Unknown,Transcriptomics,Genomics,Proteomics

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An integrative genomic and transcriptomic analysis reveals potential targets associated with cell proliferation in uterine leiomyomas

ABSTRACT: Transcriptional profiling of uterine leiomyoma tumor samples for integrative analysis with copy number alterations data. Goal was to identify up- and/or down-expressed genes associated with genomic gains and/or losses, respectively. After, it was applied to GSEA and CONEXIC algorithm to integrate the data. Protein-protein interactions also was building and the data were validated using qRT-PCR and IHC techniques. Experiment condition, 51 uterine leiomyoma samples from patients at the secretory or proliferative menstrual cycle phases were labeled with Cy3 and adjacent normal myometrium reference samples were labeled with Cy5. Each uterine leiomyoma and adjacent normal myometrium sample were obtained from the same patient and were mixed and hybridized on a glass slide Agilent 4x44 platform.

ORGANISM(S): Homo sapiens

SUBMITTER: Priscila Cirilo

PROVIDER: E-GEOD-42939 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Uterine leiomyomata, or fibroids, are benign tumors of the uterine myometrium that significantly affect up to 30% of reproductive-age women. Despite being the primary cause of hysterectomy in the United States, accounting for up to 200,000 procedures annually, the etiology of leiomyoma remains largely unknown. Due to the lack of an effective medicinal therapy for these tumors, this disease continues to have a tremendous negative impact on women’s health. As a basis for understanding leiomyoma pathogenesis and identifying targets for pharmacotherapy, we conducted transcriptional profiling of leiomyoma and unaffected myometrium from humans and Eker rats, the best characterized preclinical model of leiomyoma. A global comparison of mRNA from leiomyoma versus myometrium in human and rat identified a highly significant overlap of dysregulated gene expression in leiomyoma. An unbiased pathway analysis using a method of gene set enrichment based on the Sigpathway algorithm detected the mammalian target of rapamycin (mTOR) pathway as one of the most highly upregulated pathways in both human and rat tumors. Activation of this pathway was confirmed in both human and rat leiomyomata at the protein level via Western. Inhibition of mTOR in female Eker rats with the rapamycin analog WAY-129327 for 2 weeks decreased mTOR signaling and cell proliferation in tumors, and treatment for 4 months significantly decreased tumor incidence, multiplicity and size. These results identify dysregulated mTOR signaling as a component of leiomyoma etiology across species and directly demonstrate the dependence of these tumors on mTOR signaling for growth in the Eker rat. Modulation of this pathway warrants additional investigation as a potential therapy for uterine leiomyoma. Experiment Overall Design: We analyzed 1-3 leiomyoma or normal myometrium biopsies from each 23 woman undergoing hysterectomy for the treatment of uterine fibroids. tment and compared it leiomyoma and normal myometrium from the Eker rat model of uterine fibroids (N=14-15)

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An integrative genomic and transcriptomic analysis reveals potential targets associated with cell proliferation in uterine leiomyomas

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