title: Laser-captured microdissection-microarray analysis of the genes involved in endometrial carcinogenesis: stepwise up-regulation of lipocalin2 expression in normal and neoplastic endometria and its functional relevance.
abstract: Endometrial carcinoma often arises from normal endometrial glandular cells via a precursor, atypical endometrial hyperplasia. However, the genetic changes involved in this carcinogenetic process are not fully understood. Differentially expressed genes were selected from glandular cells of normal proliferative-phase endometria, atypical endometrial hyperplasia, and endometrial carcinoma using laser-captured microdissection and microarray. The microarray analysis revealed a total of 51 genes to be up-regulated and 23 genes to be down-regulated in neoplastic endometrial epithelia. We focused on lipocalin2 (LCN2), which showed the largest magnitude of up-regulation. Immunostaining for lipocalin2 confirmed a stepwise increase in its expression in endometrial hyperplasia and carcinoma. In addition, elevated expression of lipocalin2 was correlated with the poor outcome of endometrial carcinoma patients. The subcellular distribution of lipocalin2 was both cytoplasmic and nuclear, despite reports that lipocalin2 is a secretory protein. Treatment of endometrial carcinoma cells with 5-azacytidine increased the expression of lipocalin2, suggesting the expression to be controlled by methylation of the promoter. The forced expression of lipocalin2 resulted in the enhanced cell proliferation and invasion in vitro. The expression of lipocalin2 increased with the endometrial carcinogenesis, and accumulation of the protein conferred biological aggressiveness to endometrial carcinoma cells. These results suggest lipocalin2 to be a novel target in the treatment of endometrial carcinoma.
authors.affiliation: Department of Obstetrics and Gynecology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Miyamoto
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Kashima
authors.forename: Akihisa
authors.initials: A
authors.lastname: Suzuki
authors.forename: Norihiko
authors.initials: N
authors.lastname: Kikuchi
authors.forename: Ikuo
authors.initials: I
authors.lastname: Konishi
authors.forename: Naohiko
authors.initials: N
authors.lastname: Seki
authors.forename: Tanri
authors.initials: T
authors.lastname: Shiozawa
mesh_terms: D000209:Acute-Phase Proteins / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002478:Cells, Cultured; D004714:Endometrial Hyperplasia / Q000235:genetics; D016889:Endometrial Neoplasms / Q000235:genetics*; D004717:Endometrium / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007834:Lasers; D000071068:Lipocalin-2; D054834:Lipocalins / Q000235:genetics*; D046228:Microarray Analysis; D042282:Microdissection; D008875:Middle Aged; D011518:Proto-Oncogene Proteins / Q000235:genetics*
chemical_list: D000209:Acute-Phase Proteins; C489506:LCN2 protein, human; D000071068:Lipocalin-2; D054834:Lipocalins; D011518:Proto-Oncogene Proteins