The diversity of sex steroid action: the role of micro-RNAs and FOXO transcription factors in cycling endometrium and cancer

Abstract

The rise and fall in ovarian oestrogen and progesterone production orchestrates a series of events that are indispensable for reproduction, including ovulation, implantation, decidualisation and menstruation. In the uterus, these events involve extensive tissue remodelling, characterised by waves of endometrial cell proliferation, differentiation, recruitment of inflammatory cells, apoptosis, tissue breakdown, menstruation and regeneration. The ability of ovarian hormones to trigger such diverse physiological responses is foremost dependent upon interaction of activated steroid receptors with specific transcription factors, such as Forkhead box class O (FOXO) proteins, involved in cell fate decisions. Furthermore, micro-RNAs (miRNAs), small non-coding RNAs that function as posttranscriptional regulators of gene expression, have emerged as a major regulator system of steroid hormone responses in the female reproductive tract. Consequently, increasing evidence shows that deregulated uterine miRNA expression underpins a spectrum of common reproductive disorders, ranging from implantation failure to endometriosis. Furthermore, by targeting FOXO transcription factors and other key regulators of tissue homeostasis, oncogenic endometrial miRNAs promote tumourigenesis and cancer progression.

Endometriosis, Leiomyoma and Adenomyosis: the Risk of Gynecologic Malignancy

“…Endometriosis associated miRNAs may have regulatory functions in hypoxia, inflammation, tissue repair, TGF-β regulated pathways, cell growth, cell proliferation, apoptosis, extracellular matrix remodeling and angiogenesis . It has been proposed that miRNAs may be associated with malignant transformation (Lam et al, 2012).…”

Proteomics Identification of Annexin A2 as a Key Mediator in the Metastasis and Proangiogenesis of Endometrial Cells in Human Adenomyosis

“…Dysregulated E2 metabolism has been reported to contribute to a variety of human diseases including leiomyoma, endometriosis, osteoporosis, Parkinson disease, and gynecological malignancies (31)(32)(33)(34)(35). Recently, Flamini et al (36) reported that E2 could regulate endometrial cell cytoskeletal remodeling and motility via focal adhesion kinase.…”

Sex‐specific regulation of aging in Caenorhabditis elegans

“…In addition, Hh signaling regulates whole‐body energy metabolism via activating the Akt/FOXO pathway (Zhang, Cheng, Wang, Leung & Mak, 2017) and also influences IIS activity in certain developmental events (Lipinski et al., 2005). This is particularly interesting as in mammals, IIS is implicated in the sex‐specific regulation of tissue differentiation (Lam, Shah & Brosens, 2012; Pitetti et al., 2013). These data prompted us to perform an in silico analysis of the human genome for the presence of conserved GLI binding sites in the FOXO3 locus (Figures S11 and S12).…”