microRNAs and Their Target Gene Networks in Uterine Leiomyomas.
Jian-Jun Wei, Zhaojian Liu, Jiri Zavadil, Patricia Soteropoulos, HuiHui Ye. Northwestern University, Chicago, IL; UMDNJ-New Jersey Medical School, Newark, NJ; New York University, NY
Background: Human uterine leiomyomas (ULMs) are characterized by dysregulation of a large number of genes and microRNAs. It is thus important to examine the roles played by the highly dysregulated microRNAs through regulation of specific target genes in tumorigenesis of ULMs. To explore the broader relationship between other dysregulated microRNAs and their target genes exhibiting aberrant expression in ULMs, global analysis of microRNA and target gene expression in ULMs is helpful to identify the potential candidates of microRNAs for tumorigenesis and growth of ULMs.
Design: Among 70 cases with ULMs, 45 cases were conducted for global microRNA expression analysis (Ambion); 5 cases for global gene expression analysis (Affymetrix); 8 cases for comparative genomic hybridization (CGH); 36 cases for immunohistochemistry; 14 cases for senescence; and 24 cases for validation. Uterine leiomyoma and myometrial cell lines with stable overexpression of lentiviral miR-29b, miR-296, miR-200a and let-7c were prepared for analysis of predicted target gene and tumor growth. Relationship of selected mRNAs in ULMs and target gene functional pathways were analyzed by GeneSpring GX11, TM4 Microarray Software Suite, DAVID and Gene set enrichment analysis.
Results: miRNA and mRNA expression were examined in paired sets of ULMs and matched myometria. Patterns of inverse association of microRNA with mRNA expression in ULMs revealed an involvement of multiple candidate pathways, including transcriptional reprogramming, cell proliferation control, MAP kinase, TGF-β, WNT, JAK/STAT signaling, remodeling of cell adhesion, cell-cell and cell-matrix contacts. Two distinct microdeletion detected by GCH might be responsible for loss of miR-15 and miR-200a clusters. These miRNAs directly regulated IGF signaling pathway, EMT pathway, and some oncogenes. These miRNAs are tumor suppressors and significantly inhibit leiomyoma cell growth in vitro. Some miRNAs may participate in the leiomyoma aging process. Those miRNAs that are associated with smooth muscle differentiation are significantly dysregulated in ULMs.
Conclusions: The levels of the most dysregulated microRNAs in ULMs show an inverse association with the expression levels of many predicted target genes, and that they may affect multiple homeostatic pathways and functions. Some but not all of them can be validated as functional targets of specific microRNAs in vitro. Dysregulated miRNAs are associated with leiomyoma growth, differentiation and aging process.
Category: Gynecologic & Obstetrics
Wednesday, March 2, 2011 1:00 PM
Poster Session VI # 182, Wednesday Afternoon