title: Lipocalin 2 Enhances Migration and Resistance against Cisplatin in Endometrial Carcinoma Cells.
abstract: Lipocalin 2 (LCN2) is a secretory protein that is involved in various physiological processes including iron transport. We previously identified LCN2 as an up-regulated gene in endometrial carcinoma, and found that the overexpression of LCN2 and its receptor, SLC22A17, was associated with a poor prognosis. However, the functions and mechanism of action of LCN2 currently remain unclear.
  
  
  
  The LCN2-overexpressing endometrial carcinoma cell lines, HHUA and RL95-2, and LCN2-low-expressing one, HEC1B, were used. The effects of LCN2 on cell migration, cell viability, and apoptosis under various stresses, including ultraviolet (UV) irradiation and cisplatin treatment, were examined using the scratch wound healing assay, WST-1 assay, and Apostrand assay, respectively.
  
  
  
  LCN2-silencing using shRNA method significantly reduced the migration ability of cells (p<0.05). Cytotoxic stresses significantly decreased the viability of LCN2-silenced cells more than that of control cells. In contrast, LCN2 overexpression was significantly increased cisplatin resistance. These effects were canceled by the addition of the iron chelator, deferoxamine. After UV irradiation, the expression of phosphorylated Akt (pAkt) was decreased in LCN2-silenced cells, and the PI3K inhibitor canceled the difference induced in UV sensitivity by LCN2. The cisplatin-induced expression of pAkt was not affected by LCN2; however, the expression of p53 and p21 was increased by LCN2-silencing.
  
  
  
  These results indicated that LCN2 was involved in the migration and survival of endometrial carcinoma cells under various stresses in an iron-dependent manner. The survival function of LCN2 may be exerted through the PI3K pathway and suppression of the p53-p21 pathway. These functions of LCN2 may increase the malignant potential of endometrial carcinoma cells.
authors.affiliation: Department of Obstetrics and Gynecology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, 390-8621, Japan.
authors.forename: Tsutomu
authors.identifier: 0000-0002-1513-9473
authors.initials: T
authors.lastname: Miyamoto
authors.affiliation: Department of Obstetrics and Gynecology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, 390-8621, Japan.
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Kashima
authors.affiliation: Department of Obstetrics and Gynecology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, 390-8621, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Yamada
authors.affiliation: Department of Obstetrics and Gynecology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, 390-8621, Japan.
authors.forename: Hisanori
authors.initials: H
authors.lastname: Kobara
authors.affiliation: Department of Obstetrics and Gynecology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, 390-8621, Japan.
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Asaka
authors.affiliation: Department of Obstetrics and Gynecology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, 390-8621, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Ando
authors.affiliation: Department of Obstetrics and Gynecology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, 390-8621, Japan.
authors.forename: Shotaro
authors.initials: S
authors.lastname: Higuchi
authors.affiliation: Department of Obstetrics and Gynecology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, 390-8621, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Ida
authors.affiliation: Department of Obstetrics and Gynecology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, 390-8621, Japan.
authors.forename: David Hamisi
authors.initials: DH
authors.lastname: Mvunta
authors.affiliation: Department of Obstetrics and Gynecology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, 390-8621, Japan.
authors.forename: Tanri
authors.initials: T
authors.lastname: Shiozawa
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000528:radiation effects; D002945:Cisplatin / Q000494:pharmacology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004717:Endometrium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000528:radiation effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000071068:Lipocalin-2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D014466:Ultraviolet Rays
chemical_list: D000970:Antineoplastic Agents; D002945:Cisplatin; D050759:Cyclin-Dependent Kinase Inhibitor p21; D000071068:Lipocalin-2; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; C489506:LCN2 protein, human