Differential expression of receptor tyrosine kinases (RTKs) and IGF-I pathway activation in human uterine leiomyomas

Cellular and Molecular Pathology Branch, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), Department of Health and Human Services (DHHS), Research Triangle Park, North Carolina, United States of America.
Molecular Medicine (Impact Factor: 4.51). 05/2008; 14(5-6):264-75. DOI: 10.2119/2007-00101.Yu
Source: PubMed


Uterine leiomyomas (fibroids) are benign tumors that are prevalent in women of reproductive age. Research suggests that activated receptor tyrosine kinases (RTKs) play an important role in the enhanced proliferation observed in fibroids. In this study, a phospho-RTK array technique was used to detect RTK activity in leiomyomas compared with myometrial tissue. We found that fifteen out of seventeen RTKs evaluated in this study were highly expressed (P < 0.02-0.03) in the leiomyomas, and included the IGF-I/IGF-IR, EGF/EGFR, FGF/FGF-R, HGF/HGF-R, and PDGF/PDGF-R gene families. Due to the higher protein levels of IGF-IR observed in leiomyomas by us in earlier studies, we decided to focus on the activation of the IGF-IR, its downstream effectors, and MAPKp44/42 to confirm our earlier findings; and validate the significance of the increased IGF-IR phosphorylation observed by RTK array analysis in this study. We used immunolocalization, western blot, or immunoprecipitation studies and confirmed that leiomyomas overexpressed IGF-IRbeta and phosphorylated IGF-IRbeta. Additionally, we showed that the downstream effectors, Shc, Grb2, and MAPKp44/42 (P < 0.02-0.001) were also overexpressed and involved in IGF-IR signaling in these tumors, while IRS-I, PI3K, and AKT were not. In vitro studies showed that IGF-I (100 ng/mL) increased the proliferation of uterine leiomyoma cells (UtLM) (P < 0.0001), and that phosphorylated IGF-IRbeta, Shc, and MAPKp44/42 were also overexpressed in IGF-I-treated UtLM cells (P < 0.05), similar to the tissue findings. A neutralizing antibody against the IGF-IRbeta blocked these effects. These data indicate that overexpression of RTKs and, in particular, activation of the IGF-IR signaling pathway through Shc/Grb2/MAPK are important in mediating uterine leiomyoma growth. These data may provide new anti-tumor targets for noninvasive treatment of fibroids.

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    • "Regulation of growth factor signaling pathways in uterine fibroids by endogenous and environmental factors Estrogen and progesterone influence leiomyoma growth through regulating growth factors and cytokines and their signaling pathways (Flake et al., 2003). Activation of steroid hormone receptors can have a myriad of effects including the regulation of growth factors and their receptor tyrosine kinases (RTKs) that can result in the activation of downstream effector proteins, such as mitogen-activated protein kinase (MAPK) p44/42 (ERK1/2) (Yu et al., 2008, 2010) (see Tables I and II). Fibroids may also be targeted by environmental chemicals whose biological effects are mediated by hormone receptors (Di et al., 2008). "
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    ABSTRACT: BACKGROUND Uterine fibroids are the most common gynecologic tumors in women of reproductive age yet the etiology and pathogenesis of these lesions remain poorly understood. Age, African ancestry, nulliparity and obesity have been identified as predisposing factors for uterine fibroids. Symptomatic tumors can cause excessive uterine bleeding, bladder dysfunction and pelvic pain, as well as associated reproductive disorders such as infertility, miscarriage and other adverse pregnancy outcomes. Currently, there are limited noninvasive therapies for fibroids and no early intervention or prevention strategies are readily available. This review summarizes the advances in basic, applied and translational uterine fibroid research, in addition to current and proposed approaches to clinical management as presented at the ‘Advances in Uterine Leiomyoma Research: 3rd NIH International Congress’. Congress recommendations and a review of the fibroid literature are also reported.
    Full-text · Article · Apr 2014 · Human Reproduction Update
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    • "A growing body of evidence indicates that leiomyomas growth is mediated by ovarian steroids (estrogen and progesterone) (Sadovsky et al., 1993;Rein et al., 1995). Growth factors have been reported to be associated with the growth of leiomyomas (Strawn et al., 1995;Shimomura et al., 1998;Yu et al., 2008). More recent studies have shown that growth factors and cytokines can induce NADPH oxidase-dependent reactive oxygen species (ROS) production, which in turn has been shown to activate mitogenactivated protein kinases that regulate downstream cell proliferation or matrix production (Ushio-Fukai et al., 1998;Svegliati et al., 2005). "
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    ABSTRACT: Uterine leiomyomas are benign tumors that develop from smooth muscle cells (SMCs). The reactive oxygen species (ROS) have been shown to be involved in the signaling pathways that stimulate proliferation of a variety of cell types. Thioredoxin-1 (TRX-1) is a redox-regulating protein, which is overexpressed in various tumors. In the present study, we investigated the expressions of TRX-1 and its related molecules in uterine leiomyomas and matched adjacent myometrium. Our results showed the expression of TRX-1 was increased in leiomyomas compared with the matched adjacent myometrium by quantitative RT–PCR and western blotting. FOXO3A expression was increased in leiomyomas compared with myometrium by western blotting. The mRNA levels of hypoxia-inducible factor-1α, cyclooxygenase-2 and cyclin D1 were increased in leiomyomas compared with the adjacent myometrium. The mRNA level of (thioredoxin-1-binding protein) TBP-2 in leiomyomas was not altered when compared with the matched adjacent myometrium. These results suggest that TRX-1 and some of its related molecules are associated with the pathogenesis of uterine leiomyomas. The identification of TRX-1 signaling pathways leading to cell proliferation points to another potential therapeutic target for treatment and/or prevention of uterine leiomyomas.
    Preview · Article · Oct 2013 · Molecular Human Reproduction
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    • "TGF-β can also activate kinase pathways (MAPK/ERK/Smad) and thereby modulate the expression of different types of genes influencing the leiomyoma growth and regression [102]. Similarly, IGF may increase cellular proliferation in uterine leiomyoma cells through activation of the MAPK pathway [103] and thus play a crucial role in leiomyoma cell growth, by upregulation of Bcl-2 protein expression in leiomyoma cells [104]. "
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    ABSTRACT: 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.
    Full-text · Article · Sep 2013 · Obstetrics and Gynecology International
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