Estrogen affects the negative feedback loop of PTENP1-miR200c to inhibit PTEN expression in the development of endometrioid endometrial carcinoma

Abstract

Endometrial carcinoma is one of the most common malignancies in the female reproductive system. It is well-known that estrogen plays an important role in the pathogenesis of endometrioid endometrial carcinoma (EEC), and induces the cancer suppressor gene PTEN deletion. However, how estrogen affects PTEN expression remains unknown. In the present study, we found in 40 EEC specimens, miR-200c level was higher in most cancer areas than that in the adjacent normal endometrium, while PTEN and PTENP1 were lower. Moreover, the expression of PTEN/PTENP1 and miR-200c also showed a converse relationship in EEC cell lines. In addition, we demonstrated that miR-200c bound directly to PTEN and PTENP1, and PTENP1 could reverse miR-200c inhibition function to PTEN using a dual-luciferase reporter and RNA binding protein immunoprecipitation (RIP) assays. Next, 17β-estradiol (E2) treatment could improve miR-200c and drop the PTEN level, which caused a consequential increase of the phospho-PI3K-AKT pathway genes. When we stably knocked down estrogen receptor α (ERα) expression in the EEC cell line, the effects of E2 on miR-200c and PTEN declined. In addition, it was demonstrated that E2 might modulate cell proliferation, migration and invasion relying on the expression of miR-200c. Taken together, it can be concluded that estrogen improves the miR-200c level by combining with ER, PTENP1 and PTEN could be inhibited by miR-200c, and then activate the PI3K-AKT pathway. This work provided a new mechanism of EEC development and a new potential therapeutic target.

MicroRNA as Epigenetic Modifiers in Endometrial Cancer: A Systematic Review

“…The miR-200 family is implicated in the PI3K/AKT/mTOR signaling pathway, at least in part through downregulation of the PTEN tumor suppressor [ 141 , 142 , 143 ]. This was recently confirmed by Chen et al who reported that miR-200c binds directly to PTEN and PTENP1 in endometrioid EC [ 102 ]. In agreement, a different study reported that estrogen stimulation increases the expression of miR-200c which is accompanied by decreased PTEN expression and activation of the PI3K-AKT pathway thereby promoting increased cellular survival [ 67 ].…”

“…They are frequently detected in patients with aberrant methylation of the MLH1 promoter regions that cause inactivation of the mismatch repair (MMR) gene [ 164 , 165 ]. The miR-200 family, miR-183 and miR-21 have been shown to target the PTEN gene, and their expression levels in endometrial tissue can be used to predict the risk of tumor progression from endometrial hyperplasia to invasive EC [ 102 , 122 ]. TP53 mutations, corresponding to the “Copy Number High” subgroups, are more common in grade 3 tumors, which are associated with poorer survival than other tumor groups.…”

“…This systematic review identified 105 original articles and two literature reviews reporting the expression pattern of miRNAs . Of the 69 articles comparing neoplastic endometrial tissue with the surrounding healthy tissue, 39 were published after October 31, 2018 and were not presented in our previous review [53][54][55][56][57][58][59]94,96,[98][99][100][101][102][103][131][132][133][134]. Overall, the 69 studies included an average of 82 endometrial tumor samples (minimum 4, maximum 579) and 22 healthy endometrial samples (minimum 5, maximum 56).…”

A disparate role of RP11-424C20.2/UHRF1 axis through control of tumor immune escape in liver hepatocellular carcinoma and thymoma

“…Pseudogenes most likely impact their parental gene expression via ceRNA network in which pseudogene RNAs interact with their counterparts through competitively binding to common miRNAs and attenuate repression on the parental genes [25]. In this context, pseudogene PTENP1 up-regulated its parental gene PTEN expression by sponging miR-19b, miR-21, miR-193-3p and miR-200c [26–29]. In this study, we observed that RP11-424C20.2 expression was strongly correlated with its parental gene UHRF1 expression in 8 types of human cancer.…”

<p>ERα, A Key Target for Cancer Therapy: A Review</p>

“…69,70 In endometrial carcinoma, estrogen contributes to carcinogenesis by activating ERα, which subsequently activates the downstream signaling pathways of phosphatidylinositol 3-kinase (PI3K)/ AKT and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) (Figure 3). 69,71 In ER+ breast cancer, estrogen activates the PI3K/AKT/mTOR signaling pathway by associating with extra-nuclear ERα, which results in drug resistance and epithelial-to-mesenchymal transition (EMT) (Figure 3). 70,72 Targeting ERα reportedly causes changes in the expression of components of the PI3K/AKTprotein kinase Cα signaling pathway, resulting in cell apoptosis.…”