Abstract
Recently, endometrial hyperplasia was identified as presenting a higher risk for progressing to endometrial carcinoma more readily than adenomyosis. The Lcn-2 gene encodes neutrophil gelatinase-associated lipocalin (NGAL), which promotes cell proliferation and serves as a cancer marker in some cancers. In our current study, we investigated the relationship between the expression of NGAL and that of pathogenic cytokines and cancer-related genes including cyclooxygenase-2 (COX-2), E-cadherin, β-catenin, and vimentin in patients with endometrial disorders. NGAL expression was examined by Western blotting, immunohistochemistry, and reverse-transcription polymerase chain reaction (RT-PCR) in hyperplasia and adenomyosis biopsy samples. Immunohistochemistry demonstrated the occurrence of NGAL in glandular epithelial cells but not in the stromal cells of hyperplasia biopsy samples. NGAL protein and mRNA expression were significantly greater in endometrial hyperplasia than in endometrial adenomyosis. Although our data showed no difference in pathogenic cytokines between patients with endometrial hyperplasia and endometrial adenomyosis, we observed high expression levels of COX-2, β-catenin, vimentin, and E-cadherin in patients with endometrial hyperplasia. NGAL mRNA expression correlated positively with COX-2 and E-cadherin mRNA expression (r = 0.41 and r = 0.57, respectively), but correlated negatively with vimentin and β-catenin mRNA expression (r = −0.42 and r = −0.61, respectively). Our data suggest that NGAL is up-regulated in patients with endometrial hyperplasia to prevent the transition from hyperplasia to carcinoma.
Similar content being viewed by others
References
Flower DR (1996) The lipocalin protein family: structure and function. Biochem J 318:1–14
Liu Q, Nilsen-Hamilton M (1995) Identification of a new acute phase protein. J Biol Chem 270:22565–22570
Liu Q, Ryon J, Nilsen-Hamilton M (1997) Uterocalin: a mouse acute phase protein expressed in the uterus around birth. Mol Reprod Dev 46:507–514
Moniaux N, Chakraborty S, Yalniz M, Gonzalez J, Shostrom VK, Standop J, Lele SM, Ouellette M, Pour PM, Sasson AR, Brand RE, Hollingsworth MA, Jain M, Batra SK (2008) Early diagnosis of pancreatic cancer: neutrophil gelatinase-associated lipocalin as a marker of pancreatic intraepithelial neoplasia. Br J Cancer 98:1540–1547
Bauer M, Eickhoff JC, Gould MN, Mundhenke C, Maass N, Friedl A (2008) Neutrophil gelatinase-associated lipocalin (NGAL) is a predictor of poor prognosis in human primary breast cancer. Breast Cancer Res Treat 108:389–397
Lim R, Ahmed N, Borregaard N, Riley C, Wafai R, Thompson EW, Quinn MA, Rice GE (2007) Neutrophil gelatinase-associated lipocalin (NGAL) an early-screening biomarker for ovarian cancer: NGAL is associated with epidermal growth factor-induced epithelial-mesenchymal transition. Int J Cancer 120:2426–2434
Yang J, Moses MA (2009) Lipocalin 2: a multifaceted modulator of human cancer. Cell Cycle 8:1–6
Roudkenar MH, Halabian R, Ghasemipour Z, Roushandeh AM, Rouhbakhsh M, Nekogoftar M, Kuwahara Y, Fukumoto M, Shokrgozar MA (2008) Neutrophil gelatinase-associated lipocalin acts as a protective factor against H2O2 toxicity. Arch Med Res 39:560–566
Huang HL, Chu ST, Chen YH (1999) Ovarian steroids regulate 24p3 expression in mouse uterus during the natural estrous cycle and the preimplantaion period. J Endocrinol 162:11–19
Lin HH, Li WW, Lee YC, Chu ST (2007) Apoptosis induced by uterine 24p3 protein in endometrial carcinoma cell line. Toxicology 234:203–215
Salamonsen LA, Lathbury L (2000) Endometrial leukocytes and menstruation. Hum Reprod Update 6:16–27
Kayisli UA, Mahutte NG, Arici A (2002) Uterine chemokines in reproductive physiology and pathology. AJRI Am J Reprod Immunol Microbiol 47:213–221
Masafumi K, Takako O, Michio U (2004) The relationship between endometrial carcinoma and coexistent adenomyosis uteri, endometriosis external and myoma uteri. Can Diet Prevent 28:94–98
Boruban MC, Altundag K, Kilic GS, Blankstein J (2008) From endometrial hyperplasia to endometrial cancer: insight into the biology and possible medical preventive measure. Eur J Can Prev 17:133–138
Cakmakoglu BA, Attar R, Kahraman OT, Dalan AB, Iyibozkurt AC, Karateke A, Attar E (2010) Cyclooxygenase-2 gene and epithelial ovarian carcinoma risk. Mol Biol Rep 38(5):3481–3486
Fujiwaki R, Lida K, Kanasaki H, Ozaki T, Hata K, Miyazaki K (2002) Cyclooxygenase-2 expression in endometrial cancer: correlation with microvessel count and expression of vascular endothelial growth factor and thymidine phosphorylase. Hum Pathol 33:213–219
Orejuela FJ, Ramondetta LM, Smith J, Brown J, Lemos LB, Li Y, Hollier LM (2005) Estrogen and progesterone receptors and cyclooxygenase-2 expression in endometrial hyperplasia, and normal endometrium. Gynecol Oncol 97:483–488
Fosslein E (2001) Molecular pathology of cyclooxygenase-2 in cancer-induced angiogenesis. Ann Clin Lab Sci 31:325–348
Bakhle YS (2001) COX-2 and cancer: a new approach to an old problem. Brit J Pharmacol 134:1137–1150
Geert B, Frans VR (2001) The E-cadherin/β-catenin complex an important gatekeeper in breast cancer tumorigenesis and malignant progression. Breast Cancer Res 3:289–293
Yang J, Bielenberg DR, Rodig SJ, Doiron R, Clifton MC, Kung AL, Strong RK, Zurakowski D, Moses MA (2009) Lipocalin 2 promotes breast cancer progression. Proc Natl Acad Sci USA 106:3913–3918
Cowling VH, Cole MD (2007) E-cadherin repression contributes to c-myc-induced epithelial cell transformation. Oncogene 26:3582–3586
Chen L, Chen W, Zhao L, Yu HZ, Li X (2009) Immunoscreening of urinary bladder cancer cDNA library and identification of potential tumor antigen. World J Urol 27:107–112
Iannetti A, Pacifico F, Acquaviva R, Lavorgna A, Crescenzi E, Vascotto C, Tell G, Salzano AM, Scaloni A, Vuttariello E, Chiappetta G, Formisano S, Leonardi A (2008) The neutrophil gelatinase-associated lipocalin (NGAL), a NF-kappaB-regulated gene, is a survival factor for thyroid neoplastic cells. Proc Natl Acad Sci USA 105:14058–14063
Arlinghaus R, Leng X (2008) Requirement of lipocalin 2 for chronic myeloid leukemia. Leuk Lymphoma 49:600–603
Leng X, Lin H, Ding T, Wang Y, Wu Y, Klumpp S, Sun T, Zhou Y, Monaco P, Belmont J, Aderem A, Akira S, Strong R, Arlinghaus R (2008) Lipocalin 2 is required for BCR-ABL-induced tumorigenesis. Oncogene 27:6110–6119
Hu L, Hittelman W, Lu T, Ji P, Arlinghaus R, Shmulerich I, Hamilton BR, Zhang W (2009) NGAL decrease E-cadherin-mediated cell-cell adhesion and increase cell mobility and invasion through Rac1 in colon carcinoma cells. Lab Invest 17:1–18
Munday JS, Brennan MM, Kiupel M (2006) Altered expression of β-catenin, E-cadherin, COX-2, and p53 protein by ovine intestinal adenocarcinoma cells. Vet Pathol 43:613–621
Jeong J-W, Lee HS, Frano HL, Broaddus RR, Taketo MM, Tsai SY, Lydon JP, DeMayo FJ (2009) β-catenin mediates glandular formation and dysregulation of β-catenin induces hyperplasia formation in the murine uterus. Oncogene 28:31–40
Ashihara K, Saito T, Mizumoto H, Nishimura M, Tanaka R, Kudo R (2002) Mutation of β-catenin gene in endometrial cancer but not in associated hyperplasia. Med Electron Microsc 35:9–15
Giles C, Thompson EW (1996) The epithelial to mesenchymal transition and metastatic progression in carcinoma. Breast J 2:83–96
Tong Z, Kunnumakkara AB, Wang H, Matsuo Y et al (2008) NGAL: a novel suppressor of invasion and angiogenesis in pancreatic cancer. Cancer Res 68:100–108
Zha S, Yegnasubramanian V, Nelson WG, Isaacs WB, De Marzo AM (2004) Cyclooxygenases in cancer: progression and perspective. Cancer Lett 215:1–20
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Liao, CJ., Huang, Y.H., Au, HK. et al. The cancer marker neutrophil gelatinase-associated lipocalin is highly expressed in human endometrial hyperplasia. Mol Biol Rep 39, 1029–1036 (2012). https://doi.org/10.1007/s11033-011-0828-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11033-011-0828-9