Weighted Gene Co-expression Network Analysis in Identification of Endometrial Cancer Prognosis Markers

  • Zhu, Xiao-Lu (Department of Obstetrics and Gynecology, Shanghai Sixth People's Hospital, Shanghai Jiaotong University) ;
  • Ai, Zhi-Hong (Department of Obstetrics and Gynecology, Shanghai Sixth People's Hospital, Shanghai Jiaotong University) ;
  • Wang, Juan (Department of Obstetrics and Gynecology, Shanghai Sixth People's Hospital, Shanghai Jiaotong University) ;
  • Xu, Yan-Li (Department of Obstetrics and Gynecology, Shanghai Sixth People's Hospital, Shanghai Jiaotong University) ;
  • Teng, Yin-Cheng (Department of Obstetrics and Gynecology, Shanghai Sixth People's Hospital, Shanghai Jiaotong University)
  • Published : 2012.09.30


Objective: Endometrial cancer (EC) is the most common gynecologic malignancy. Identification of potential biomarkers of EC would be helpful for the detection and monitoring of malignancy, improving clinical outcomes. Methods: The Weighted Gene Co-expression Network Analysis method was used to identify prognostic markers for EC in this study. Moreover, underlying molecular mechanisms were characterized by KEGG pathway enrichment and transcriptional regulation analyses. Results: Seven gene co-expression modules were obtained, but only the turquoise module was positively related with EC stage. Among the genes in the turquoise module, COL5A2 (collagen, type V, alpha 2) could be regulated by PBX (pre-B-cell leukemia homeobox 1)1/2 and HOXB1(homeobox B1) transcription factors to be involved in the focal adhesion pathway; CENP-E (centromere protein E, 312kDa) by E2F4 (E2F transcription factor 4, p107/p130-binding); MYCN (v-myc myelocytomatosis viral related oncogene, neuroblastoma derived [avian]) by PAX5 (paired box 5); and BCL-2 (B-cell CLL/lymphoma 2) and IGFBP-6 (insulin-like growth factor binding protein 6) by GLI1. They were predicted to be associated with EC progression via Hedgehog signaling and other cancer related-pathways. Conclusions: These data on transcriptional regulation may provide a better understanding of molecular mechanisms and clues to potential therapeutic targets in the treatment of EC.


  1. Adamovic T, Trossö F, Roshani L, et al (2005). Oncogene amplification in the proximal part of chromosome 6 in rat endometrial adenocarcinoma as revealed by combined BAC/PAC FISH, chromosome painting, zoo-FISH, and allelotyping. Genes Chromosome Canc, 44, 139-53.
  2. Adams JM, Cory S (1998). The Bcl-2 protein family: arbiters of cell survival. Science, 281, 1322-6.
  3. Akar U, Chaves-Reyez A, Barria M, et al (2008). Silencing of Bcl-2 expression by small interfering RNA induces autophagic cell death in MCF-7 breast cancer cells. Autophagy, 4, 669.
  4. Bokhman JV (1983). Two pathogenetic types of endometrial carcinoma. Gynecol Oncol, 15, 10-7.
  5. Bray K, Chen HY, Karp CM, et al (2009). Bcl-2 modulation to activate apoptosis in prostate cancer. Mol Cancer Res, 7, 1487-96.
  6. Catalano S, Giordano C, Rizza P, et al (2009). Evidence that leptin through STAT and CREB signaling enhances cyclin D1 expression and promotes human endometrial cancer proliferation. J Cell Physiol, 218, 490-500.
  7. Catasus L, Gallardo A, Prat J (2009). Molecular genetics of endometrial carcinoma. Diagnostic Histopathol, 15, 554-63.
  8. Deerberg F, Kaspareit J (1987). Endometrial carcinoma in BD II/Han rats: model of a spontaneous hormone-dependent tumor. J Natil Cancer I, 78, 1245.
  9. Erdem O, Erdem M, Dursun A, et al (2003). Angiogenesis, p53, and bcl-2 expression as prognostic indicators in endometrial cancer: comparison with traditional clinicopathologic variables. Int J Gynecol Pathol, 22, 254.
  10. Feng YZ, Shiozawa T, Miyamoto T, et al (2007). Overexpression of hedgehog signaling molecules and its involvement in the proliferation of endometrial carcinoma cells. Clin Cancer Res, 13, 1389-98.
  11. Fischer H, Stenling R, Rubio C, Lindblom A (2001). Colorectal carcinogenesis is associated with stromal expression of COL11A1 and COL5A2. Carcinogenesis, 22, 875-8.
  12. Horvath S, Dong J (2008). Geometric interpretation of gene coexpression network analysis. PLoS Com Biol, 4, e1000117.
  13. Horvath S, Zhang B, Carlson M, et al (2006). Analysis of oncogenic signaling networks in glioblastoma identifies ASPM as a molecular target. P Natl Acad Sci, 103, 17402-7.
  14. Jemal A, Siegel R, Ward E, et al (2009). Cancer statistics, 2009. CA Cancer J Clin, 59, 225-49.
  15. Jiang C, Xuan Z, Zhao F, Zhang MQ (2007). TRED: a transcriptional regulatory element database, new entries and other development. Nucleic Acids Res, 35, D137-40.
  16. Karlsson A, Helou K, Walentinsson A, et al (2001). Amplification of Mycn, Ddx1, Rrm2, and Odc1 in rat uterine endometrial carcinomas. Genes Chromosomes Canc, 31, 345-56.
  17. Kim T, Franco H, Jung S, et al (2010). The synergistic effect of Mig-6 and Pten ablation on endometrial cancer development and progression. Oncogene, 29, 3770-80.
  18. Kuo YS, Tang YB, Lu TY, et al (2010). IGFBP-6 plays a role as an oncosuppressor gene in NPC pathogenesis through regulating EGR-1 expression. J Pathol, 222, 299-309.
  19. Langfelder P, Zhang B, Horvath S (2008). Defining clusters from a hierarchical cluster tree: the Dynamic Tree Cut package for R. Bioinformatics, 24, 719-20.
  20. Leng SL, Leeding KS, Whitehead RH, Bach LA (2001). Insulinlike growth factor (IGF)-binding protein-6 inhibits IGF-IIinduced but not basal proliferation and adhesion of LIM 1215 colon cancer cells. Mol Cell Endocrinol, 174, 121-7.
  21. Liao X, Siu MKY, Au CWH, et al (2009). Aberrant activation of hedgehog signaling pathway contributes to endometrial carcinogenesis through $\beta$-catenin. Mod Pathol, 22, 839-47.
  22. Liu Z, Ling K, Wu X, et al (2009). Reduced expression of cenp-e in human hepatocellular carcinoma. J Exp Clin Cancer Res, 28, 1-8.
  23. Luparello C, Sirchia R (2005). Type V collagen regulates the expression of apoptotic and stress response genes by breast cancer cells. J Cell Physiol, 202, 411-21.
  24. Matys V, Fricke E, Geffers R, et al (2003). TRANSFAC: transcriptional regulation, from patterns to profiles. Nucleic Acids Res, 31, 374-8.
  25. McEwen BF, Chan GKT, Zubrowski B, et al (2001). CENP-E is essential for reliable bioriented spindle attachment, but chromosome alignment can be achieved via redundant mechanisms in mammalian cells. Mol Biol Cell, 12, 2776-89.
  26. McGill GG, Horstmann M, Widlund HR, et al (2002). Bcl2 regulation by the melanocyte master regulator Mitf modulates lineage survival and melanoma cell viability. Cell, 109, 707-18.
  27. Nutt SL, Morrison AM, Dörfler P, et al (1998). Identification of BSAP (Pax-5) target genes in early B-cell development by loss-and gain-of-function experiments. The EMBO J, 17, 2319-33.
  28. Oehler M, Norbury C, Hague S, et al (2001). Adrenomedullin inhibits hypoxic cell death by upregulation of Bcl-2 in endometrial cancer cells: a possible promotion mechanism for tumour growth. Oncogene, 20, 2937.
  29. Penkov D, Tanaka S, Di Rocco G, et al (2000). Cooperative interactions between PBX, PREP, and HOX proteins modulate the activity of the $\alpha 2$ (V) collagen (COL5A2) promoter. J Biol Chem, 275, 16681-9.
  30. Plesca D, Crosby ME, Gupta D, Almasan A (2007). E2F4 function in G2: maintaining G2-arrest to prevent mitotic entry with damaged DNA. Cell Cycle, 6, 1147.
  31. Rose PG (1996). Endometrial carcinoma. New Engl J Med, 335, 640-9.
  32. Rutanen EM, Nyman T, Lehtovirta P, et al (1994). Suppressed expression of insulin-like growth factor binding protein-1 mRNA in the endometrium: A molecular mechanism associating endometrial cancer with its risk factors. Int J Cancer, 59, 307-12.
  33. Shi Z, Derow C, Zhang B (2010). Co-expression module analysis reveals biological processes, genomic gain, and regulatory mechanisms associated with breast cancer progression. Bmc Systems Biology, 4, 74.
  34. SuYan L, YaGuang W, Yan C (2009). Downregulation of CENP-E gene expression enhances the sensitivity of human cervix cancer cells to paclitaxel. Tumor, 29, 135-8.
  35. Vaskivuo TE, Stenbäck F, Tapanainen JS (2002). Apoptosis and apoptosis-related factors Bcl-2, Bax, tumor necrosis factor-$\alpha$, and NF-$\kappa B$ in human endometrial hyperplasia and carcinoma. Cancer, 95, 1463-71.
  36. Xu X, Guo C, Liu J, et al (2009). Gli1 maintains cell survival by up-regulating IGFBP6 and Bcl-2 through promoter regions in parallel manner in pancreatic cancer cells. J Carcinogenesis, 8, 13.
  37. Yao X, Abrieu A, Zheng Y, et al (2000). CENP-E forms a link between attachment of spindle microtubules to kinetochores and the mitotic checkpoint. Nat Cell Biol, 2, 484-91.
  38. Yi H, Hwang P, Yang DH, et al (2001). Expression of the insulinlike growth factors (IGFs) and the IGF-binding proteins (IGFBPs) in human gastric cancer cells. Eur J Cancer, 37, 2257-63.

Cited by

  1. Gene co-expression network and function modules in three types of glioma vol.11, pp.4, 2014,
  2. Construction of a Protein-Protein Interaction Network for Chronic Myelocytic Leukemia and Pathway Prediction of Molecular Complexes vol.15, pp.13, 2014,
  3. Shortest Path Analyses in the Protein-Protein Interaction Network of NGAL (Neutrophil Gelatinase-associated Lipocalin) Overexpression in Esophageal Squamous Cell Carcinoma vol.15, pp.16, 2014,
  4. Accuracy of Intraoperative Gross Examination of Myometrial Invasion in Stage I-II Endometrial Cancer vol.15, pp.17, 2014,
  5. Protein-protein Interaction Network Analyses for Elucidating the Roles of LOXL2-delta72 in Esophageal Squamous Cell Carcinoma vol.15, pp.5, 2014,
  6. HOXB1 Is a Tumor Suppressor Gene Regulated by miR-3175 in Glioma vol.10, pp.11, 2015,
  7. The Polymorphism of Hypoxia-inducible Factor-1a Gene in Endometrial Cancer vol.15, pp.23, 2015,
  8. Differential analysis of biological networks vol.16, pp.1, 2015,
  9. Relations of Serum Visfatin and Resistin Levels with Endometrial Cancer and Factors Associated with its Prognosis vol.16, pp.11, 2015,
  10. Role of exon 7 PTEN Gene in Endometrial Carcinoma vol.16, pp.11, 2015,
  11. Genomic and transcriptome analysis revealing an oncogenic functional module in meningiomas pp.1092-0684, 2013,
  12. Construction of protein interaction network involved in lung adenocarcinomas using a novel algorithm vol.12, pp.3, 2016,
  13. Gene coexpression network analysis identified potential biomarkers in gestational diabetes mellitus progression pp.23249269, 2018,
  14. Identification of gene coexpression modules, hub genes, and pathways related to spinal cord injury using integrated bioinformatics methods pp.07302312, 2019,