Involvement of FKHR (FOXO1) transcription factor in human uterus leiomyoma growth

Kovács, Kálmán; Lengyel, Ferenc; Wilhelm, Ferenc; Vértes, Zsuzsanna; Sümegi, Balázs; Vértes, Marietta

doi:10.1016/j.fertnstert.2009.07.1670

Cited by 10 publications

(10 citation statements)

References 17 publications

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“…3b). Our results are consistent with a previous study reporting elevated FOXO1 expression in UL compared to matched myometrium 44 , especially levels of phosphorylated (p) FOXO1 (pSer 256 ). Normally, p-FOXO1 interacts with 14-3-3γ protein in the nucleus, resulting in translocation of FOXO1 to the cytoplasm and its transcriptional inactivation.…”

supporting

confidence: 93%

Genome-wide association analysis identifies 27 novel loci associated with uterine leiomyomata revealing common genetic origins with endometriosis

Gallagher

Mäkinen

Harris

et al. 2018

Preprint

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Uterine leiomyomata (UL), also known as uterine fibroids, are the most common neoplasms of the reproductive tract and the primary cause for hysterectomy, leading to considerable impact on women's lives as well as high economic burden 1,2 . Genetic epidemiologic studies indicate that heritable risk factors contribute to UL pathogenesis 3 . Previous genome-wide association studies (GWAS) identified five loci associated with UL at genome-wide significance (P < 5 x 10 -8 ) 4-6 . We conducted GWAS meta-analysis in 20,406 cases and 223,918 female controls of white European ancestry, identifying 24 genome-wide significant independent loci; 17 replicated in an unrelated cohort of 15,068 additional cases and 43,587 female controls. Aggregation of discovery and replication studies (35,474 cases and 267,505 female controls) revealed six additional significant loci. Interestingly, four of the 17 loci identified and replicated in these analyses have also been associated with risk for endometriosisanother common gynecologic disorder. These findings increase our understanding of the biological mechanisms underlying UL development, and suggest overlapping genetic origins with endometriosis.UL are hormone-driven tumors that occur in 70-80% of all women by age 50 7 . Although the majority of UL are asymptomatic, about 25% of women with UL are symptomatic, and may experience excessive bleeding, abdominal pain, and infertility 2 . Currently, the only essentially curative treatment is uterine extirpation via total hysterectomy. Known risk factors for UL include increasing age up to menopause, ethnicity (particularly African ancestry), family history of UL, and increased body mass index (BMI) 3 . Studies on familial aggregation and twins, as well as racial differences in prevalence and morbidity, suggest heritable factors influence the risk for developing UL 8-13 . To date, previous GWAS including up to approximately 1,600 cases have identified five was provided by the

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supporting

confidence: 93%

Genome-wide association analysis identifies 27 novel loci associated with uterine leiomyomata revealing common genetic origins with endometriosis

Gallagher

Mäkinen

Harris

et al. 2018

Preprint

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“…In our previous study, 14-3-3 γ was significantly downregulated in uterine leiomyoma compared to normal myometrium [16]; these results were then confirmed by several studies [25, 26], indicating that 14-3-3 γ may play a role in the origin or growth of uterine leiomyomas. Wei et al found that TSC2 was downregulated in uterine leiomyoma compared to normal myometrium from 60 hysterectomy specimens [27].…”

Section: Discussionsupporting

confidence: 69%

“…Wei et al found that TSC2 was downregulated in uterine leiomyoma compared to normal myometrium from 60 hysterectomy specimens [27]. Kovács et al reported that total FOXO1 protein exhibited nonsignificant difference, but phosphorylation FOXO1 protein was increased in leiomyoma compared with normal myometrium [25]. TSC2 and FOXO are regulated by specific interactions with 14-3-3 proteins [15].…”

Section: Discussionmentioning

confidence: 99%

The Effects of Guizhi Fuling Capsule Drug Serum on Uterine Leiomyoma Cells and Its Mechanism

Shen

et al. 2016

Evidence-Based Complementary and Alternative Medicine

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Aims. To observe the effects of Guizhi Fuling Capsule (GZFLC) drug serum on uterine leiomyoma cells and explore its mechanism. Main Methods. Sixty Sprague Dawley rats were randomly divided into two groups (normal saline lavage group and GZFLC lavage group), then, respectively, blank serum and GZFLC drug serum were collected, and finally human uterine leiomyoma cells were treated. Human leiomyoma tissues were collected from 20 patients who underwent uterine leiomyomas operations, and leiomyoma cells were primary cultured. The leiomyoma cells were treated by GZFLC drug serum in different concentrations (10%, 20%, and 30%) and variable treatment time (12 h, 24 h, 36 h, 48 h, and 72 h). Cell proliferation was observed using CCK8 assay. Flow cytometry and Annexin V/PI were used to assay the effects of GZFLC drug serum on cell apoptosis. Western blot analysis was used to assay the effects of GZFLC drug serum on TSC2, FOXO, and 14-3-3γ expression in uterine leiomyoma cells. Key Findings. In the concentrations of 10%～30%, GZFLC drug serum could inhibit proliferation of leiomyoma cells in dose-dependent manner; at the time of 36 h, cell inhibition rate was at the peak; GZFLC drug serum could induce apoptosis of leiomyoma also in a dose-dependent manner, and apoptosis rate quickly achieved maximum at 12 h time points, and then second apoptosis peak appeared at 36 h. Compared to nontreatment group, TSC2, FOXO, and 14-3-3γ expressions in drug serum group were significantly changed after 12 h treatment. Significance. GZFLC drug serum can efficiently inhibit the proliferation and induce apoptosis of leiomyoma cells, which is related to the 14-3-3γ pathway.

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“…Tumors from menopausal women also showed reduced p-AKT levels compared to pre-menopausally derived tumors. AKT effectors such as, GSK3b and FOXO1 have also been shown to be more highly phosphorylated in leiomyoma tumors versus myometrium [88,89]. Specifically, levels of pSer256-FOXO1 were higher in leiomyoma than in matched myometrium and interestingly, the pSer256-FOXO1 was localized mostly in the nuclear fraction presumably due to inadequate shuttling of FOXO1 by 14-3-3 [88].…”

Section: Activation Of Signaling Pathways In Leiomyoma By Estrogen Anmentioning

confidence: 99%

“…AKT effectors such as, GSK3b and FOXO1 have also been shown to be more highly phosphorylated in leiomyoma tumors versus myometrium [88,89]. Specifically, levels of pSer256-FOXO1 were higher in leiomyoma than in matched myometrium and interestingly, the pSer256-FOXO1 was localized mostly in the nuclear fraction presumably due to inadequate shuttling of FOXO1 by 14-3-3 [88]. Levels of pGSK3alpha and cyclin D2 proteins were elevated significantly in the leiomyoma compared with the normal myometrium [89].…”

Section: Activation Of Signaling Pathways In Leiomyoma By Estrogen Anmentioning

confidence: 99%

The role of progesterone signaling in the pathogenesis of uterine leiomyoma

Kim

Sefton

2012

Molecular and Cellular Endocrinology

162

120

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Uterine leiomyomas are benign tumors that originate from the myometrium. Evidence points to ovarian steroid hormones, in particular, progesterone as major promoters of leiomyoma development and growth. While progesterone action in leiomyomas involves the classical nuclear receptor effects on gene regulation, there is growing evidence that signaling pathways are directly activated by the progesterone receptor (PR) and that PR can interact with growth factor signaling systems to promote proliferation and survival of leiomyomas. Studies investigating the genomic and non-genomic actions of PR and its role in leiomyoma growth are summarized here. Studies testing various selective progesterone receptor modulators for the treatment of leiomyomas are also highlighted. An increased understanding of the mechanisms associated with progesterone-driven growth of leiomyomas is critical in order to develop more efficient and targeted therapies for this prevalent disease.

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Involvement of FKHR (FOXO1) transcription factor in human uterus leiomyoma growth

Cited by 10 publications

References 17 publications

Genome-wide association analysis identifies 27 novel loci associated with uterine leiomyomata revealing common genetic origins with endometriosis

Genome-wide association analysis identifies 27 novel loci associated with uterine leiomyomata revealing common genetic origins with endometriosis

The Effects of Guizhi Fuling Capsule Drug Serum on Uterine Leiomyoma Cells and Its Mechanism

The role of progesterone signaling in the pathogenesis of uterine leiomyoma

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