Effect of endometriosis-linked microRNAs on hepatic gene expression

OBJECTIVE: To determine if microRNAs that are altered in the circulation of women with endometriosis affect metabolic gene expression in hepatic cells. DESIGN: In vitro study. SUBJECTS: Deidentified tissue from women with endometriosis. EXPOSURE: MicroRNAs were used to induce or suppress target genes in hepatic cells. MAIN OUTCOME MEASURES: Effect of the microRNAs that are aberrantly expressed in endometriosis on hepatic cell gene expression using quantitative polymerase chain reaction. RESULTS: Prior microarray studies on the serum of women with endometriosis showed differential expression of microRNAs miR-Let-7b, miR-125b-5p, miR-150-5p, and miR-3613-5p. Bioinformatic analyses revealed that these microRNAs have predicted binding sites in multiple genes involved in liver metabolism. Transfection of these miRs in HepG2 cells followed by real-time quantitative polymerase chain reaction showed that miR-Let-7b mimic increased the expression of Igfbp1 by 8-fold and reduced the expression of Mrc1 by 3.2-fold, whereas its inhibitor reduced Igfbp1 by 2.8-fold and increased Mrc1 by 5.2-fold. MiR-3613-5p mimic reduced the expression of Cyp2r1 by 2.2-fold and Mrc1 by 4-fold. MiR-125b-5p mimic increased the expression of Fabp4 by 4.1-fold, whereas miR-150-5p mimic increased the expression of Mrc1 by 1.8-fold and Cyp2r1 by 2.5-fold. Inhibitors of both miR-125b-5p and miR-150-5p did not show any effect on any of the genes. CONCLUSION: Circulating microRNAs, known to be aberrant in endometriosis-regulated hepatic gene expression, likely contribute to the metabolic defects seen in this disease. Treatment with miR-Let-7b and miR-3613-5p, which are downregulated in endometriosis, reversed the effect of endometriosis on the expression of IGFBP1, MRC1, and CYP2r1 genes. Therefore, miR-Let-7b and miR-3613-5p may be novel candidate therapies for endometriosis, potentially correcting the metabolic changes seen in patients with endometriosis.