Abstract
Endometrial cancer is the third most common gynecologic malignancy and the ninth most common malignancy for females overall in Hong Kong. Approximately 80% or more of these cancers are endometrioid endometrial adenocarcinomas. The aim of this study was to reveal genes contributing to the development of endometrioid endometrial cancer, which may impact diagnosis, prognosis and treatment of the disease. Whole-genome gene expression analysis was completed for a set of 55 microdissected sporadic endometrioid endometrial adenocarcinomas and 29 microdissected normal endometrium specimens using the Affymetrix Human U133 Plus 2.0 oligonucleotide microarray. Selected genes of interest were validated by quantitative real-time-polymerase chain reaction (qRT-PCR). Pathway analysis was performed to reveal gene interactions involved in endometrial tumorigenesis. Unsupervised hierarchical clustering displayed a distinct separation between the endometrioid adenocarcinomas and normal endometrium samples. Supervised analysis identified 117 highly differentially regulated genes (⩾4.0-fold change), which distinguished the endometrial cancer specimens from normal endometrium. Twelve novel genes including DKK4, ZIC1, KIF1A, SAA2, LOC16378, ALPP2, CCL20, CXCL5, BST2, OLFM1, KLRC1 and MBC45780 were deregulated in the endometrial cancer, and further validated in an independent set of 56 cancer and 29 normal samples using qRT-PCR. In addition, 10 genes were differentially regulated in late-stage cancer, as compared to early-stage disease, and may be involved in tumor progression. Pathway analysis of the expression data from this tumor revealed an interconnected network consisting of 21 aberrantly regulated genes involved in angiogenesis, cell proliferation and chromosomal instability. The results of this study highlight the molecular features of endometrioid endometrial cancer and provide insight into the events underlying the development and progression of endometrioid endometrial cancer.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Accession codes
Accessions
GenBank/EMBL/DDBJ
References
Abeler VM, Kjorstad KE . (1991). Clear cell carcinoma of the endometrium: a histopathological and clinical study of 97 cases. Gynecol Oncol 40: 207–217.
Acs G, Pasha T, Zhang PJ . (2004). WT1 is differentially expressed in serous, endometrioid, clear cell, and mucinous carcinomas of the peritoneum, fallopian tube, ovary, and endometrium. Int J Gynecol Pathol 23: 110–118.
Albright CD, Kaufman DG . (2001). Lactoferrin: a tamoxifen-responsive protein in normal and malignant human endometrial cells in culture. Exp Mol Pathol 70: 71–76.
Amant F, Moerman P, Neven P, Timmerman D, Van Limbergen E, Vergote I . (2005). Endometrial cancer. Lancet 366: 491–505.
Bein K, Simons M . (2000). Thrombospondin type 1 repeats interact with matrix metalloproteinase 2. Regulation of metalloproteinase activity. J Biol Chem 275: 32167–32173.
Bein K, Ware JA, Simons M . (1998). Myb-dependent regulation of thrombospondin 2 expression. Role of mRNA stability. J Biol Chem 273: 21423–21429.
Bonome T, Lee JY, Park DC, Radonovich M, Pise-Masison C, Brady J et al. (2000). Expression profiling of serous low malignant potential, low-grade, and high-grade tumors of the ovary. Cancer Res 65: 10602–10612.
Bui TD, Zhang L, Rees MC, Bicknell R, Harris AL . (1997). Expression and hormone regulation of Wnt2, 3, 4, 5a, 7a, 7b and 10b in normal human endometrium and endometrial carcinoma. Br J Cancer 75: 1131–1136.
Cao QJ, Belbin T, Socci N, Balan R, Prystowsky MB, Childs G et al. (2004). Distinctive gene expression profiles by cDNA microarrays in endometrioid and serous carcinomas of the endometrium. Int J Gynecol Pathol 23: 321–329.
Cha HJ, Park MT, Chung HY, Kim ND, Sato H, Seiki M et al. (1988). Ursolic acid-induced down-regulation of MMP-9 gene is mediated through the nuclear translocation of glucocorticoid receptor in HT1080 human fibrosarcoma cells. Oncogene 16: 771–778.
Dai H, van't Veer L, Lamb J, He YD, Mao M, Fine BM et al. (2005). A cell proliferation signature is a marker of extremely poor outcome in a subpopulation of breast cancer patients. Cancer Res 65: 4059–4066.
Dhanesuan N, Sharp JA, Blick T, Price JT, Thompson EW . (2002). Doxycycline-inducible expression of SPARC/Osteonectin/BM40 in MDA-MB-231 human breast cancer cells results in growth inhibition. Breast Cancer Res Treat 75: 73–85.
Duncan RE, El-Sohemy A, Archer MC . (2004). Mevalonate promotes the growth of tumors derived from human cancer cells in vivo and stimulates proliferation in vitro with enhanced cyclin-dependent kinase-2 activity. J Biol Chem 279: 33079–33084.
Ferguson SE, Olshen AB, Viale A, Barakat RR, Boyd J . (2005). Stratification of intermediate-risk endometrial cancer patients into groups at high risk or low risk for recurrence based on tumor gene expression profiles. Clin Cancer Res 11: 2252–2257.
Fernandez CA, Yan L, Louis G, Yang J, Kutok JL, Moses MA . (2005). The matrix metalloproteinase-9/neutrophil gelatinase-associated lipocalin complex plays a role in breast tumor growth and is present in the urine of breast cancer patients. Clin Cancer Res 11: 5390–5395.
Harper JW, Burton JL, Solomon MJ . (2002). The anaphase-promoting complex: it's not just for mitosis any more. Genes Dev 16: 2179–2206.
Hedge SP, Kumar A, Kurschner C, Shapiro LH . (1998). c-Maf interacts with c-Myb to regulate transcription of an early myeloid gene during differentiation. Mol Cell Biol 18: 2729–2737.
Hendrickson M, Ross J, Eifel P, Martinez A, Kempson R . (1982). Uterine papillary serous carcinoma: a highly malignant form of endometrial adenocarcinoma. Am J Surg Pathol 6: 93–108.
Hojilla CV, Mohammed FF, Khokha R . (2003). Matrix metalloproteinases and their tissue inhibitors direct cell fate during cancer development. Br J Cancer 89: 1817–1821.
Hong Kong Cancer Registry. (2005). Hong Kong Cancer Stat 2002. Hong Kong Authority, Hong Kong.
Hrzenjak A, Tippl M, Kremser ML, Strohmeier B, Guelly C, Neumeister D et al. (2004). Inverse correlation of secreted frizzled-related protein 4 and beta-catenin expression in endometrial stromal sarcomas. J Pathol 204: 19–27.
Ilvan S, Akyildiz EU, Calay Z, Celikoyar M, Sahinler I . (2004). Endometrial clear cell carcinoma metastatic to the paranasal sinuses: a case report and review of the literature. Gynecol Oncol 94: 232–234.
Kalsheker N, Morley S, Morgan K . (2002). Gene regulation of the serine proteinase inhibitors alpha1-antitrypsin and alpha1-antichymotrypsin. Biochem Soc Trans 30: 93–98.
Kamochi J, Tokunaga T, Tomii Y, Abe Y, Hatanaka H, Kijima H et al. (2003). Overexpression of the thrombospondin 2 (TSP2) gene modulated by the matrix metalloproteinase family expression and production in human colon carcinoma cell line. Oncol Rep 10: 881–884.
Lax SF, Kendall B, Tashiro H, Slebos RJ, Hedrick L . (2000). The frequency of p53, K-ras mutations, and microsatellite instability differs in uterine endometrioid and serous carcinoma: evidence of distinct molecular genetic pathways. Cancer 88: 814–824.
Li C, Wong W . (2003). DNA-Chip Analyzer (dChip): The Analysis of Gene Expression Data, Methods and Software. Springer-Verlag: New York.
Liu WM, Guerra-Vladusic FK, Kurakata S, Lupu R, Kohwi-Shigematsu T . (1999). HMG-I(Y) recognizes base-unpairing regions of matrix attachment sequences and its increased expression is directly linked to metastatic breast cancer phenotype. Cancer Res 59: 5695–5703.
Liu YH, Teng CT . (1991). Characterization of estrogen-responsive mouse lactoferrin promoter. J Biol Chem 266: 21880–21885.
Loeb DM, Korz D, Katsnelson M, Burwell EA, Friedman AD, Sukumar S . (2002). Cyclin E is a target of WT1 transcriptional repression. J Biol Chem 277: 19627–19632.
Massaad-Massade L, Tacine R, Dulauroy S, Reeves R, Barouki R . (2004). The functional interaction between HMGA1 and the estrogen receptor requires either the N- or the C-terminal domain of the receptor. FEBS Lett 559: 89–95.
Maxwell GL, Chandramouli GV, Dainty L, Litzi TJ, Berchuck A, Barrett JC et al. (2005). Microarray analysis of endometrial carcinomas and mixed mullerian tumors reveals distinct gene expression profiles associated with different histologic types of uterine cancer. Clin Cancer Res 11: 4056–4066.
McCann S, Sullivan J, Guerra J, Arcinas M, Boxer LM . (1995). Repression of the c-myb gene by WT1 protein in T and B cell lines. J Biol Chem 270: 23785–23789.
Milde-Langosch K, Bamberger AM, Goemann C, Rossing E, Rieck G, Kelp B et al. (2001). Expression of cell-cycle regulatory proteins in endometrial carcinomas: correlations with hormone receptor status and clinicopathologic parameters. J Cancer Res Clin Oncol 127: 537–544.
Miyashita R, Tsuchiya N, Hikami K, Kuroki K, Fukazawa T, Bijl M et al. (2004). Molecular genetic analyses of human NKG2C (KLRC2) gene deletion. Int Immunol 16: 163–168.
Mizumoto H, Saito T, Ashihara K, Nishimura M, Tanaka R, Kudo R . (2002). Acceleration of invasive activity via matrix metalloproteinases by transfection of the estrogen receptor-alpha gene in endometrial carcinoma cells. Int J Cancer 100: 401–406.
Moreno-Bueno G, Sanchez-Estevez C, Cassia R, Rodriguez-Perales S, Diaz-Uriarte R, Dominguez O et al. (2003). Differential gene expression profile in endometrioid and nonendometrioid endometrial carcinoma: STK15 is frequently overexpressed and amplified in nonendometrioid carcinomas. Cancer Res 63: 5697–5702.
Motamed K, Funk SE, Koyama H, Ross, Raines EW, Sage EH . (2002). Inhibition of PDGF-stimulated and matrix-mediated proliferation of human vascular smooth muscle cells by SPARC is independent of changes in cell shape or cyclin-dependent kinase inhibitors. J Cell Biochem 84: 759–771.
Muller C, Yang R, Idos G, Tidow N, Diederichs S, Koch OM et al. (1999). c-myb transactivates the human cyclin A1 promoter and induces cyclin A1 gene expression. Blood 94: 4255–4262.
Muller-Tidow C, Diederichs S, Schrader MG, Vogt U, Miller K, Berdel WE et al. (2003). Cyclin A1 is highly expressed in aggressive testicular germ cell tumors. Cancer Lett 190: 89–95.
Murphy G, Knauper V . (1997). Relating matrix metalloproteinase structure to function: why the “hemopexin” domain? Matrix Biol 15: 511–518.
Mutter GL, Baak JP, Fitzgerald JT, Gray R, Neuberg D, Kust GA et al. (2001). Global expression changes of constitutive and hormonally regulated genes during endometrial neoplastic transformation. Gynecol Oncol 83: 177–185.
O'Connor DS, Grossman D, Plescia J, Li F, Zhang H, Villa A et al. (2000). Regulation of apoptosis at cell division by p34cdc2 phosphorylation of survivin. Proc Natl Acad Sci USA 97: 13103–13107.
Pellikainen JM, Ropponen KM, Kataja VV, Kellokoski JK, Eskelinen MJ, Kosma VM . (2004). Expression of matrix metalloproteinase (MMP)-2 and MMP-9 in breast cancer with a special reference to activator protein-2, HER2, and prognosis. Clin Cancer Res 10: 7621–7628.
Pepper MS . (2001). Role of the matrix metalloproteinase and plasminogen activator-plasmin systems in angiogenesis. Arterioscler Thromb Vasc Biol 21: 1104–1117.
Reeves R, Edberg DD, Li Y . (2001). Architectural transcription factor HMGI(Y) promotes tumor progression and mesenchymal transition of human epithelial cells. Mol Cell Biol 21: 575–594.
Risinger JI, Maxwell GL, Chandramouli GVR, Aprelikova O, Litzi T, Asad Umar A et al. (2005). Gene expression profiling of microsatellite unstable and microsatellite stable endometrial cancers indicates distinct pathways of aberrant signaling. Cancer Res 65: 5031–5037.
Risinger JI, Maxwell GL, Chandramouli GV, Jazaeri A, Aprelikova O, Patterson T et al. (2003). Microarray analysis reveals distinct gene expression profiles among different histologic types of endometrial cancer. Cancer Res 63: 6–11.
Rutanen EM, Nyman T, Lehtovirta P, Ammala M, Pekonen F . (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: 307–312.
Saidi SA, Holland CM, Kreil DP, MacKay DJ, Charnock-Jones DS, Print CG et al. (2004). Independent component analysis of microarray data in the study of endometrial cancer. Oncogene 23: 6677–6683.
Schafer KA . (1998). The cell cycle: a review. Vet Pathol 35: 461–478.
Schutyser E, Struyf S, Van Damme J . (2003). The CC chemokine CCL20 and its receptor CCR6. Cytokine Growth Factor Rev 14: 409–426.
Sivak JM, West-Mays JA, Yee A, Williams T, Fini ME . (2004). Transcription Factors Pax6 and AP-2alpha interact to coordinate corneal epithelial repair by controlling expression of matrix metalloproteinase gelatinase B. Mol Cell Biol 24: 245–257.
Smid-Koopman E, Blok LJ, Helmerhorst TJ, Chadha-Ajwani S, Burger CW, Brinkmann AO et al. (2004). Gene expression profiling in human endometrial cancer tissue samples: utility and diagnostic value. Gynecol Oncol 93: 292–300.
Stetler-Stevenson WG, Seo DW . (2005). TIMP-2: an endogenous inhibitor of angiogenesis. Trends Mol Med 11: 97–103.
Streit M, Riccardi L, Velasco P, Brown LF, Hawighorst T, Bornstein P et al. (1999). Thrombospondin-2: a potent endogenous inhibitor of tumor growth and angiogenesis. Proc Natl Acad Sci USA 96: 14888–14893.
Suzumori N, Katano K, Suzumori K . (2004). Peritoneal fluid concentrations of epithelial neutrophil-activating peptide-78 correlate with the severity of endometriosis. Fertil Steril 81: 305–308.
Takeba Y, Suzuki N, Kaneko A, Asai T, Sakane T . (2001). Endorphin and enkephalin ameliorate excessive synovial cell functions in patients with rheumatoid arthritis. J Rheumatol 28: 2176–2183.
Tanaka T, Tatsuno I, Noguchi Y, Uchida D, Oeda T, Narumiya S et al. (1998). Activation of cyclin-dependent kinase 2 (Cdk2) in growth-stimulated rat astrocytes. Geranylgeranylated Rho small GTPase(s) are essential for the induction of cyclin E gene expression. J Biol Chem 273: 26772–26778.
Tashiro H, Isacson C, Levine R, Kurman RJ, Cho KR, Hedrick L . (1997). p53 gene mutations are common in uterine serous carcinoma and occur early in their pathogenesis. Am J Pathol 150: 177–185.
Tong W, Pollard JW . (1999). Progesterone inhibits estrogen-induced cyclin D1 and cdk4 nuclear translocation, cyclin E- and cyclin A-cdk2 kinase activation, and cell proliferation in uterine epithelial cells in mice. Mol Cell Biol 19: 2251–2264.
Walmer DK, Padin CJ, Wrona MA, Healy BE, Bentley RC, Tsao MS et al. (1995). Malignant transformation of the human endometrium is associated with overexpression of lactoferrin messenger RNA and protein. Cancer Res 55: 1168–1175.
Warren CD, Brady DM, Johnston RC, Hanna JS, Hardwick KG, Spencer FA . (2002). Distinct chromosome segregation roles for spindle checkpoint proteins. Mol Biol Cell 13: 3029–3041.
Yan L, Borregaard N, Kjeldsen, Moses MA . (2001). The high molecular weight urinary matrix metalloproteinase (MMP) activity is a complex of gelatinase B/MMP-9 and neutrophil gelatinase-associated lipocalin (NGAL). Modulation of MMP-9 activity by NGAL. J Biol Chem 276: 37258–37265.
Yang JJ . (2002). Mixed lineage kinase ZAK utilizing MKK7 and not MKK4 to activate the c-Jun N-terminal kinase and playing a role in the cell arrest. Biochem Biophys Res Commun 297: 105–110.
Ying J, Srivastava G, Hsieh WS, Gao Z, Murray P, Liao SK et al. (2005). The stress-responsive gene GADD45G is a functional tumor suppressor, with its response to environmental stresses frequently disrupted epigenetically in multiple tumors. Clin Cancer Res 11: 6442–6449.
Yoshida S, Harada T, Iwabe T, Taniguchi F, Fujii A, Sakamoto Y et al. (2002). Induction of hepatocyte growth factor in stromal cells by tumor-derived basic fibroblast growth factor enhances growth and invasion of endometrial cancer. J Clin Endocrinol Metab 87: 2376–2383.
Yuan B, Xu Y, Woo JH, Wang Y, Bae YK, Yoon DS et al. (2006). Increased expression of mitotic checkpoint genes in breast cancer cells with chromosomal instability. Clin Cancer Res 12: 405–410.
Acknowledgements
This work was supported by a Hong Kong Research Grant Council Earmarked Grant (RGC) (4427/03M).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Wong, Y., Cheung, T., Lo, K. et al. Identification of molecular markers and signaling pathway in endometrial cancer in Hong Kong Chinese women by genome-wide gene expression profiling. Oncogene 26, 1971–1982 (2007). https://doi.org/10.1038/sj.onc.1209986
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1209986
Keywords
This article is cited by
-
A robust immune-related gene pairs signature for predicting the overall survival of esophageal cancer
BMC Genomics (2023)
-
Expression and potential role of SNF5 in endometrial carcinoma
BMC Women's Health (2019)
-
Prognostic significance of CXCL5 expression in cancer patients: a meta-analysis
Cancer Cell International (2018)
-
B49, a BST-2-based peptide, inhibits adhesion and growth of breast cancer cells
Scientific Reports (2018)
-
miREC: a database of miRNAs involved in the development of endometrial cancer
BMC Research Notes (2015)