Gene expression and tissue concentrations of IGF-I in human myometrium and fibroids under different hormonal conditions

Englund, Katarina; Lindblom, Bo; Carlström, Kjell; Gustavsson, Inger; Sjöblom, Peter; Blanck, Agneta

doi:10.1093/molehr/6.10.915

Cited by 44 publications

(40 citation statements)

References 28 publications

(19 reference statements)

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“…It exerts its mitogenic action by increasing DNA synthesis, accelerating the progression of the cell cycle from G-to S-phase, and inhibiting apoptosis (6). Several studies have indicated increased expression of IGF-I mRNA and higher tissue concentrations of IGF-I protein in leiomyomas versus corresponding myometrium (37)(38)(39). Our previous study also found that IGF-I peptide immunolocalized to the leiomyoma cells and the fibroblasts in the bands of intervening connective tissue comprising the extracellular matrix in some leiomyomas; the latter was not seen in the myometrial samples.…”

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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“…Englund et al (2000) reported that leiomyomas taken from premenopausal women contained more IGF-I mRNA than tumors taken from postmenopausal women and that IGF-I concentrations correlated with serum E 2 concentrations (Englund et al 2000). Likewise, Giudice et al (1993) reported that myometrium and leiomyomas taken from the follicular phase of the cycle, when E 2 levels peak, express higher levels of IGF-I transcripts than tumors and myometrium from the luteal phase.…”

Section: Discussionmentioning

confidence: 99%

“…Boehm et al (1990) reported IGF-I mRNAs to be higher in leiomyomas than normal tissue, whereas a study by Gloudemans et al (1990) concluded that no difference existed. Investigations in which tissue samples were grouped according to menstrual cycle reported that leiomyomas contained higher levels of IGF-I message than like-staged myometrium, but these data either failed to reach statistical significance (2-fold) or were marginal (1·1-to 1·4-fold) (Vollenhoven et al 1993, Englund et al 2000. In a study by Giudice et al (1993), IGF-I was expressed by follicular phase leiomyoma and normal myometrium, but small sample size and lack of quantitation made correlation of changes in IGF-I levels with phase of menstrual cycle problematic.…”

Section: Introductionmentioning

confidence: 99%

Dysregulation of IGF-I signaling in uterine leiomyoma

Burroughs¹,

Howe²,

Okubo³

et al. 2002

Journal of Endocrinology

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IGF-I expression has been observed in human uterine leiomyomas. To examine whether autocrine IGF-I signaling plays a role in the growth of these tumors, we used an animal model of uterine leiomyoma (the Eker rat) to investigate regulation of IGF-I and the IGF-I receptor (IGF-IR) expression in tumors and normal myometrium. During the normal estrous cycle, myometrial IGF-I expression peaked on the day of proestrus when the rate of proliferation in this tissue is greatest. In leiomyomas, the expression of IGF-I was increased 7·5-fold compared with the age-matched normal tissue. The level of IGF-IR mRNA in both tumor and non-tumor tissues was found to inversely correlate with that of IGF-I. Changes observed in IGF-I signaling components correlated with the activation state of the signal-transducing protein insulin receptor substrate-1 (IRS-1). During diestrus and proestrus when IGF-I levels were increasing, tyrosine phosphorylation of IRS-1 was increased up to 5·7-fold in the normal myometrium relative to estrus, when IGF-I levels were the lowest. Additionally, IRS-1 phosphorylation was 4-fold greater in leiomyomas relative to agematched normal myometrium. Autocrine stimulation of the IGF-IR may, therefore, play a role in regulating the normal growth of the myometrium, and dysregulation of IGF-I signaling could contribute to the neoplastic growth of uterine leiomyomas.

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“…The immunoreactivities for insulin-like growth factor 1 and insulin-like growth factor receptor were significantly higher in leiomyomata than in myometrium (Po0.03 and o0.001), which is consistent with the previous studies. 28,29 It has been shown that AKT and phosphatidylinositol 3-kinase were upregulated in fibroid. 30 Our data showed a similar finding but statistically insignificant due to a large variation ( Figure 2, Table 2).…”

Section: Immunohistochemical Data In the Panelsmentioning

confidence: 99%

Expression profile of tuberin and some potential tumorigenic factors in 60 patients with uterine leiomyomata

et al. 2005

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Human uterine leiomyomata are the most common tumors in women of reproductive age. The pathogenesis of leiomyomata remains unknown. An animal model of Eker rats with deleted tuberous sclerosis complex gene 2 (tuberin) shows increased incidence of leiomyomata. The role of tuberin in human leiomyomata is unknown. In this study, we designed a tissue microarray with tissue cores of leiomyomata and the matched myometrium from 60 hysterectomy specimens. We examined the expression of tuberin and tuberous sclerosis complex gene 1 product hamartin, proteins of the insulin-signaling pathway, steroid receptors and some of their cofactors, and human mobility group gene A2 by immunohistochemistry. We found that nearly half of the cases displayed either reduction or loss of tuberin in leiomyomata compared with matched normal myometrium. No change of hamartin was noted. Furthermore, a significant reduction of glucocorticoid receptor was found in leiomyomata with reduced tuberin. The proteins insulin like growth factor 1, insulin-like growth factor receptor b, AKT kinase, and phosphatidylinositol 3-kinase were upregulated. Nearly half of leiomyomata show upregulation of human mobility group gene A2, along with the steroid receptor cofactors. Our findings suggest that there are two broad groups of uterine leiomyomata. One group is associated with an alteration of tuberin and glucocorticoid receptor. The other group is associated with upregulation of human mobility group gene A2 and steroid receptor cofactors.

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Gene expression and tissue concentrations of IGF-I in human myometrium and fibroids under different hormonal conditions

Cited by 44 publications

References 28 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

Dysregulation of IGF-I signaling in uterine leiomyoma

Expression profile of tuberin and some potential tumorigenic factors in 60 patients with uterine leiomyomata

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