Different Proliferative and Apoptotic Activity in Peripheral versus Central Parts of Human Uterine Leiomyomas

Bourlev, Vladimir; Pavlovitch, Stanislav; Stygar, Denis; Volkov, N. I.; Lindblom, Bo; Olovsson, Matts

doi:10.1159/000072074

Cited by 24 publications

(10 citation statements)

References 25 publications

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“…Also, other studies comparing estrogen receptor protein expression in leiomyomas from women in the proliferative and secretory phases have shown that ER was expressed at lower levels during the secretory phase. This supports the concept that progesterone may be decreasing the levels of ERα, thereby making less receptor available for phosphorylation [3, 22, 43]. …”

Section: Discussionsupporting

confidence: 83%

Estrogen receptor alpha (ERα) phospho-serine-118 is highly expressed in human uterine leiomyomas compared to matched myometrium

Hermon

Moore

et al. 2008

Virchows Arch

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It is thought that the growth of uterine leiomyomas may be mediated by the interaction of estrogen receptor alpha (ERα) and growth factor pathways and that phosphorylation of ERα at serine 118 (ERα-phospho-Ser118) is important in this interaction. In this study, immunoblotting and immunohistochemistry were used to investigate the expression of ERα-phospho-Ser118, NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript phosphorylated p44/42 mitogen-activated protein kinase (phospho-p44/42 MAPK), and proliferating cell nuclear antigen (PCNA) in human leiomyoma and myometrial tissues during the proliferative and secretory phases of the menstrual cycle. We found that tumors taken from the proliferative phase expressed significantly higher levels of ERα-phospho-Ser118, phospho-p44/42 MAPK, and PCNA compared to patient-matched myometria and had significantly higher ERα-phospho-Ser118 and PCNA expression compared to secretory phase tumors. Also, enhanced colocalization and association of phospho-p44/42 MAPK and ERα-phospho-Ser118 were observed in proliferative phase tumors by confocal microscopy and immunoprecipitation, respectively. These data suggest that ERα-phospho-Ser118 may be important in leiomyoma growth and is possibly phosphorylated by phospho-p44/42 MAPK.

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Section: Discussionsupporting

confidence: 83%

Estrogen receptor alpha (ERα) phospho-serine-118 is highly expressed in human uterine leiomyomas compared to matched myometrium

Hermon

Moore

et al. 2008

Virchows Arch

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“…The reason that the xenograft tissues obtained by LAM and TAH failed to grow after implantation might be due to mechanical tissue damage induced by the device and long-term blood occlusion of feeder arteries before hysterectomy, respectively. In regard to the size of the myoma and the sites of tissue harvesting, although no statistically significant difference was found in the capacity for growth between the central site and the marginal site in myomas, larger-sized myomas have cells in the marginal sites that are highly mitogenically active, which results in more outer growth 16 , 17 .…”

Section: Discussionmentioning

confidence: 92%

Establishment of a novel mouse xenograft model of human uterine leiomyoma

Suzuki

Masaaki

Saito

et al. 2018

Sci Rep

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Uterine leiomyoma is the most common benign tumour in women, and an appropriate animal model for leiomyoma would be useful for exploring new therapeutic strategies. Therefore, we have been challenged to develop a new simple mouse model for human leiomyoma. Leiomyoma tissues were harvested from myomas resected by different surgical procedures with or without gonadotropin-releasing hormone agonist (GnRHa) treatment and were subcutaneously implanted into BALB/c nude mice with an estradiol/progesterone-releasing pellet. The implanted leiomyoma tissues that were obtained from the marginal site of large myomas resected by abdominal myomectomy with GnRHa treatment exhibited sufficient tumour growth in the transplanted mice. The leiomyomas that were treated with GnRHa highly expressed the estrogen/progesterone receptor genes, insulin-like growth factor 2 (IGF2) and embryonic smooth muscle myosin heavy chain (SMemb), which suggests that these factors are critical in the establishment of a mouse model of growing leiomyoma. As a result, this model will be useful for the development of new therapeutic strategies.

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“…Pertinently, peripheral parts of leiomyomas have been shown to have a higher turnover of cells compared with the central parts30. In addition to pAkt, the tumour suppressor LKB1 also regulates the mTOR pathway.…”

Section: Discussionmentioning

confidence: 99%

PI3K/Akt/mTOR signaling & its regulator tumour suppressor genes PTEN & LKB1 in human uterine leiomyomas

Makker¹,

Goel²,

Mahdi³

et al. 2016

Indian Journal of Medical Research

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Background & objectives:Despite their high occurrence and associated significant level of morbidity manifesting as spectrum of clinical symptoms, the pathogenesis of uterine leiomyomas (ULs) remains unclear. We investigated expression profile of tumour suppressor genes PTEN (phosphatase and tensin homolog deleted on chromosome ten) and LKB1 (liver kinase B1), and key signaling components of P13K (phosphatidylinositol 3-kinase)/Akt (protein kinase B)/mTOR (mammalian target of rapamycin) pathway in leiomyomas and adjacent normal myometrium in women of reproductive age, to explore the possibility of targeting this pathway for future therapeutic implications.Methods:Real time PCR (qPCR) was used to quantify relative gene expression levels of PTEN, Akt1, Akt2, mTOR, LKB1 and VEGFA (vascular endothelial growth factor A) in leiomyoma as compared to adjacent normal myometrium. Immunohistochemistry was subsequently performed to analyze expression of PTEN, phospho-Akt, phospho-mTOR, phospho-S6, LKB1 and VEGFA in leiomyoma and adjacent normal myometrium.Results:Significant upregulation of PTEN (2.52 fold; P=0.03) and LKB1 (3.93 fold; P=0.01), and downregulation of VEGFA (2.95 fold; P=0.01) genes were observed in leiomyoma as compared to normal myometrium. Transcript levels of Akt1, Akt2 and mTOR did not vary significantly between leiomyoma and myometrium. An increased immunoexpression of PTEN (P=0.015) and LKB1 (P<0.001) and decreased expression of VEGFA (P=0.01) was observed in leiomyoma as compared to myometrium. Immunostaining for activated (phosphorylated) Akt, mTOR and S6 was absent or low in majority of leiomyoma and myometrium.Interpretation & conclusions:Upregulation of PTEN and LKB1 in concert with negative or low levels of activated Akt, mTOR and S6 indicates that PI3K/Akt/mTOR pathway may not play a significant role in pathogenesis of leiomyoma.

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Different Proliferative and Apoptotic Activity in Peripheral versus Central Parts of Human Uterine Leiomyomas

Cited by 24 publications

References 25 publications

Estrogen receptor alpha (ERα) phospho-serine-118 is highly expressed in human uterine leiomyomas compared to matched myometrium

Estrogen receptor alpha (ERα) phospho-serine-118 is highly expressed in human uterine leiomyomas compared to matched myometrium

Establishment of a novel mouse xenograft model of human uterine leiomyoma

PI3K/Akt/mTOR signaling & its regulator tumour suppressor genes PTEN & LKB1 in human uterine leiomyomas

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