
  13. Osella Matteo, Bosia Carla, Corá Davide, Caselle Michele, The Role of Incoherent MicroRNA-Mediated Feedforward Loops in Noise Buffering, 10.1371/journal.pcbi.1001101
  14. Ebert Margaret S., Sharp Phillip A., Roles for MicroRNAs in Conferring Robustness to Biological Processes, 10.1016/j.cell.2012.04.005
  15. Laudadio Ilaria, Manfroid Isabelle, Achouri Younes, Schmidt Dominic, Wilson Michael D., Cordi Sabine, Thorrez Lieven, Knoops Laurent, Jacquemin Patrick, Schuit Frans, Pierreux Christophe E., Odom Duncan T., Peers Bernard, Lemaigre Frédéric P., A Feedback Loop Between the Liver-Enriched Transcription Factor Network and Mir-122 Controls Hepatocyte Differentiation, 10.1053/j.gastro.2011.09.001
  16. Barh D., Malhotra R., Ravi B., Sindhurani P., Microrna let-7: an emerging next-generation cancer therapeutic, 10.3747/co.v17i1.356
  17. Kumar M. S., Erkeland S. J., Pester R. E., Chen C. Y., Ebert M. S., Sharp P. A., Jacks T., Suppression of non-small cell lung tumor development by the let-7 microRNA family, 10.1073/pnas.0712321105
  18. Peter Marcus E., Let-7 and miR-200 microRNAs: Guardians against pluripotency and cancer progression, 10.4161/cc.8.6.7907
  19. Ventura Andrea, Jacks Tyler, MicroRNAs and Cancer: Short RNAs Go a Long Way, 10.1016/j.cell.2009.02.005
  20. Iliopoulos Dimitrios, Jaeger Savina A., Hirsch Heather A., Bulyk Martha L., Struhl Kevin, STAT3 Activation of miR-21 and miR-181b-1 via PTEN and CYLD Are Part of the Epigenetic Switch Linking Inflammation to Cancer, 10.1016/j.molcel.2010.07.023
  21. Mathews Lesley A., Crea Francesco, Farrar W.L., Epigenetic gene regulation in stem cells and correlation to cancer, 10.1016/j.diff.2009.04.002
  22. Muñoz Purificación, Iliou Maria S., Esteller Manel, Epigenetic alterations involved in cancer stem cell reprogramming, 10.1016/j.molonc.2012.10.006
  23. Hatziapostolou Maria, Iliopoulos Dimitrios, Epigenetic aberrations during oncogenesis, 10.1007/s00018-010-0624-z
  24. A Vincent, Biochim Biophys Acta, 1826, 83 (2012)
  25. Goldberg Aaron D., Allis C. David, Bernstein Emily, Epigenetics: A Landscape Takes Shape, 10.1016/j.cell.2007.02.006
  26. Poliseno Laura, Salmena Leonardo, Zhang Jiangwen, Carver Brett, Haveman William J., Pandolfi Pier Paolo, A coding-independent function of gene and pseudogene mRNAs regulates tumour biology, 10.1038/nature09144
  27. Salmena Leonardo, Poliseno Laura, Tay Yvonne, Kats Lev, Pandolfi Pier Paolo, A ceRNA Hypothesis: The Rosetta Stone of a Hidden RNA Language?, 10.1016/j.cell.2011.07.014
  28. Tay Yvonne, Kats Lev, Salmena Leonardo, Weiss Dror, Tan Shen Mynn, Ala Ugo, Karreth Florian, Poliseno Laura, Provero Paolo, Di Cunto Ferdinando, Lieberman Judy, Rigoutsos Isidore, Pandolfi Pier Paolo, Coding-Independent Regulation of the Tumor Suppressor PTEN by Competing Endogenous mRNAs, 10.1016/j.cell.2011.09.029
  29. Poliseno L., Pseudogenes: Newly Discovered Players in Human Cancer, 10.1126/scisignal.2002858
  30. Gao Bin, Wang Hua, Lafdil Fouad, Feng Dechun, STAT proteins – Key regulators of anti-viral responses, inflammation, and tumorigenesis in the liver, 10.1016/j.jhep.2012.01.029
  31. Loffler D., Brocke-Heidrich K., Pfeifer G., Stocsits C., Hackermuller J., Kretzschmar A. K., Burger R., Gramatzki M., Blumert C., Bauer K., Cvijic H., Ullmann A. K., Stadler P. F., Horn F., Interleukin-6 dependent survival of multiple myeloma cells involves the Stat3-mediated induction of microRNA-21 through a highly conserved enhancer, 10.1182/blood-2007-03-081133
  32. Niu Guilian, Wright Kenneth L, Huang Mei, Song Lanxi, Haura Eric, Turkson James, Zhang Shumin, Wang Tianhong, Sinibaldi Dominic, Coppola Domenico, Heller Richard, Ellis Lee M, Karras James, Bromberg Jacqueline, Pardoll Drew, Jove Richard, Yu Hua, Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis, 10.1038/sj.onc.1205260
  33. Yu Hua, Pardoll Drew, Jove Richard, STATs in cancer inflammation and immunity: a leading role for STAT3, 10.1038/nrc2734
  34. Frank David A., STAT3 as a central mediator of neoplastic cellular transformation, 10.1016/j.canlet.2006.10.017
  35. Bromberg Jacqueline F, Wrzeszczynska Melissa H, Devgan Geeta, Zhao Yanxiang, Pestell Richard G, Albanese Chris, Darnell James E, Stat3 as an Oncogene, 10.1016/s0092-8674(00)81959-5
  36. García Mariana G., Alaniz Laura D., Cordo Russo Rosalía I., Alvarez Elida, Hajos Silvia E., PI3K/Akt inhibition modulates multidrug resistance and activates NF-κB in murine lymphoma cell lines, 10.1016/j.leukres.2008.06.010
  37. Guigon C J, Zhao L, Willingham M C, Cheng S-Y, PTEN deficiency accelerates tumour progression in a mouse model of thyroid cancer, 10.1038/onc.2008.407
  38. Hoffmann A., The Ikappa B-NF-kappa B Signaling Module: Temporal Control and Selective Gene Activation, 10.1126/science.1071914
  39. Kearns Jeffrey D., Basak Soumen, Werner Shannon L., Huang Christine S., Hoffmann Alexander, IκBε provides negative feedback to control NF-κB oscillations, signaling dynamics, and inflammatory gene expression, 10.1083/jcb.200510155
  40. Ashall L., Horton C. A., Nelson D. E., Paszek P., Harper C. V., Sillitoe K., Ryan S., Spiller D. G., Unitt J. F., Broomhead D. S., Kell D. B., Rand D. A., See V., White M. R. H., Pulsatile Stimulation Determines Timing and Specificity of NF- B-Dependent Transcription, 10.1126/science.1164860
  41. Rao Ping, Hayden Mathew S., Long Meixiao, Scott Martin L., West A. Philip, Zhang Dekai, Oeckinghaus Andrea, Lynch Candace, Hoffmann Alexander, Baltimore David, Ghosh Sankar, IκBβ acts to inhibit and activate gene expression during the inflammatory response, 10.1038/nature09283
  42. Basak Soumen, Behar Marcelo, Hoffmann Alexander, Lessons from mathematically modeling the NF-κB pathway : Mathematical modeling the NF-κB pathway, 10.1111/j.1600-065x.2011.01092.x
  43. Shields D J, Murphy E A, Desgrosellier J S, Mielgo A, Lau S K M, Barnes L A, Lesperance J, Huang M, Schmedt C, Tarin D, Lowy A M, Cheresh D A, Oncogenic Ras/Src cooperativity in pancreatic neoplasia, 10.1038/onc.2010.589
  44. Feinberg A. P., Irizarry R. A., Stochastic epigenetic variation as a driving force of development, evolutionary adaptation, and disease, 10.1073/pnas.0906183107
  45. Tay Savaş, Hughey Jacob J., Lee Timothy K., Lipniacki Tomasz, Quake Stephen R., Covert Markus W., Single-cell NF-κB dynamics reveal digital activation and analogue information processing, 10.1038/nature09145
  46. Turner D. A., Paszek P., Woodcock D. J., Nelson D. E., Horton C. A., Wang Y., Spiller D. G., Rand D. A., White M. R. H., Harper C. V., Physiological levels of TNF  stimulation induce stochastic dynamics of NF- B responses in single living cells, 10.1242/jcs.069641
  47. Garcia-Cao Isabel, Song Min Sup, Hobbs Robin M., Laurent Gaelle, Giorgi Carlotta, de Boer Vincent C.J., Anastasiou Dimitrios, Ito Keisuke, Sasaki Atsuo T., Rameh Lucia, Carracedo Arkaitz, Vander Heiden Matthew G., Cantley Lewis C., Pinton Paolo, Haigis Marcia C., Pandolfi Pier Paolo, Systemic Elevation of PTEN Induces a Tumor-Suppressive Metabolic State, 10.1016/j.cell.2012.02.030
  48. Giovannetti E., Funel N., Peters G. J., Del Chiaro M., Erozenci L. A., Vasile E., Leon L. G., Pollina L. E., Groen A., Falcone A., Danesi R., Campani D., Verheul H. M., Boggi U., MicroRNA-21 in Pancreatic Cancer: Correlation with Clinical Outcome and Pharmacologic Aspects Underlying Its Role in the Modulation of Gemcitabine Activity, 10.1158/0008-5472.can-09-4467
  49. Ebert Margaret S., Sharp Phillip A., Emerging Roles for Natural MicroRNA Sponges, 10.1016/j.cub.2010.08.052
  50. Karreth Florian A., Tay Yvonne, Perna Daniele, Ala Ugo, Tan Shen Mynn, Rust Alistair G., DeNicola Gina, Webster Kaitlyn A., Weiss Dror, Perez-Mancera Pedro A., Krauthammer Michael, Halaban Ruth, Provero Paolo, Adams David J., Tuveson David A., Pandolfi Pier Paolo, In Vivo Identification of Tumor- Suppressive PTEN ceRNAs in an Oncogenic BRAF-Induced Mouse Model of Melanoma, 10.1016/j.cell.2011.09.032
  51. Kaufmann Benjamin B, Yang Qiong, Mettetal Jerome T, van Oudenaarden Alexander, Heritable Stochastic Switching Revealed by Single-Cell Genealogy, 10.1371/journal.pbio.0050239
  52. Raj Arjun, van Oudenaarden Alexander, Nature, Nurture, or Chance: Stochastic Gene Expression and Its Consequences, 10.1016/j.cell.2008.09.050
  53. Acar Murat, Becskei Attila, van Oudenaarden Alexander, Enhancement of cellular memory by reducing stochastic transitions, 10.1038/nature03524
  54. Davis Craig B., Killeen Nigel, Crooks M.E.Casey, Raulet David, Littman Dan R., Evidence for a stochastic mechanism in the differentiation of mature subsets of T lymphocytes, 10.1016/0092-8674(93)90226-g
  55. Weinberger Leor S., Burnett John C., Toettcher Jared E., Arkin Adam P., Schaffer David V., Stochastic Gene Expression in a Lentiviral Positive-Feedback Loop: HIV-1 Tat Fluctuations Drive Phenotypic Diversity, 10.1016/j.cell.2005.06.006
  56. Bouchard Louise, Lamarre Louis, Tremblay Patrick J., Jolicoeur Paul, Stochastic appearance of mammary tumors in transgenic mice carrying the MMTV/c-neu oncogene, 10.1016/0092-8674(89)90331-0
  57. Dingli David, Traulsen Arne, Pacheco Jorge M., Stochastic Dynamics of Hematopoietic Tumor Stem Cells, 10.4161/cc.6.4.3853
  58. Frank Steven A., Rosner Marsha Rich, Nonheritable Cellular Variability Accelerates the Evolutionary Processes of Cancer, 10.1371/journal.pbio.1001296
  59. Gupta Piyush B., Fillmore Christine M., Jiang Guozhi, Shapira Sagi D., Tao Kai, Kuperwasser Charlotte, Lander Eric S., Stochastic State Transitions Give Rise to Phenotypic Equilibrium in Populations of Cancer Cells, 10.1016/j.cell.2011.07.026
  60. Hatziapostolou Maria, Polytarchou Christos, Aggelidou Eleni, Drakaki Alexandra, Poultsides George A., Jaeger Savina A., Ogata Hisanobu, Karin Michael, Struhl Kevin, Hadzopoulou-Cladaras Margarita, Iliopoulos Dimitrios, An HNF4α-miRNA Inflammatory Feedback Circuit Regulates Hepatocellular Oncogenesis, 10.1016/j.cell.2011.10.043
  61. Cesana Marcella, Cacchiarelli Davide, Legnini Ivano, Santini Tiziana, Sthandier Olga, Chinappi Mauro, Tramontano Anna, Bozzoni Irene, A Long Noncoding RNA Controls Muscle Differentiation by Functioning as a Competing Endogenous RNA, 10.1016/j.cell.2011.09.028
  62. Ala U., Karreth F. A., Bosia C., Pagnani A., Taulli R., Leopold V., Tay Y., Provero P., Zecchina R., Pandolfi P. P., Integrated transcriptional and competitive endogenous RNA networks are cross-regulated in permissive molecular environments, 10.1073/pnas.1222509110
  63. Gillespie Daniel T., Exact stochastic simulation of coupled chemical reactions, 10.1021/j100540a008
  64. Goldbeter A., Koshland D. E., An amplified sensitivity arising from covalent modification in biological systems., 10.1073/pnas.78.11.6840
  65. Wagner A., Circuit topology and the evolution of robustness in two-gene circadian oscillators, 10.1073/pnas.0501094102
  66. Zhang Zhuo, Qin Yong-Wen, Brewer Gary, Jing Qing, MicroRNA degradation and turnover: regulating the regulators : MicroRNA degradation and turnover, 10.1002/wrna.1114
  67. Schwanhäusser Björn, Busse Dorothea, Li Na, Dittmar Gunnar, Schuchhardt Johannes, Wolf Jana, Chen Wei, Selbach Matthias, Global quantification of mammalian gene expression control, 10.1038/nature10098
Bibliographic reference Gérard, Claude ; Gonze, Didier ; Lemaigre, Frédéric ; Novák, Béla. A model for the epigenetic switch linking inflammation to cell transformation: deterministic and stochastic approaches. In: PLoS Computational Biology, Vol. 10, no. 1, p. e1003455 (2014)
Permanent URL http://hdl.handle.net/2078.1/140531