Abstract

miR-93/106b and their host gene minichromosome maintenance complex component 7 (MCM7) reside at chr7q22, a region frequently rearranged in leiomyomas. We explored the expression of miR-93/106b in leiomyoma and paired myometrium (n = 63) from untreated and patients exposed to hormonal therapies (GnRH agonist, Depo-Provera, and oral contraceptives) from African-Americans and Caucasians and their regulatory functions in isolated paired (n = 15) leiomyoma and myometrial smooth muscle cells and the leiomyosarcoma cell line. At tissue level leiomyomas expressed significantly lower levels of miR-93 and elevated MCM7 as compared with myometrium with limited racial influence or hormonal exposure on their expression. Assessing the regulatory function of miR-93/106b through doxycycline-inducible lentiviral transduction in a microarray analysis, tissue factor (F3) and IL8 were identified as their possible targets. At the tissue level, leiomyomas expressed a significantly lower level of F3 and an elevated IL-8 level, which exhibited an inverse relationship with miR-93 but with limited racial or hormonal influences. The gain of function of miR-93/106b in leiomyoma smooth muscle cells, myometrial smooth muscle cells, and the leiomyosarcoma cell line dose dependently repressed F3 and IL8 through direct interactions with their respective 3'-untranslated region and indirectly through F3 repression inhibited IL8, CTGF, and PAI-1 expression, confirmed by using small interfering RNA silencing or factor Vlla (FVIIa) activation of F3, as well as reducing the rate of proliferation, while increasing caspase-3/7 activity. We concluded that differential expression of miR-93/106b and their direct and/or indirect regulatory functions on F3, IL8, CTGF, and PAI-1 expression, with key roles in inflammation and tissue turnover may be of significance in the outcome of leiomyoma growth and associated symptoms.

Links

Publisher Full Text

Authors

Chuang TD, Luo X, Panda H, Chegini N

Institution

Department of Obstetrics and Gynecology, University of Florida, Gainesville, FL 32610, USA.

Source

Molecular endocrinology (Baltimore, Md.) 26:6 2012 Jun pg 1028-42

MeSH

Adult
Caspases
Cell Cycle Proteins
Cell Proliferation
Cell Survival
Cells, Cultured
Cluster Analysis
DNA-Binding Proteins
Female
Gene Expression
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Humans
Interleukin-8
Leiomyoma
Menstrual Cycle
MicroRNAs
Middle Aged
Myometrium
Nuclear Proteins
RNA Interference
Thromboplastin
Uterine Neoplasms
Young Adult

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

22556343