Progesterone and mifepristone regulate L-type amino acid transporter 2 and 4F2 heavy chain expression in uterine leiomyoma cells.
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.
Luo
Xia
X
Division of Reproductive Biology Research, Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA. s-bulun@northwestern.edu
Yin
Ping
P
Reierstad
Scott
S
Ishikawa
Hiroshi
H
Lin
Zhihong
Z
Pavone
Mary Ellen
ME
Zhao
Hong
H
Marsh
Erica E
EE
Bulun
Serdar E
SE
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
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