Insulin and insulin-like growth factor signaling increases proliferation and hyperplasia of the ovarian surface epithelium and decreases follicular integrity through upregulation of the PI3-kinase pathway

Abstract

BackgroundThe ovarian surface epithelium responds to cytokines and hormonal cues to initiate proliferation and migration following ovulation. Although insulin and IGF are potent proliferative factors for the ovarian surface epithelium and IGF is required for follicle development, increased insulin and IGF activity are correlated with at least two gynecologic conditions: polycystic ovary syndrome and epithelial ovarian cancer. Although insulin and IGF are often components of in vitro culture media, little is known about the effects that these growth factors may have on the ovarian surface epithelium morphology or how signaling in the ovarian surface may affect follicular health and development.MethodsOvaries from CD1 mice were cultured in alginate hydrogels in the presence or absence of 5 μg/ml insulin or IGF-I, as well as small molecule inhibitors of IR/IGF1R, PI 3-kinase signaling, or MAPK signaling. Tissues were analyzed by immunohistochemistry for expression of cytokeratin 8 to mark the ovarian surface epithelium, Müllerian inhibiting substance to mark secondary follicles, and BrdU incorporation to assess proliferation. Changes in gene expression in the ovarian surface epithelium in response to insulin or IGF-I were analyzed by transcription array. Extracellular matrix organization was evaluated by expression and localization of collagen IV.ResultsCulture of ovarian organoids with insulin or IGF-I resulted in formation of hyperplastic OSE approximately 4–6 cell layers thick with a high rate of proliferation, as well as decreased MIS expression in secondary follicles. Inhibition of the MAPK pathway restored MIS expression reduced by insulin but only partially restored normal OSE growth and morphology. Inhibition of the PI 3-kinase pathway restored MIS expression reduced by IGF-I and restored OSE growth to a single cell layer. Insulin and IGF-I altered organization of collagen IV, which was restored by inhibition of PI 3-kinase signaling.ConclusionsWhile insulin and IGF are often required for propagation of primary cells, these cytokines may act as potent mitogens to disrupt cell growth, resulting in formation of hyperplastic OSE and decreased follicular integrity as measured by MIS expression and collagen deposition. This may be due partly to altered collagen IV deposition and organization in the ovary in response to insulin and IGF signaling mediated by PI 3-kinase.

Tumor suppressor role of miR-217 in human epithelial ovarian cancer by targeting IGF1R

“…To investigate the potential target gene which miR-217 could regulate in ovarian cancer cells, we used two publicly available algorithms (Targetscan6.2 and miRanda) to predict miR-217 targets in EOC. Among the candidate target genes, IGF1R attracted our attention since it functions as an oncogene in various cancers, including ovarian cancer (15). As shown in Fig.…”

Kaempferol Exhibits Progestogenic Effects in Ovariectomized Rats

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The Effect of Capsaicin on IGF-I and IGF-IR Expression in Ovarian Granulosa Cells

“…Ozden-Akkaya and et al, (2017) injected methoxychlor to fetal and neonatal rats and they found that IGF-I expression increased in granulosa cells. On the other hand, the increase in IGF-I expression in interstitial cells was directly related to the polycystic ovary syndrome (Schildkraut et al, 1996;King et al, 2013). To our knowledge, the studies have been conducted on the expression of IGF-I and IGF-IR after CAP treatment on ovarian granulosa cells have not been reported.…”