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From 2646 to 15: differentially regulated miRNAs between progenitors from normal myometrium and leiomyoma.

BACKGROUND: Uterine leiomyomas (fibroids) are smooth muscle neoplasms of the myometrial layer of the uterus and the most common benign tumors in women. Although their etiology is still unclear, progenitor cells (PCs) seem to be implicated.

OBJECTIVE(S): To identify the dysregulated pathways involved in leiomyoma onset by microRNA (miRNA) profiling of PCs isolated from normal myometrium and leiomyoma tissue.

STUDY DESIGN: Pairs of normal myometrium and uterine fibroid specimens were collected from 12 myomectomy patients. Myometrial PCs (MPCs) and leiomyoma PCs (LPCs) were isolated and characterized for stemness. After total RNA extraction and profiling of their 2646 miRNAs, DIANA-miRPath analysis was applied to find any dysregulated pathways.

RESULTS: Only 30 miRNAs showed a significant differential regulation between MPCs and LPCs. Removal of those whose values were close to the cut-off or were not consistent among triplicates left 15 miRNAs, of which 7 were downregulated and 8 were upregulated in LPCs compared to MPCs. According to DIANA-miRPath analysis, the 7 downregulated miRNAs (hsa-miR-146b-5p; hsa-miR-335-3p; hsa-miR-335-5p; hsa-miR-135b-5p; hsa-miR-10a-3p; hsa-miR-10a-5p; hsa-miR-200a-3p) are all related to three pathways, "ECM-receptor interaction" (33 targeted genes), "Adherens junction" (33 targeted genes), and "Hippo signaling" (69 targeted genes), whereas the 8 upregulated miRNAs (hsa-miR-146a-5p; hsa-miR-576-3p; hsa-miR-122-5p; hsa-miR-1246; hsa-miR-595; hsa-miR-658; hsa-miR-4284; hsa-miR-924) are related to four pathways, "PI3K-Akt signaling pathway" (71 targeted genes), "Pathways in Cancer" (80 targeted genes), "Cell Cycle" (37 targeted genes), and "Regulation of actin cytoskeleton" (41 targeted genes).

CONCLUSION(S): The finding that only 15/2646 miRNAs are differentially regulated in normal myometrium and leiomyoma and that they are involved in seven dysregulated pathways provides interesting insights into the development of uterine fibroids and lends support to the hypothesis that leiomyoma onset is the result of alterations affecting PCs.

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