Role of microRNA-21 and programmed cell death 4 in the pathogenesis of human uterine leiomyomas.
OBJECTIVE
To determine whether programmed cell death 4 (PDCD-4) is altered in autologous leiomyoma and myometrial tissues and what microRNA-21's (miR-21) role is in PDCD-4 expression, apoptosis, and translation.


METHODS
Laboratory research.


METHODS
Academic medical center.


METHODS
Myometrial and leiomyoma tissues from patients with symptomatic leiomyomata.


METHODS
Tissue analysis and miR-21 knockdown in cultured immortalized myometrial (UtM) and leiomyoma (UtLM) cells.


METHODS
MiR-21 and PDCD-4 mRNA and protein expression.


RESULTS
Leiomyoma tissues robustly expressed the full-length 51 kd isoform of PDCD-4, but normal myometrial tissue had negligible expression. Consistent with autologous tissues, UtLM cells expressed elevated miR-21 and a similar pattern of PDCD-4 compared with UtM cells. Knockdown of miR-21 increased PDCD-4 levels in UtM cells and UtLM cells, indicating that it can regulate PDCD-4 expression. Loss of miR-21 also increased cleavage of caspase-3 (apoptosis marker) and increased phosphorylation of elongation factor-2 (marker of reduced translation) in both cell lines.


CONCLUSIONS
Elevated leiomyoma miR-21 levels are predicted to decrease PDCD-4 levels, thus leiomyomas differ from other tumors where loss of PDCD-4 is associated with tumor progression. Our studies indicate regulation of PDCD-4 expression is not a primary miR-21 function in leiomyomas, but instead miR-21 is able to impact cellular apoptosis and translation, through unknown targets, in a manner consistent with its involvement in the pathophysiology of uterine fibroids.
Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
J Browning
JB
Fitzgerald
Vargheese
V
Chennathukuzhi
Faezeh
F
Koohestani
Romana A
RA
Nowak
Lane K
LK
Christenson
D051017:Apoptosis Regulatory Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007889:Leiomyoma / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D035683:MicroRNAs / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D016601:RNA-Binding Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D014594:Uterine Neoplasms / Q000209:etiology* / Q000235:genetics / Q000473:pathology
D051017:Apoptosis Regulatory Proteins; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; C114487:PDCD4 protein, human; D012333:RNA, Messenger; D016601:RNA-Binding Proteins