The role of amphiregulin in ovarian function and disease

Abstract

Amphiregulin (AREG) is an epidermal growth factor (EGF)-like growth factor that binds exclusively to the EGF receptor (EGFR). Treatment with luteinizing hormone (LH) and/or human chorionic gonadotropin dramatically induces the expression of AREG in the granulosa cells of the preovulatory follicle. In addition, AREG is the most abundant EGFR ligand in human follicular fluid. Therefore, AREG is considered a predominant propagator that mediates LH surge-regulated ovarian functions in an autocrine and/or paracrine manner. In addition to the well-characterized stimulatory effect of LH on AREG expression, recent studies discovered that several local factors and epigenetic modifications participate in the regulation of ovarian AREG expression. Moreover, aberrant expression of AREG has recently been reported to contribute to the pathogenesis of several ovarian diseases, such as ovarian hyperstimulation syndrome, polycystic ovary syndrome, and epithelial ovarian cancer. Furthermore, increasing evidence has elucidated new applications of AREG in assisted reproductive technology. Collectively, these studies highlight the importance of AREG in female reproductive health and disease. Understanding the normal and pathological roles of AREG and elucidating the molecular and cellular mechanisms of AREG regulation of ovarian functions will inform innovative approaches for fertility regulation and the prevention and treatment of ovarian diseases. Therefore, this review summarizes the functional roles of AREG in ovarian function and disease.

Keywords: Amphiregulin; Assisted reproductive technology; Granulosa cells; Ovary.

Fig. 1

Schematic diagram summarizing the features of AREG gene and protein structure and the AREG proteolytic processing. A Schematic representation of chromosomal localization, the structure of AREG and AREGB genes, mature AREG mRNA, and pro-AREG protein. B Schematic representation of the proteolytic processing of pro-AREG protein. BTC, betacellulin; CTF, cytosolic fragment; EPGN, epigen; EREG, epiregulin; HB domain, heparin-binding domain; TM, transmembrane domain. The figure is derived based on figures published by Berasain and Avila [8]

Fig. 2

Schematic diagram summarizing mechanisms for how AREG expression is controlled before and after the LH surge in the ovaries. Before the LH surge, PMSG-stimulated HDAC3 suppresses the transcription of AREG. The LH surge decreases HDAC3 expression, which enables H3K14 acetylation and binding of the SP1 transcription factor to the AREG promoter to stimulate the transcription of AREG (left panel). YAP protein is rapidly recruited to the TSS of the AREG promoter after LH/hCG treatment which contributes to the rapid upregulation of AREG expression in response to LH/hCG. Later, LH/hCG inactivates and downregulates YAP by activating PKA and ERK1/2 signaling pathways, which contributes to the transient expression of AREG in response to LH/hCG (right panel). H3K14, histone H3 lysine 14; hCG, human chorionic gonadotropin; HDAC3, histone deacetylase 3; LH, luteinizing hormone; PMSG, pregnant mare serum gonadotropin; TSS, transcription start site

Fig. 3

Schematic diagram summarizing mechanisms for the regulatory roles of AREG in steroidogenesis. AREG activates the ERK1/2 and PI3K/AKT signaling pathways in human granulosa-lutein cells. The activation of ERK1/2 is required for the induction of StAR expression and progesterone production by AREG. The activation of the PI3K/AKT signaling pathway is required for the induction of CYP19A1 expression and estradiol production by AREG

Fig. 4

Schematic diagram summarizing mechanisms for the effects of AREG on oocyte maturation. High levels of cAMP within the oocyte are required for maintaining meiotic arrest by activating PKA, which consequently inhibits the activity of MPF and maintains the meiotic arrest. The cAMP generated by granulosa cells or cumulus cells may be diffused from cumulus cells to oocytes via gap junctions. Oocyte itself also produces cAMP by GPR3, which is a constitutive activator of adenylate cyclase, and it activates adenylate cyclase in the absence of a ligand. The cGMP produced by granulosa cells and cumulus cells diffuses to oocytes, and there keeps a sustained high level of intra-oocyte cAMP after inhibition of the activity of oocyte PDE3A. The binding of CNP to its receptor guanylyl cyclase NPR2 produces cGMP. Diffusion of cGMP from mural granulosa cells and cumulus cells to oocytes through gap junction inhibits meiotic resumption. AREG induces oocyte meiotic resumption by decreasing CNP/NPR2-mediated cGMP production and gap junction communication between somatic cells and the oocyte. CC, cumulus cell; CNP, C-natriuretic peptide; GC, granulosa cell, GPR3, G-protein-coupled receptor 3; MPF, maturation promoting factor; NPR2, natriuretic peptide receptor 2; PDE3A, phosphodiesterase-3; PKA, protein kinase A. The figure is derived based on figures published by Conti et al. [92]

Fig. 5

Schematic diagram summarizing mechanisms for the regulatory roles of AREG in cumulus expansion. AREG stimulates HAS2, TNFAIP6, PTX3, and PTGS2 in granulosa cells. These genes mediate the AREG-induced cumulus expansion and ovulation. HA, hyaluronic acid; HAS2, hyaluronan synthase 2; PGE2, prostaglandin E2; PTGS2, prostaglandin-endoperoxide synthase 2; PTX3, pentraxin 3; TNFAIP6, tumor necrosis factor-induced protein 6

Fig. 6

Schematic diagram summarizing the local factors that regulate AREG expression in the corpus luteum. The LH levels are reduced in the luteal phase. The expression of AREG in the corpus luteum can be regulated by the AREG autocrine loop or by factors that are expressed in the corpus luteum, such as PGE2, EREG, EGF, LPA, E2, and versican. AREG stimulates the expression of StAR and CYP19A1, which subsequently contributes to the production of progesterone and estradiol. E2, estradiol; EGF, epidermal growth factor; EREG, epiregulin; LPA, lysophosphatidic acid; PGE2, prostaglandin E2