Pathway Crosstalk Analysis Based on Protein-protein Network Analysis in Ovarian Cancer

  • Pan, Xiao-Hua
  • Published : 2012.08.31


Ovarian cancer is the fifth leading cause of cancer death in women aged 35 to 74 years. Although there are several popular hypothesis of ovarian cancer pathogenesis, the genetic mechanisms are far from being clear. Recently, systems biology approaches such as network-based methods have been successfully applied to elucidate the mechanisms of diseases. In this study, we constructed a crosstalk network among ovarian cancer related pathways by integrating protein-protein interactions and KEGG pathway information. Several significant pathways were identified to crosstalk with each other in ovarian cancer, such as the chemokine, Notch, Wnt and NOD-like receptor signaling pathways. Results from these studies will provide the groundwork for a combination therapy approach targeting multiple pathways which will likely be more effective than targeting one pathway alone.


Ovarian cancer;protein-protein network;pathway crosstalk


  1. Adesina AM, Lopez-Terrada D, Wong KK, et al (2009). Gene expression profiling reveals signatures characterizing histologic subtypes of hepatoblastoma and global deregulation in cell growth and survival pathways. Hum Pathol, 40, 843-53.
  2. Axelrod JD, Matsuno K, Artavanis-Tsakonas S, Perrimon N (1996). Interaction between Wingless and Notch signaling pathways mediated by dishevelled. Science, 271, 1826-32.
  3. Ayyanan A, Civenni G, Ciarloni L, et al (2006). Increased Wnt signaling triggers oncogenic conversion of human breast epithelial cells by a Notch-dependent mechanism. Proc Natl Acad Sci USA, 103, 3799-804.
  4. Barbieri F, Bajetto A, Florio T (2010). Role of chemokine network in the development and progression of ovarian cancer: a potential novel pharmacological target. J Oncol, 426956.
  5. Berchuck A, Elbendary A, Havrilesky L, et al (1994). Pathogenesis of ovarian cancers. J Soc Gynecol Investig, 1, 181-90.
  6. Bowen NJ, Walker LD, Matyunina LV, et al (2009). Gene expression profiling supports the hypothesis that human ovarian surface epithelia are multipotent and capable of serving as ovarian cancer initiating cells. BMC Med Genomics, 2, 71.
  7. Bray SJ (2006). Notch signalling: a simple pathway becomes complex. Nat Rev Mol Cell Biol, 7, 678-89.
  8. Bruserud O, Kittang AO (2010). The chemokine system in experimental and clinical hematology. Curr Top Microbiol Immunol, 341, 3-12.
  9. Bruserud O, Ryningen A, Olsnes AM, et al (2007). Subclassification of patients with acute myelogenous leukemia based on chemokine responsiveness and constitutive chemokine release by their leukemic cells. Haematologica, 92, 332-41.
  10. Colomiere M, Ward AC, Riley C, et al (2009). Cross talk of signals between EGFR and IL-6R through JAK2/STAT3 mediate epithelial-mesenchymal transition in ovarian carcinomas. Br J Cancer, 100, 134-44.
  11. De Paepe B, Creus KK, De Bleecker JL (2008). Chemokines in idiopathic inflammatory myopathies. Front Biosci, 13, 2548-77.
  12. Francesconi M, Remondini D, Neretti N, et al (2008). Reconstructing networks of pathways via significance analysis of their intersections. BMC Bioinformatics, 9 Suppl 4, S9.
  13. Gatcliffe TA, Monk BJ, Planutis K, Holcombe RF (2008). Wnt signaling in ovarian tumorigenesis. Int J Gynecol Cancer, 18, 954-62.
  14. Hayward P, Brennan K, Sanders P, et al (2005). Notch modulates Wnt signalling by associating with Armadillo/beta-catenin and regulating its transcriptional activity. Development, 132, 1819-30.
  15. Hembruff SL, Cheng N (2009). Chemokine signaling in cancer: Implications on the tumor microenvironment and therapeutic targeting. Cancer Ther, 7, 254-67.
  16. Ideker T, Sharan R(2008). Protein networks in disease. Genome Res, 18, 644-52.
  17. Keshava Prasad TS, Goel R, Kandasamy K, et al (2009). Human Protein Reference Database--2009 update. Nucleic Acids Res, 37, D767-72.
  18. Li Y, Agarwal P, Rajagopalan D (2008). A global pathway crosstalk network. Bioinformatics, 24, 1442-7.
  19. Liu ZP, Wang Y, Zhang XS, Chen L (2010). Identifying dysfunctional crosstalk of pathways in various regions of Alzheimer's disease brains. BMC Syst Biol, 4 Suppl 2: S11.
  20. Merritt MA, Cramer DW (2011). Molecular pathogenesis of endometrial and ovarian cancer. Cancer Biomark, 9, 287- 305.
  21. Moreno CS (2010). The Sex-determining region Y-box 4 and homeobox C6 transcriptional networks in prostate cancer progression: crosstalk with the Wnt, Notch, and PI3K pathways. Am J Pathol, 176, 518-27.
  22. Nanjundan M, Cheng KW, Zhang F, et al (2008). Overexpression of SnoN/SkiL, amplified at the 3q26.2 locus, in ovarian cancers: a role in ovarian pathogenesis. Mol Oncol, 2, 164-81.
  23. Obata K, Hoshiai H (2000). Common genetic changes between endometriosis and ovarian cancer. Gynecol Obstet Invest, 50, 39-43.
  24. Oliva E, Sarrio D, Brachtel EF, et al (2006). High frequency of beta-catenin mutations in borderline endometrioid tumours of the ovary. J Pathol, 208, 708-13.
  25. Rose SL (2009). Notch signaling pathway in ovarian cancer. Int J Gynecol Cancer, 19, 564-6.
  26. Rose SL, Kunnimalaiyaan M, Drenzek J, Seiler N (2010). Notch 1 signaling is active in ovarian cancer. Gynecol Oncol, 117, 130-3.
  27. Saito M, Okamoto A, Kohno T, et al (2000). Allelic imbalance and mutations of the PTEN gene in ovarian cancer. Int J Cancer, 85, 160-5.;2-5
  28. Shih Ie M, Davidson B (2009). Pathogenesis of ovarian cancer: clues from selected overexpressed genes. Future Oncol, 5, 1641-57.
  29. Shih Ie M, Kurman RJ (2004). Ovarian tumorigenesis: a proposed model based on morphological and molecular genetic analysis. Am J Pathol, 164, 1511-8.
  30. Sieben NL, Macropoulos P, Roemen GM, et al (2004). In ovarian neoplasms, BRAF, but not KRAS, mutations are restricted to low-grade serous tumours. J Pathol, 202, 336-40.
  31. Singer G, Kurman RJ, Chang HW, et al (2002). Diverse tumorigenic pathways in ovarian serous carcinoma. Am J Pathol, 160, 1223-8.
  32. Singer G, Oldt R, 3rd, Cohen Y, et al (2003). Mutations in BRAF and KRAS characterize the development of low-grade ovarian serous carcinoma. J Natl Cancer Inst, 95, 484-6.
  33. Singer G, Stohr R, Cope L, et al (2005). Patterns of p53 mutations separate ovarian serous borderline tumors and low- and high-grade carcinomas and provide support for a new model of ovarian carcinogenesis: a mutational analysis with immunohistochemical correlation. Am J Surg Pathol, 29, 218-24.
  34. Stark C, Breitkreutz BJ, Chatr-Aryamontri A, et al (2011). The BioGRID Interaction Database: 2011 update. Nucleic Acids Res, 39, D698-704.
  35. Team RDC (2011). R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing.
  36. Torpy JM, Burke AE, Golub RM (2011). JAMA patient page. Ovarian cancer. JAMA, 305, 2484.
  37. Turashvili G, Bouchal J, Baumforth K, et al (2007). Novel markers for differentiation of lobular and ductal invasive breast carcinomas by laser microdissection and microarray analysis. Bmc Cancer, 7, 55.
  38. Van Es JH, Jay P, Gregorieff A, et al (2005). Wnt signalling induces maturation of Paneth cells in intestinal crypts. Nat Cell Biol, 7(4): 381-386.
  39. Wang Z, Li Y, Kong D, et al (2010). Cross-talk between miRNA and Notch signaling pathways in tumor development and progression. Cancer Lett, 292, 141-8.
  40. Zabel BA, Zuniga L, Ohyama T, et al (2006). Chemoattractants, extracellular proteases, and the integrated host defense response. Exp Hematol, 34, 1021-32.
  41. Zhao XM, Wang RS, Chen L, Aihara K (2008). Uncovering signal transduction networks from high-throughput data by integer linear programming. Nucleic Acids Res, 36, e48.

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