Differentially expressed plasma microRNAs in premature ovarian failure patients and the potential regulatory function of mir-23a in granulosa cell apoptosis

Abstract

Recent studies implicate the regulatory function of microRNAs (miRNAs) in oocyte maturation and ovarian follicular development. Differentially expressed miRNAs are found in the plasma of premature ovarian failure (POF) patients and normal cycling women. In this study, miRNA-regulated signaling pathways and related genes were described using Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis. The effect of mir-23a on granulosa cell apoptosis was also studied by examining the protein expression of X-linked inhibitor of apoptosis protein (XIAP) and caspase-3, followed by subsequent counting of apoptotic cells after Hoechst 33258 staining. Both GO analysis and pathway analysis suggested that many signaling pathways, including the AKT signaling pathway, steroid hormone receptor signaling pathways, and others, were regulated by this group of differentially expressed miRNAs. A decrease in XIAP expression (mRNA and protein level) and caspase-3 protein levels and an increase in cleaved caspase-3 protein were observed in human ovarian granulosa cells transfected with pre-mir-23a, along with an increased occurrence of apoptosis. In conclusion, differentially expressed miRNAs in the plasma of POF patients may have regulatory effects on proliferation and apoptosis of granulosa cells by affecting different signaling pathways. Mir-23a may play important roles in regulating apoptosis via decreasing XIAP expression in human ovarian granulosa cells.

Involvement of miRNAs in ovarian follicular and luteal development

“…In addition, the clinical relevance of miRNAs has steadily grown over the past few years particularly in relation to their significant potential as biomarkers of tissue function (Laterza et al 2009, Schwarzenbach et al 2011. Also, the possibility that miRNAs associated with certain clinical diseases, including ovarian diseases (Yang et al 2012), could be therapeutically targeted has generated enormous interest within medical communities (Pfeifer & Lehmann 2010). An increased understanding of ovarian miRNAs over the coming years will facilitate the application of this potential in clinical reproduction.…”

“…Yan et al (2012) reported attenuation of activininduced proliferation of mouse granulosa cells by miR-145 targeting of both activin receptor 1B and cyclin D2. In another study, Yang et al (2012) showed that miR-23a was pro-apoptotic in cultured human luteinised granulosa cells presumably by decreasing the levels of X-linked inhibitor of apoptosis protein (XIAP) and increasing caspase-3 cleavage, although it was not clarified whether these were actually direct targets of miR-23a in granulosa cells. Finally, using a microarray approach in porcine ovarian follicles, Lin et al (2012) found that miR-26b expression increased during follicular atresia and further showed that this miRNA could induce granulosa cell death by directly targeting ataxia telangiectasia mutated (ATM), a gene involved in DNA repair.…”

Characterization of microRNAs differentially expressed during bovine follicle development

“…Several studies have already reported effects of specific miRNAs on different aspects of granulosa cell function , including steroidogenesis (Yao et al 2010, Xu et al 2011, Yin et al 2012, Dai et al 2013, proliferation (Yao et al 2010, Yan et al 2012, Dai et al 2013, survival (Carletti et al 2010, Yang et al 2012, terminal differentiation (Kitahara et al 2013), and cumulus expansion (Yao et al 2014). With a few exceptions (Carletti et al 2010, Kitahara et al 2013, most evidence on follicular roles of miRNAs has been obtained using cultured cells, particularly rodent cells, and in some cases actual changes in the expression of these miRNAs during follicle development have not been demonstrated.…”

Genetics of primary ovarian insufficiency: a review

“…Recently, other analyses using exome sequencing, in a family with nine affected women [75], and in a consanguineous Middle-Eastern family with five affected women [76,77], have suggested new candidate genes (Table 4). Moreover, recent studies relate the regulatory function of microRNAs (miRNAs) in oocyte maturation and folliculogenesis, and different miRNA expression profiles in the plasma of POI patients and fertile women have been detected when a miRNA microarray analysis was performed [78]. Similar results have been observed in an animal model in which a different profile for differentially expressed miRNAs has been observed between normal rats and 4-vinylcyclohexene diepoxide (VCD)-induced rat POF when miRNA microarrays were used [79].…”