Roles of microRNA-21 and programmed cell death 4 in the pathogenesis of human uterine leiomyomas
PDCD-4 is unexpectedly elevated in leiomyomas, but normal myometrium does not express the protein; the expected inverse correlation of microRNA-21 and its target PDCD-4 is absent in fibroids.
J. Browning Fitzgerald, B.S., Vargheese Chennathukuzhi, Ph.D., Faezeh Koohestani, M.S., Romana A. Nowak, Ph.D., Lane K. Christenson, Ph.D.
Volume 98, Issue 3, Pages 726-734.e2, September 2012
To determine if programmed cell death 4 (PDCD-4) is altered in autologous leiomyoma and
34 myometrial tissues and microRNA-21’s (miR-21) role in PDCD-4 expression, apoptosis and translation.
Academic medical center.
Myometrial and leiomyoma tissues from patients with symptomatic leiomyomata.
Tissue analysis and miR-21 knockdown in cultured immortalized myometrial (UtM) and leiomyoma (UtLM) cells.
Main Outcome Measure(s):
MiR-21 and PDCD-4 mRNA and protein expression.
Leiomyoma tissues robustly expressed the full-length 51kDA isoform of PDCD-4, while normal myometrial tissue had negligible expression Consistent with autologous tissues, UtLM cells expressed elevated miR-21 and a similar pattern of PDCD-4 compared to 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.
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.