Activation of protein kinase B by WNT4 as a regulator of uterine leiomyoma stem cell function

Liu, Shimeng; Yin, Ping; Dotts, Ariel J.; Kujawa, Stacy; Coon, John S.; Wei, Jian Jun; Chakravarti, Debabrata; Bulun, Serdar E.

doi:10.1016/j.fertnstert.2020.06.045

Cited by 13 publications

(9 citation statements)

References 49 publications

(82 reference statements)

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“…A comparison of the Figure indicates slightly higher levels of Wnt4 expression in stem cells compared with the mature cells. Earlier reports showed Wnt4 was primarily expressed in leiomyoma intermediate and differentiated cells, while FZD6 was predominantly expressed in stem cells 37 …”

Section: Resultsmentioning

confidence: 90%

“…Mature cells release Wnt ligands, which may act on stem cells and induce self‐renewal and proliferation by paracrine fashion 15,16 . Additionally, Wnt4 enhances the expression of pro‐proliferative genes, c‐Myc and cyclin D1, in leiomyoma stem cells 37 . Recently, we found that simvastatin reduces the expression of Wnt4 and total β‐catenin, and downstream target of the Wnt/β‐catenin pathway in UL cells 44 .…”

Section: Discussionmentioning

confidence: 99%

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Simvastatin inhibits stem cell proliferation in human leiomyoma via TGF‐β3 and Wnt/β‐Catenin pathways

Afrin

Ali

Sabeh

et al. 2022

J Cellular Molecular Medi

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Uterine leiomyoma (UL) is the most common gynaecologic tumour, affecting an estimated 70 to 80% of women. Leiomyomas develop from the transformation of myometrial stem cells into leiomyoma stem (or tumour‐initiating) cells. These cells undergo self‐renewal and differentiation to mature cells, both are necessary for the maintenance of tumour stem cell niche and tumour growth, respectively. Wnt/β‐catenin and TGF‐β/SMAD pathways, both overactive in UL, promote stem cell self‐renewal, crosstalk between stem and mature cells, cellular proliferation, extracellular matrix (ECM) accumulation and drive overall UL growth. Recent evidence suggests that simvastatin, an antihyperlipidemic drug, may have anti‐leiomyoma properties. Herein, we investigated the effects of simvastatin on UL stem cells. We isolated leiomyoma stem cells by flow cytometry using DyeCycle Violet staining and Stro‐1/CD44 surface markers. We found that simvastatin inhibits proliferation and induces apoptosis in UL stem cells. In addition, it also suppressed the expression of the stemness markers Nanog, Oct4 and Sox2. Simvastatin significantly decreased the production of the key ECM proteins, collagen 1 and fibronectin. Finally, it inhibited genes and/or proteins expression of TGF‐β1, 2 and 3, SMAD2, SMAD4, Wnt4, β‐Catenin, LRP6, AXIN2 and Cyclin D1 in UL stem cells, all are key drivers of the TGF‐β3/SMAD2 and Wnt4/β‐Catenin pathways. Thus, we have identified a novel stem cell‐targeting anti‐leiomyoma simvastatin effect. Further studies are needed to replicate these findings in vivo.

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Section: Resultsmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Simvastatin inhibits stem cell proliferation in human leiomyoma via TGF‐β3 and Wnt/β‐Catenin pathways

Afrin

Ali

Sabeh

et al. 2022

J Cellular Molecular Medi

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“…Ono et al [ 207 ] have reported that estrogen and progesterone activate canonical WNT/CTNNB1 signaling to stimulate cellular proliferation in the leiomyoma side population of stem-like cells, but this is not seen in the myometrial cells. The group also shows that WNT4 is overexpressed in CD34 + /CD49b − leiomyoma cells and can stimulate leiomyoma cell proliferation via WNT/CTNNB1 signaling and AKT [ 209 ]. Additionally, MED12 mutations have been implicated in the misregulation of WNT/CTNNB1 signaling, providing additional linage between two common mechanisms of leiomyoma development [ 206 , 210 , 211 , 212 ].…”

Section: Leiomyoma (Uterine Fibroids)mentioning

confidence: 99%

Progesterone Actions and Resistance in Gynecological Disorders

MacLean

Hayashi

2022

Cells

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Estrogen and progesterone and their signaling mechanisms are tightly regulated to maintain a normal menstrual cycle and to support a successful pregnancy. The imbalance of estrogen and progesterone disrupts their complex regulatory mechanisms, leading to estrogen dominance and progesterone resistance. Gynecological diseases are heavily associated with dysregulated steroid hormones and can induce chronic pelvic pain, dysmenorrhea, dyspareunia, heavy bleeding, and infertility, which substantially impact the quality of women’s lives. Because the menstrual cycle repeatably occurs during reproductive ages with dynamic changes and remodeling of reproductive-related tissues, these alterations can accumulate and induce chronic and recurrent conditions. This review focuses on faulty progesterone signaling mechanisms and cellular responses to progesterone in endometriosis, adenomyosis, leiomyoma (uterine fibroids), polycystic ovary syndrome (PCOS), and endometrial hyperplasia. We also summarize the association with gene mutations and steroid hormone regulation in disease progression as well as current hormonal therapies and the clinical consequences of progesterone resistance.

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“…Disruptions in Wnt/β-catenin signaling, a conserved pathway that regulates proliferation, migration, and tissue homeostasis among other processes, have been reported in different cancer types, including breast and gynecological cancers such as ovarian cancer [166]. In uLM, activation of this pathway stimulates proliferation and stem cell function [167], while inhibiting it can lead to reduced cell growth [132]. Besides, environmental conditions such as hypoxia or serum starvation may inhibit this pathway in cultured human leiomyoma cells, and induce their transdifferentiation, leading to the development of lipoleiomyomas, a less prevalent variant of uLM with a high content in adipocytes [168].…”

Section: Wnt/β-catenin Pathwaymentioning

confidence: 99%

Molecular and Cellular Insights into the Development of Uterine Fibroids

Machado-Lopez

Simón

Mas

2021

IJMS

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Uterine leiomyomas represent the most common benign gynecologic tumor. These hormone-dependent smooth-muscle formations occur with an estimated prevalence of ~70% among women of reproductive age and cause symptoms including pain, abnormal uterine bleeding, infertility, and recurrent abortion. Despite the prevalence and public health impact of uterine leiomyomas, available treatments remain limited. Among the potential causes of leiomyomas, early hormonal exposure during periods of development may result in developmental reprogramming via epigenetic changes that persist in adulthood, leading to disease onset or progression. Recent developments in unbiased high-throughput sequencing technology enable powerful approaches to detect driver mutations, yielding new insights into the genomic instability of leiomyomas. Current data also suggest that each leiomyoma originates from the clonal expansion of a single transformed somatic stem cell of the myometrium. In this review, we propose an integrated cellular and molecular view of the origins of leiomyomas, as well as paradigm-shifting studies that will lead to better understanding and the future development of non-surgical treatments for these highly frequent tumors.

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Activation of protein kinase B by WNT4 as a regulator of uterine leiomyoma stem cell function

Cited by 13 publications

References 49 publications

Simvastatin inhibits stem cell proliferation in human leiomyoma via TGF‐β3 and Wnt/β‐Catenin pathways

Simvastatin inhibits stem cell proliferation in human leiomyoma via TGF‐β3 and Wnt/β‐Catenin pathways

Progesterone Actions and Resistance in Gynecological Disorders

Molecular and Cellular Insights into the Development of Uterine Fibroids

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