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Possible involvement of a MEG3-miR-21-SPRY1-NF-kB feedback loop in spermatogenic cells proliferation, autophagy and apoptosis

ABSTRACT: Non-obstructive azoospermia (NOA) is the most incurable male infertility with complex etiology. The molecular mechanism that determines the amount of spermatogenesis in NOA patients is still unclear. LncRNAs have been verified to associate with the regulation of spermatogenesis. However, the specific function and molecular mechanism remain to be confirmed. We use RNA-seq analysis for preliminary screening of different lncRNAs between NOA and normal male and find that MEG3 was upregulated in NOA testicular tissues and inhibit cell proliferation and promote cell autophagy and apoptosis in vitro and vivo. Through RNA immunoprecipitation (RIP), biotin pull-down assays and Dual Luciferase Reporter assays, MEG3 is proved to act as competing endogenous RNA of miR-21 and thus influence the SPRY1/ERK/mTOR signal pathway. In addition, SPRY1 positively regulates MEG3 through SPRY1/NF-κB/MEG3 feedback loop. These findings firstly demonstrate that LncRNA MEG3-miR-21-SPRY1-NF-κB acts as a new feedback loop leading to the occurrence of azoospermia through inhibiting the proliferation, promoting autophagy and apoptosis of spermatogenic cells, which provides a new target and theoretical basis for diagnosis and treatment of non-obstructive azoospermia.

ORGANISM(S): Homo sapiens

PROVIDER: GSE241326 | GEO | 2024/09/14

REPOSITORIES: GEO

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Project description:Infertility affects about one in six couples attempting pregnancy, with the man responsible in approximately half of the cases. Because the pathophysiology underlying azoospermia is not elucidated, most male infertility is diagnosed as idiopathic. Genome-wide gene expression analyses with microarray on testis specimens from 47 non-obstructive azoospermia (NOA) and 11 obstructive azoospermia (OA) patients were performed, and 2,611 transcripts that preferentially included genes relevant to gametogenesis and reproduction according to Gene Ontology classification were found to be differentially expressed. Using a set of 945 of the 2,611 transcripts without missing data, NOA was further categorized into three classes using the non-negative matrix factorization method. These three subclasses showed differences in Johnsenâs score, FSH level, and LH level. In addition, the 52 genes showing high statistical difference between NOA subclasses (P < 0.01 with Tukey's post hoc test) were subjected to allelic association analyses to identify genetic susceptibilities in 442 NOA patients and 475 fertile men. After two rounds of screening, SNPs of the ADP-ribosyltransferase 3 (ART3) gene were associated with NOA with highest significance with ART3-SNP25 (rs6836703; P = 0.0025). Haplotypes with 5 SNPs were constructed, and the most common haplotype was found to be under-represented in patients (NOA 26.6 % versus control 35.3 %, P = 0.000073). Subjects having the most common haplotype showed an elevated level of testosterone, suggesting a protective effect of the haplotype on spermatogenesis. Thus, genome-wide gene expression analyses were used to identify genes involved in the pathogenesis of NOA, and ART3 was subsequently identified as a susceptibility gene for NOA. These findings clarify the molecular pathophysiology of NOA and suggest a novel therapeutic target in the treatment of NOA. Experiment Overall Design: Comparative analysis of two disease phenotypes, using testicular biopsy specimens from 47 NOA and 11 OA patients. No experimental replicates.

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Possible involvement of a MEG3-miR-21-SPRY1-NF-kB feedback loop in spermatogenic cells proliferation, autophagy and apoptosis

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