Inference of Low and High-Grade Glioma Gene Regulatory Networks Delineates the Role of Rnd3 in Establishing Multiple Hallmarks of Cancer

English version České info

Gliomas are aggressive brain tumours that are invasive, heterogeneous, refractory to treatment and show poor survival rates. Surgical resection and chemotherapy can increase patient survival but ultimately the disease is fatal. Multiple grades of glioma exist, with lower grades associated to better prognosis. While the majority of high-grade gliomas occur de novo, it is common that low-grade gliomas progress to the more aggressive form known as glioblastoma. In this article, we have shown that by combining advanced network biology approaches with the right experimental models, we are able to reveal novel regulatory circuits controlling multiple hallmarks of glioma. Through analysis of multiple network models representing protein-protein interaction or gene co-expression data we have revealed a switch in the role of regulatory Rho GTPases between low and high-grade gliomas. Amongst these, we show that RND3 is up-regulated in glioblastomas and is a key regulator of tumour proliferation, migration and invasion. We confirm that expression and genomic copy number of RND3 are predictive of clinical outcome, suggesting that changes in the activity of this particular Rho GTPase could be an early event associated to transformation and tumour expansion.

Vyšlo v časopise: Inference of Low and High-Grade Glioma Gene Regulatory Networks Delineates the Role of Rnd3 in Establishing Multiple Hallmarks of Cancer. PLoS Genet 11(7): e32767. doi:10.1371/journal.pgen.1005325
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005325

Souhrn

Zdroje

1. Maher EA, Furnari FB, Bachoo RM, Rowitch DH, Louis DN, Cavenee WK, et al. Malignant glioma: genetics and biology of a grave matter. Genes Dev. 2001;15: 1311–33. doi: 10.1101/gad.891601 11390353

2. Claus EB, Black PM. Survival rates and patterns of care for patients diagnosed with supratentorial low-grade gliomas: data from the SEER program, 1973–2001. Cancer. 2006;106: 1358–63. doi: 10.1002/cncr.21733 16470608

3. Furnari FB, Fenton T, Bachoo RM, Mukasa A, Stommel JM, Stegh A, et al. Malignant astrocytic glioma: genetics, biology, and paths to treatment. Genes Dev. 2007;21: 2683–710. doi: 10.1101/gad.1596707 17974913

4. Ohgaki H, Dessen P, Jourde B, Horstmann S, Nishikawa T, Di Patre P-L, et al. Genetic pathways to glioblastoma: a population-based study. Cancer Res. 2004;64: 6892–9. doi: 10.1158/0008-5472.CAN-04-1337 15466178

5. Lee JC, Vivanco I, Beroukhim R, Huang JHY, Feng WL, DeBiasi RM, et al. Epidermal growth factor receptor activation in glioblastoma through novel missense mutations in the extracellular domain. PLoS Med. 2006;3: 2264–2273. doi: 10.1371/journal.pmed.0030485

6. Fan QW, Cheng C, Gustafson WC, Charron E, Zipper P, Wong R, et al. EGFR Phosphorylates Tumor-Derived EGFRvIII Driving STAT3/5 and Progression in Glioblastoma. Cancer Cell. 2013;24: 438–449. doi: 10.1016/j.ccr.2013.09.004 24135280

7. Clarke ID, Dirks PB. A human brain tumor-derived PDGFR-alpha deletion mutant is transforming. Oncogene. 2003;22: 722–733. doi: 10.1038/sj.onc.1206160 12569364

8. Verhaak RGW, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 2010;17: 98–110. doi: 10.1016/j.ccr.2009.12.020 20129251

9. Talasila KM, Soentgerath A, Euskirchen P, Rosland G V, Wang J, Huszthy PC, et al. EGFR wild-type amplification and activation promote invasion and development of glioblastoma independent of angiogenesis. Acta Neuropathol. 2013;125: 683–98. doi: 10.1007/s00401-013-1101-1 23429996

10. Roberts PJ, Der CJ. Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene. 2007;26: 3291–3310. doi: 10.1038/sj.onc.1210422 17496923

11. Holland EC, Celestino J, Dai C, Schaefer L, Sawaya RE, Fuller GN. Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice. Nat Genet. Nature Publishing Group; 2000;25: 55–7. doi: 10.1038/75596

12. Salhia B, Tran NL, Chan A, Wolf A, Nakada M, Rutka F, et al. The guanine nucleotide exchange factors trio, Ect2, and Vav3 mediate the invasive behavior of glioblastoma. Am J Pathol. 2008;173: 1828–1838. doi: 10.2353/ajpath.2008.080043 19008376

13. Katoh H, Hiramoto K, Negishi M. Activation of Rac1 by RhoG regulates cell migration. J Cell Sci. 2006;119: 56–65. doi: 10.1242/jcs.02720 16339170

14. Kwiatkowska A, Didier S, Fortin S, Chuang Y, White T, Berens ME, et al. The small GTPase RhoG mediates glioblastoma cell invasion. Mol Cancer. 2012;11: 65. doi: 10.1186/1476-4598-11-65 22966858

15. Yan B, Chour HH, Peh BK, Lim C, Salto-Tellez M. RhoA protein expression correlates positively with degree of malignancy in astrocytomas. Neurosci Lett. 2006;407: 124–126. doi: 10.1016/j.neulet.2006.08.032 16978776

16. Hagedorn M, Javerzat S, Gilges D, Meyre A, de Lafarge B, Eichmann A, et al. Accessing key steps of human tumor progression in vivo by using an avian embryo model. Proc Natl Acad Sci U S A. 2005;102: 1643–8. doi: 10.1073/pnas.0408622102 15665100

17. Santarius T, Shipley J, Brewer D, Stratton MR, Cooper CS. A census of amplified and overexpressed human cancer genes. Nat Rev Cancer. 2010;10: 59–64. doi: 10.1038/nrc2771 20029424

18. Futreal PA, Coin L, Marshall M, Down T, Hubbard T, Wooster R, et al. A census of human cancer genes. Nat Rev Cancer. 2004;4: 177–183. doi: 10.1038/nrc1299 14993899

19. Danussi C, Akavia UD, Niola F, Jovic A, Lasorella A, Pe’er D, et al. RHPN2 drives mesenchymal transformation in malignant glioma by triggering RhoA activation. Cancer Res. 2013;73: 5140–50. doi: 10.1158/0008-5472.CAN-13-1168-T 23774217

20. Salhia B, Rutten F, Nakada M, Beaudry C, Berens M, Kwan A, et al. Inhibition of Rho-kinase affects astrocytoma morphology, motility, and invasion through activation of Rac1. Cancer Res. 2005;65: 8792–8800. doi: 10.1158/0008-5472.CAN-05-0160 16204049

21. Reyes SB, Narayanan AS, Lee HS, Tchaicha JH, Aldape KD, Lang FF, et al. αvβ8 integrin interacts with RhoGDI1 to regulate Rac1 and Cdc42 activation and drive glioblastoma cell invasion. Mol Biol Cell. 2013;24: 474–82. doi: 10.1091/mbc.E12-07-0521 23283986

22. Fortin SP, Ennis MJ, Schumacher CA, Zylstra-Diegel CR, Williams BO, Ross JTD, et al. Cdc42 and the guanine nucleotide exchange factors Ect2 and trio mediate Fn14-induced migration and invasion of glioblastoma cells. Mol Cancer Res. 2012;10: 958–968. doi: 10.1158/1541-7786.MCR-11-0616 22571869

23. Riento K, Guasch RM, Garg R, Jin B, Ridley AJ. RhoE binds to ROCK I and inhibits downstream signaling. Mol Cell Biol. 2003;23: 4219–29. Available: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=156133&tool=pmcentrez&rendertype=abstract 12773565

24. Chardin P. Function and regulation of Rnd proteins. Nat Rev Mol Cell Biol. 2006;7: 54–62. doi: 10.1038/nrm1788 16493413

25. Lonjedo M, Poch E, Mocholí E, Hernández-Sánchez M, Ivorra C, Franke TF, et al. The Rho family member RhoE interacts with Skp2 and is degraded at the proteasome during cell cycle progression. J Biol Chem. 2013;288: 30872–82. doi: 10.1074/jbc.M113.511105 24045951

26. J M, B B, D B, B D, P K, M L, et al. Regulation of Rnd3 localization and function by protein kinase Calpha-mediated phosphorylation. Portland Press Ltd.; 2009; Available: http://www.biochemj.org/bj/424/bj4240153.htm

27. Zhu Z, Todorova K, Lee KK, Wang J, Kwon E, Kehayov I, et al. Small GTPase RhoE/Rnd3 Is a Critical Regulator of Notch1 Signaling. Cancer Res. 2014;74: 2082–93. doi: 10.1158/0008-5472.CAN-12-0452 24525741

28. Li J, Deng M, Wei Q, Liu T, Tong X, Ye X. Phosphorylation of MCM3 protein by cyclin E/cyclin-dependent kinase 2 (Cdk2) regulates its function in cell cycle. J Biol Chem. 2011;286: 39776–85. doi: 10.1074/jbc.M111.226464 21965652

29. Madhavan S, Zenklusen J-C, Kotliarov Y, Sahni H, Fine HA, Buetow K. Rembrandt: helping personalized medicine become a reality through integrative translational research. Mol Cancer Res. 2009;7: 157–67. doi: 10.1158/1541-7786.MCR-08-0435 19208739

30. Heng JI-T, Nguyen L, Castro DS, Zimmer C, Wildner H, Armant O, et al. Neurogenin 2 controls cortical neuron migration through regulation of Rnd2. Nature. 2008;455: 114–118. doi: 10.1038/nature07198 18690213

31. Murphy C, Saffrich R, Olivo-Marin JC, Giner A, Ansorge W, Fotsis T, et al. Dual function of rhoD in vesicular movement and cell motility. Eur J Cell Biol. 2001;80: 391–398. doi: 10.1078/0171-9335-00173 11484930

32. Ellis S, Mellor H. The novel Rho-family GTPase Rif regulates coordinated actin-based membrane rearrangements. Curr Biol. 2000;10: 1387–1390. doi: 10.1016/S0960-9822(00)00777-6 11084341

33. Gampel A, Parker PJ, Mellor H. Regulation of epidermal growth factor receptor traffic by the small GTPase RhoB. Curr Biol. 1999;9: 955–958. doi: 10.1016/S0960-9822(99)80422-9 10508588

34. Huang M, Duhadaway JB, Prendergast GC, Laury-Kleintop LD. RhoB regulates PDGFR-beta trafficking and signaling in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 2007;27: 2597–2605. doi: 10.1161/ATVBAHA.107.154211 17951322

35. Matthys A, Van Craenenbroeck K, Lintermans B, Haegeman G, Vanhoenacker P. RhoBTB3 interacts with the 5-HT7a receptor and inhibits its proteasomal degradation. Cell Signal. 2012;24: 1053–1063. doi: 10.1016/j.cellsig.2011.12.027 22245496

36. Lu A, Pfeffer SR. Golgi-associated RhoBTB3 targets cyclin E for ubiquitylation and promotes cell cycle progression. J Cell Biol. 2013;203: 233–50. doi: 10.1083/jcb.201305158 24145166

37. Baldwin RM, Parolin DAE, Lorimer IAJ. Regulation of glioblastoma cell invasion by PKC iota and RhoB. Oncogene. 2008;27: 3587–95. doi: 10.1038/sj.onc.1211027 18212741

38. Ma Y, Gong Y, Cheng Z, Loganathan S, Kao C, Sarkaria JN, et al. Critical functions of RhoB in support of glioblastoma tumorigenesis. Neuro Oncol. 2014; doi: 10.1093/neuonc/nou228

39. Chan AY, Coniglio SJ, Chuang Y, Michaelson D, Knaus UG, Philips MR, et al. Roles of the Rac1 and Rac3 GTPases in human tumor cell invasion. Oncogene. 2005;24: 7821–7829. doi: 10.1038/sj.onc.1208909 16027728

40. Zhang H, Zhu W, Su X, Wu S, Lin Y, Li J, et al. Triptolide inhibits proliferation and invasion of malignant glioma cells. J Neurooncol. 2012;109: 53–62. doi: 10.1007/s11060-012-0885-5 22562416

41. Khalil BD, Hanna S, Saykali BA, El-Sitt S, Nasrallah A, Marston D, et al. The regulation of RhoA at focal adhesions by StarD13 is important for astrocytoma cell motility. Exp Cell Res. 2014;321: 109–22. doi: 10.1016/j.yexcr.2013.11.023 24333506

42. Sasayama T, Nishihara M, Kondoh T, Hosoda K, Kohmura E. MicroRNA-10b is overexpressed in malignant glioma and associated with tumor invasive factors, uPAR and RhoC. Int J Cancer. 2009;125: 1407–13. doi: 10.1002/ijc.24522 19536818

43. Goldberg L, Kloog Y. A Ras inhibitor tilts the balance between Rac and Rho and blocks phosphatidylinositol 3-kinase-dependent glioblastoma cell migration. Cancer Res. 2006;66: 11709–17. doi: 10.1158/0008-5472.CAN-06-1878 17178866

44. Yoon C-H, Hyun K-H, Kim R-K, Lee H, Lim E-J, Chung H-Y, et al. The small GTPase Rac1 is involved in the maintenance of stemness and malignancies in glioma stem-like cells. FEBS Lett. 2011;585: 2331–8. doi: 10.1016/j.febslet.2011.05.070 21704033

45. Zhou X, Qian J, Hua L, Shi Q, Liu Z, Xu Y, et al. Geranylgeranyltransferase I promotes human glioma cell growth through Rac1 membrane association and activation. J Mol Neurosci. 2013;49: 130–9. doi: 10.1007/s12031-012-9905-3 23073905

46. Poch E, Miñambres R, Mocholí E, Ivorra C, Pérez-Aragó A, Guerri C, et al. RhoE interferes with Rb inactivation and regulates the proliferation and survival of the U87 human glioblastoma cell line. Exp Cell Res. 2007;313: 719–31. doi: 10.1016/j.yexcr.2006.11.006 17182035

47. Ongusaha PP, Kim H-G, Boswell SA, Ridley AJ, Der CJ, Dotto GP, et al. RhoE is a pro-survival p53 target gene that inhibits ROCK I-mediated apoptosis in response to genotoxic stress. Curr Biol. 2006;16: 2466–72. doi: 10.1016/j.cub.2006.10.056 17174923

48. Bektic J, Pfeil K, Berger AP, Ramoner R, Pelzer A, Schäfer G, et al. Small G-protein RhoE is underexpressed in prostate cancer and induces cell cycle arrest and apoptosis. Prostate. 2005;64: 332–40. doi: 10.1002/pros.20243 15754346

49. Sun L, Hui A-M, Su Q, Vortmeyer A, Kotliarov Y, Pastorino S, et al. Neuronal and glioma-derived stem cell factor induces angiogenesis within the brain. Cancer Cell. Neuro-Oncology Branch, National Cancer Institute/National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA.; 2006;9: 287–300. doi: 10.1016/j.ccr.2006.03.003 16616334

50. Irizarry RA, Hobbs B, Collin F, Beazer-Barclay YD, Antonellis KJ, Scherf U, et al. Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostat Oxford Engl. 2003;4: 249–264. Available: http://www.ncbi.nlm.nih.gov/pubmed/12925520

51. Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Ser B Methodol. 1995;57: 289–300. doi: 10.2307/2346101

52. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. National Academy of Sciences; 2005;102: 15545–15550. doi: 10.1073/pnas.0506580102

53. Tarcea V, Weymouth T, Ade A. Michigan molecular interactions r2: from interacting proteins to pathways. Nucleic acids …. 2009;37. doi: 10.1093/nar/gkn722

54. Stark C, Breitkreutz B-J, Reguly T, Boucher L, Breitkreutz A, Tyers M. BioGRID: a general repository for interaction datasets. Nucleic Acids Res. 2006;34: D535–D539. doi: 10.1093/nar/gkj109 16381927

55. Peri S, Navarro JD, Amanchy R, Kristiansen TZ, Jonnalagadda CK, Surendranath V, et al. Development of human protein reference database as an initial platform for approaching systems biology in humans. Genome Res. 2003;13: 2363–2371. doi: 10.1101/gr.1680803 14525934

56. Chin C-S, Samanta MP. Global snapshot of a protein interaction network-a percolation based approach. Bioinformatics. 2003;19: 2413–2419. doi: 10.1093/bioinformatics/btg339 14668225

57. Su G, Kuchinsky A, Morris JH, States DJ, Meng F. GLay: community structure analysis of biological networks. Bioinformatics. 2010;26: 3135–3137. doi: 10.1093/bioinformatics/btq596 21123224

58. Margolin A, Wang K, Lim W, Kustagi M, Nemenman I, Califano A. Reverse engineering cellular networks. Nat Protoc. Department of Biomedical Informatics, Columbia University, New York, New York 10032, USA.: Nature Publishing Group; 2006;1: 662–671. doi: 10.1038/nprot.2006.106 17406294

59. Van Der Laan M J. A new algorithm for hybrid hierarchical clustering with visualization and the bootstrap. J Stat Plan Inference. 2003;117: 275–303. doi: 10.1016/S0378-3758(02)00388-9

60. Ryan KR, Lock FE, Heath JK, Hotchin NA. Plakoglobin-dependent regulation of keratinocyte apoptosis by Rnd3. J Cell Sci. 2012;125: 3202–9. doi: 10.1242/jcs.101931 22454524

61. Lock FE, Hotchin NA. Distinct roles for ROCK1 and ROCK2 in the regulation of keratinocyte differentiation. PLoS One. 2009;4: e8190. doi: 10.1371/journal.pone.0008190 19997641

62. Aryee MJ, Gutiérrez-Pabello JA, Kramnik I, Maiti T, Quackenbush J. An improved empirical bayes approach to estimating differential gene expression in microarray time-course data: BETR (Bayesian Estimation of Temporal Regulation). BMC Bioinformatics. 2009;10: 409. doi: 10.1186/1471-2105-10-409 20003283

63. Tusher VG, Tibshirani R, Chu G. Significance analysis of microarrays applied to the ionizing radiation response. Proc Natl Acad Sci U S A. 2001;98: 5116–5121. doi: 10.1073/pnas.091062498 11309499

64. Dittrich MT, Klau GW, Rosenwald A, Dandekar T, Muller T. Identifying functional modules in protein-protein interaction networks: An integrated exact approach. Bioinformatics. 2008;24. doi: 10.1093/bioinformatics/btn161