Expression and functional analysis of platelet-derived growth factor in uterine leiomyomata

Mao, Liang; Wang, Hongbo; Zhang, Yuan; Lu, Shi Jiang; Wang, Zehua

doi:10.4161/cbt.5.1.2234

Cited by 41 publications

(41 citation statements)

References 30 publications

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“…The expression of FGF receptor protein was also reported to be more intense in leiomyomas than in the myometrium (25). Another potent mitogen for smooth muscle cells is PDGF, its mRNA is expressed in both leiomyomas and in myometrium, and its receptor sites per cell are seen more in leiomyomas than in the myometrium (26,27). However, it appears that PDGF does not act alone, but acts in concert with other growth factors such as TGF-β, EGF, and the IGFs.…”

Section: Discussionmentioning

confidence: 99%

Differential Expression of Receptor Tyrosine Kinases (RTKs) and IGF-I Pathway Activation in Human Uterine Leiomyomas

Saile

Swartz

et al. 2008

Mol Med

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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-IRβ and phosphorylated IGF-IRβ. 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-IRβ, 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-IRβ 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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Section: Discussionmentioning

confidence: 99%

Differential Expression of Receptor Tyrosine Kinases (RTKs) and IGF-I Pathway Activation in Human Uterine Leiomyomas

Saile

Swartz

et al. 2008

Mol Med

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“…Platelet-derived growth factor stimulates DNA and protein synthesis, increases collagen α1 expression, and modulates the rate of cell proliferation in myometrium and leiomyoma cells [13]. In this study, PDGF-A mRNA expression in leiomyoma and normal myometrium was decreased after treatment with SPRM; PCNA protein was increased in leiomyoma.…”

Section: Commentmentioning

confidence: 73%

“…Several growth factors, including epidermal (EGF) [9], insulin-like (IGF) [10,11], vascular endothelial (VEGF) [12], platelet-derived (PDGF) [13], and transforming (TGF)-β growth factors [14], are associated with leiomyoma growth. Furthermore, some apoptotic factors such as p53 tumor suppressor [15], B-cell lymphoma (Bcl)-2 [16,17], and tumor necrosis factor (TNF)-α [18] are involved in leiomyoma apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Changes in proliferating and apoptotic markers of leiomyoma following treatment with a selective progesterone receptor modulator or gonadotropin-releasing hormone agonist

Yun¹,

Seong²,

Hyun³

et al. 2015

European Journal of Obstetrics & Gynecology and Reproductiv

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“…Since it has been shown that IGF-I treatment can increase leiomyoma proliferation [103,116,117], it remains to be clarified how progesterone regulation of IGFs contributes to leiomyoma growth. The differential expression of PDGFs in leiomyoma and myometrial cells is conflicting depending on the study [105,118–122]. It has been shown that increased PDGF-BB expression occurs during the secretory phase compared to the proliferative phase in leiomyomas [118].…”

Section: Regulation Of Growth Factors and Their Receptors By Progestementioning

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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Expression and functional analysis of platelet-derived growth factor in uterine leiomyomata

Cited by 41 publications

References 30 publications

Differential Expression of Receptor Tyrosine Kinases (RTKs) and IGF-I Pathway Activation in Human Uterine Leiomyomas

Differential Expression of Receptor Tyrosine Kinases (RTKs) and IGF-I Pathway Activation in Human Uterine Leiomyomas

Changes in proliferating and apoptotic markers of leiomyoma following treatment with a selective progesterone receptor modulator or gonadotropin-releasing hormone agonist

The role of progesterone signaling in the pathogenesis of uterine leiomyoma

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