Upregulation of ATP-sensitive potassium channels for estrogen-mediated cell proliferation in human uterine leiomyoma cells

Park, Sung-Hee; Ramachandran, Sabarish; Kwon, Sang-Hoon; Cha, Soon-Do; Seo, Eul Won; Bae, Insoo; Cho, Chi-Heum; Song, Dae‐Kyu

doi:10.1080/09513590801893315

Cited by 22 publications

(16 citation statements)

References 22 publications

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“…Furthermore, the rapid loss of ESR1 and PGR expression in primary LM cell culture (42) is undoubtedly due to the overgrowth of TAFs, which express ESR1 and PGR at lower levels compared to LM SMCs. Several studies have demonstrated the growth-promoting effect of estrogens on primary LM cell cultures (43,44), contradicting with results from our PDTX studies, in which E2 does not stimulate the growth of LM SMCs. These conflicting observations can also be explained by the overgrowth of TAFs in LM cell culture as their growth is stimulated by E2 alone.…”

Section: Discussioncontrasting

confidence: 99%

Subtype-Specific Tumor-Associated Fibroblasts Contribute to the Pathogenesis of Uterine Leiomyoma

Wu¹,

Serna²,

Thomas³

et al. 2017

Cancer Research

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Recent genomic studies have identified subtypes of uterine leiomyoma (LM) with distinctive genetic alterations. Here we report the elucidation of the biological characteristics of the two most prevalent LM subtypes, MED12 mutant (MED12-LM) and HMGA2-overexpressing (HMGA2-LM) LM. Since each tumor carries only one genetic alteration, both subtypes are considered to be monoclonal. Approximately 90% of cells in HMGA2-LM were smooth muscle cells (SMC) with HMGA2 overexpression. In contrast, MED12-LM consisted of similar numbers of SMC and non-SMC, which were mostly tumor-associated fibroblasts (TAF). Paradoxically, TAF carried no mutations in MED12, suggesting an interaction between SMC and TAF to coordinate their growth. The higher amount of ECM in MED12-LM than HMGA2-LM was partially due to the high concentration of collagen-producing TAF. SMC growth in a xenograft assay was driven by progesterone in both LM subtypes. In contrast, TAF in MED12-LM proliferated in response to estradiol, whereas progesterone had no effect. The high concentration of estrogen-responsive TAF in MED12-LM explains the inconsistent discoveries between in vivo and in vitro studies on the mitogenic effect of estrogen and raises questions regarding the accuracy of previous studies utilizing MED12-LM cell culture. In addition, the differential effects of estradiol and progesterone on these LM subtypes emphasize the importance of subtypes and genotypes in designing non-surgical therapeutic strategies for LM.

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Section: Discussioncontrasting

confidence: 99%

Subtype-Specific Tumor-Associated Fibroblasts Contribute to the Pathogenesis of Uterine Leiomyoma

Wu¹,

Serna²,

Thomas³

et al. 2017

Cancer Research

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“…It has been indicated that down-regulation of ATP-sensitive potassium channel (K ATP channel) subunits may facilitate myometrial function during late pregnancy in humans [ 63 ]. In another study in humans, it has been revealed that estrogen may induce the activation of K ATP channels to promote cell proliferation in the myometrial [ 65 ]. Therefore, the ABCC9 gene can be considered as a potential candidate gene in dairy cattle and may have a role in cell proliferation of myometrial cells and resuming the reproduction cycle after calving.…”

Section: Resultsmentioning

confidence: 99%

Genome-wide association for milk production and female fertility traits in Canadian dairy Holstein cattle

Sargolzaei²,

et al. 2016

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BackgroundGenome-wide association studies (GWAS) are a powerful tool for detecting genomic regions explaining variation in phenotype. The objectives of the present study were to identify or refine the positions of genomic regions affecting milk production, milk components and fertility traits in Canadian Holstein cattle, and to use these positions to identify genes and pathways that may influence these traits.ResultSeveral QTL regions were detected for milk production (MILK), fat production (FAT), protein production (PROT) and fat and protein deviation (FATD, PROTD respectively). The identified QTL regions for production traits (including milk production) support previous findings and some overlap with genes with known relevant biological functions identified in earlier studies such as DGAT1 and CPSF1. A significant region on chromosome 21 overlapping with the gene FAM181A and not previous linked to fertility in dairy cattle was identified for the calving to first service interval and days open. A functional enrichment analysis of the GWAS results yielded GO terms consistent with the specific phenotypes tested, for example GO terms GO:0007595 (lactation) and GO:0043627 (response to estrogen) for milk production (MILK), GO:0051057 (positive regulation of small GTPase mediated signal transduction) for fat production (FAT), GO:0040019 (positive regulation of embryonic development) for first service to calving interval (CTFS) and GO:0043268 (positive regulation of potassium ion transport) for days open (DO). In other cases the connection between the enriched GO terms and the traits were less clear, for example GO:0003279 (cardiac septum development) for FAT and GO:0030903 (notochord development) for DO trait.ConclusionThe chromosomal regions and enriched pathways identified in this study confirm several previous findings and highlight new regions and pathways that may contribute to variation in production or fertility traits in dairy cattle.Electronic supplementary materialThe online version of this article (doi:10.1186/s12863-016-0386-1) contains supplementary material, which is available to authorized users.

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“…These estrogen actions are accomplished through the rapid activation of different kinds of kinases; some of them [75] result to be increased in both immortalized uterine smooth muscle and leiomyoma cell lines under estrogen stimulation. In addition, Park and colleagues reported that estrogens may also stimulate the proliferation of leiomyoma cells by activating ATP-sensitive potassium channels [76]. …”

Section: Pathogenesis Of Uterine Leiomyomamentioning

confidence: 99%

Uterine Fibroids: Pathogenesis and Interactions with Endometrium and Endomyometrial Junction

Ciavattini

Giuseppe

Stortoni

et al. 2013

Obstetrics and Gynecology International

171

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Uterine leiomyomas (fibroids or myomas) are benign tumors of uterus and clinically apparent in a large part of reproductive aged women. Clinically, they present with a variety of symptoms: excessive menstrual bleeding, dysmenorrhoea and intermenstrual bleeding, chronic pelvic pain, and pressure symptoms such as a sensation of bloatedness, increased urinary frequency, and bowel disturbance. In addition, they may compromise reproductive functions, possibly contributing to subfertility, early pregnancy loss, and later pregnancy complications. Despite the prevalence of this condition, myoma research is underfunded compared to other nonmalignant diseases. To date, several pathogenetic factors such as genetics, microRNA, steroids, growth factors, cytokines, chemokines, and extracellular matrix components have been implicated in the development and growth of leiomyoma. This paper summarizes the available literature regarding the ultimate relative knowledge on pathogenesis of uterine fibroids and their interactions with endometrium and subendometrial myometrium.

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Upregulation of ATP-sensitive potassium channels for estrogen-mediated cell proliferation in human uterine leiomyoma cells

Abstract: Estrogen may induce the proliferation of leiomyoma cells, at least in part, by activating the K(ATP) channel. Increased expression of the K(ATP) channel may be a causal factor for the high growth rate of uterine leiomyoma.

Cited by 22 publications

References 22 publications

Subtype-Specific Tumor-Associated Fibroblasts Contribute to the Pathogenesis of Uterine Leiomyoma

Subtype-Specific Tumor-Associated Fibroblasts Contribute to the Pathogenesis of Uterine Leiomyoma

Genome-wide association for milk production and female fertility traits in Canadian dairy Holstein cattle

Uterine Fibroids: Pathogenesis and Interactions with Endometrium and Endomyometrial Junction

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