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Dysregulated chaperones associated with cell proliferation and negative apoptosis regulation in the uterine leiomyoma.

ABSTRACT: Uterine leiomyomas are benign smooth muscle cell tumors that originate from the myometrium. In this study we focus on dysregulated chaperones associated with cell proliferation and apoptosis. Paired tissue samples of 15 leiomyomas and adjacent myometria were obtained and analyzed by two-dimensional gel electrophoresis (2-DE). Mass spectrometry was used for protein identification and western blotting for 2-DE data validation. The values of 6 chaperones were found to be significantly different in the leiomyoma when compared with the myometrium. A total of 4 proteins were upregulated in the leiomyoma and 2 proteins were downregulated. Calreticulin and 78 kDa glucose-regulated protein were further validated by western blotting because the first is considered a marker of cell proliferation, while the second protects against apoptotic cell death. In addition, we also validated the two downregulated proteins heat shock protein ?-1 and heat shock 70 kDa protein 1A. Our study shows the existence of a dysregulation of chaperone proteins associated with leiomyoma development. Functional studies are needed to ascertain the role of these chaperones in the leiomyoma. This may be crucial for the further development of specific inhibitors against the activity of these proteins in order to block the growth of the leiomyoma.

SUBMITTER: Ura B

PROVIDER: S-EPMC5920642 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Dysregulated chaperones associated with cell proliferation and negative apoptosis regulation in the uterine leiomyoma.

Ura Blendi B Scrimin Federica F Arrigoni Giorgio G Aloisio Michelangelo M Monasta Lorenzo L Ricci Giuseppe G

Oncology letters 20180322 5

Uterine leiomyomas are benign smooth muscle cell tumors that originate from the myometrium. In this study we focus on dysregulated chaperones associated with cell proliferation and apoptosis. Paired tissue samples of 15 leiomyomas and adjacent myometria were obtained and analyzed by two-dimensional gel electrophoresis (2-DE). Mass spectrometry was used for protein identification and western blotting for 2-DE data validation. The values of 6 chaperones were found to be significantly different in ...[more]

PMID: 29731911

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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)

Dataset Information

Dysregulated chaperones associated with cell proliferation and negative apoptosis regulation in the uterine leiomyoma.

Publications

Dysregulated chaperones associated with cell proliferation and negative apoptosis regulation in the uterine leiomyoma.

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