title: Clinical implications of aldo-keto reductase family 1 member C3 and its relationship with lipocalin 2 in cancer of the uterine cervix.
abstract: OBJECTIVE
  Over-expression of the aldo-keto reductase family 1 member C3 (AKR1C3) has been demonstrated in many human cancers. Lipocalin 2 (LCN2) is reported to inhibit cervical cancer metastasis but little is known regarding its relationship with AKR1C3 in the development and progression of uterine cervical cancer. This study aimed to investigate the involvement of AKR1C3 and its relationship with LCN2 in cervical cancer.
  
  
  METHODS
  The roles of AKR1C3 and LCN2 were investigated using the lentivirus shRNA system in SiHa and Caski cervical cancer cells. LCN2 and matrix metalloproteinase-2 (MMP-2) promoters were constructed to demonstrate transcriptional regulation by shAKR1C3 and shLCN2, respectively. The influences of metastatic phenotypes were analyzed by wound healing, Boyden chamber, and immunofluorescence assays. The activity of MMP-2 was determined by zymography assay. The impacts of AKR1C3 and LCN2 on patient prognosis were evaluated using tissue microarrays by Cox regression and Kaplan-Meier models.
  
  
  RESULTS
  Silencing of the AKR1C3 gene increased the expression of LCN2 and decreased the migratory and invasive abilities and changed the cytoskeleton of cervical cancer cells. When AKR1C3 was over-expressed, it decreased LCN2 promoter activity and LCN2 expression and increased cell migration. The mRNA level and enzyme activity of MMP-2 increased in silenced LCN2 cells. Positive AKR1C3 and negative LCN2 were correlated with higher recurrence and poorer survival of cervical cancer patients.
  
  
  CONCLUSIONS
  Silencing of AKR1C3 increases LCN2 expression and inhibits metastasis in cervical cancer. Both AKR1C3 and LCN2 serve as molecular targets for cancer therapy to improve the clinical outcome of cervical cancer patients.
authors: Institute of Medicine, Chung Shan Medical University, No. 110, Section 1, Chien-Kuo North Road, Taichung 40201, Taiwan.
authors: Chih-Hsien
authors: CH
authors: Wu
authors: Institute of Medicine, Chung Shan Medical University, No. 110, Section 1, Chien-Kuo North Road, Taichung 40201, Taiwan; Department of Obstetrics and Gynecology, Chung Shan Medical University Hospital, No. 110, Section 1, Chien-Kuo North Road, Taichung 40201, Taiwan. Electronic address: jlko@csmu.edu.tw.
authors: Jiunn-Liang
authors: JL
authors: Ko
authors: School of Medicine, Chung Shan Medical University, Taichung, Taiwan; Department of Family and Community Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan.
authors: Shiuan-Chih
authors: SC
authors: Chen
authors: Institute of Medicine, Chung Shan Medical University, No. 110, Section 1, Chien-Kuo North Road, Taichung 40201, Taiwan.
authors: Yu-Wen
authors: YW
authors: Lin
authors: Department of Obstetrics and Gynecology, Chung Shan Medical University Hospital, No. 110, Section 1, Chien-Kuo North Road, Taichung 40201, Taiwan; School of Medicine, Chung Shan Medical University, Taichung, Taiwan; Department of Pathology, Chung Shan Medical University Hospital, Taichung, Taiwan.
authors: Chih-Ping
authors: CP
authors: Han
authors: School of Medicine, Taipei Medical University, No. 250, Wuxing Street, Xinyi District, Taipei 11042, Taiwan.
authors: Ti-Yuan
authors: TY
authors: Yang
authors: Laboratory of Molecular and Cellular Toxicology, Institute of Toxicology, College of Medicine and Angiogenesis Research Center, National Taiwan University, No. 1, Section 1, Ren-Ai Road, Taipei 10016, Taiwan; Taipei Medical University and Wang-Fang Hospital, Taipei 116, Taiwan.
authors: Ming-Hsien
authors: MH
authors: Chien
authors: Institute of Medicine, Chung Shan Medical University, No. 110, Section 1, Chien-Kuo North Road, Taichung 40201, Taiwan; Department of Obstetrics and Gynecology, Chung Shan Medical University Hospital, No. 110, Section 1, Chien-Kuo North Road, Taichung 40201, Taiwan; School of Medicine, Chung Shan Medical University, Taichung, Taiwan. Electronic address: wang84921346@yahoo.com.tw.
authors: Po-Hui
authors: PH
authors: Wang
mesh_terms: D015096:3-Hydroxysteroid Dehydrogenases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000209:Acute-Phase Proteins / Q000096:biosynthesis* / Q000235:genetics; D000074425:Aldo-Keto Reductase Family 1 Member C3; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D003599:Cytoskeleton / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D005260:Female; D020868:Gene Silencing; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000071068:Lipocalin-2; D054834:Lipocalins / Q000096:biosynthesis* / Q000235:genetics; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000235:genetics; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D014162:Transfection; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D000209:Acute-Phase Proteins; C489506:LCN2 protein, human; D000071068:Lipocalin-2; D054834:Lipocalins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D015096:3-Hydroxysteroid Dehydrogenases; D006911:Hydroxyprostaglandin Dehydrogenases; C487341:AKR1C3 protein, human; D000074425:Aldo-Keto Reductase Family 1 Member C3; D020778:Matrix Metalloproteinase 2
keywords: Aldo-keto reductase family 1 member C3; Cancer of the uterine cervix; Lipocalin 2; Matrix metalloproteinase-2; Metastasis