title: Progesterone and mifepristone regulate L-type amino acid transporter 2 and 4F2 heavy chain expression in uterine leiomyoma cells.
abstract: BACKGROUND
  Progesterone and its receptor (PR) play key roles in uterine leiomyoma growth. Previously, using chromatin immunoprecipitation-based cloning, we uncovered L-type amino acid transporter 2 (LAT2) as a novel PR target gene. LAT2 forms heterodimeric complexes with 4F2 heavy chain (4F2hc), a single transmembrane domain protein essential for LAT2 to exert its function in the plasma membrane. Until now, little is known about the roles of LAT2/4F2hc in the regulation of the growth of human uterine leiomyoma.
  
  
  OBJECTIVE
  The aim of the study is to investigate the regulation of LAT2 and 4F2hc by progesterone and the antiprogestin mifepristone and their functions in primary human uterine leiomyoma smooth muscle (LSM) cells and tissues from 39 premenopausal women.
  
  
  RESULTS
  In primary LSM cells, progesterone significantly induced LAT2 mRNA levels, and this was blocked by cotreatment with mifepristone. Progesterone did not alter 4F2hc mRNA levels, whereas mifepristone significantly induced 4F2hc mRNA expression. Small interfering RNA knockdown of LAT2 or 4F2hc markedly increased LSM cell proliferation. LAT2, PR-B, and PR-A levels were significantly higher in freshly isolated LSM cells vs. adjacent myometrial cells. In vivo, mRNA levels of LAT2 and PR but not 4F2hc were significantly higher in leiomyoma tissues compared with matched myometrial tissues.
  
  
  CONCLUSIONS
  We present evidence that progesterone and its antagonist mifepristone regulate the amino acid transporter system LAT2/4F2hc in leiomyoma tissues and cells. Our findings suggest that products of the LAT2/4F2hc genes may play important roles in leiomyoma cell proliferation. We speculate that critical ratios of LAT2 to 4F2hc regulate leiomyoma growth.
authors.affiliation: Division of Reproductive Biology Research, Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA. s-bulun@northwestern.edu
authors.forename: Xia
authors.initials: X
authors.lastname: Luo
authors.forename: Ping
authors.initials: P
authors.lastname: Yin
authors.forename: Scott
authors.initials: S
authors.lastname: Reierstad
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ishikawa
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Lin
authors.forename: Mary Ellen
authors.initials: ME
authors.lastname: Pavone
authors.forename: Hong
authors.initials: H
authors.lastname: Zhao
authors.forename: Erica E
authors.initials: EE
authors.lastname: Marsh
authors.forename: Serdar E
authors.initials: SE
authors.lastname: Bulun
mesh_terms: D000328:Adult; D027182:Amino Acid Transport System y+ / Q000235:genetics*; D002470:Cell Survival; D017931:DNA Primers; D005260:Female; D005498:Follicular Phase; D027282:Fusion Regulatory Protein 1, Heavy Chain / Q000235:genetics*; D027301:Fusion Regulatory Protein 1, Light Chains / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007889:Leiomyoma / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D008183:Luteal Phase; D008598:Menstruation; D008875:Middle Aged; D015735:Mifepristone / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D011374:Progesterone / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics*; D012334:RNA, Neoplasm / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D014594:Uterine Neoplasms / Q000235:genetics* / Q000473:pathology / Q000601:surgery
chemical_list: D027182:Amino Acid Transport System y+; D017931:DNA Primers; D027282:Fusion Regulatory Protein 1, Heavy Chain; D027301:Fusion Regulatory Protein 1, Light Chains; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; C420646:SLC7A8 protein, human; D015735:Mifepristone; D011374:Progesterone