Expression of miRNAs and PTEN in endometrial specimens ranging from histologically normal to hyperplasia and endometrial adenocarcinoma

Abstract

We investigated the relationship between frequently deregulated microRNAs (miRNAs) and enodometrial pathology in an attempt to find the most dependable miRNA or combination of miRNAs to identify normal, hyperplastic and malignant endometrial tissues. We also investigated the association between those miRNAs and PTEN status. We measured the expression of six miRNAs (miR-21, 182, 183, 200a, 200c and 205) in 75 formalin-fixed, paraffin-embedded normal, hyperplastic, and malignant endometrial tissue blocks using Taqman-based real-time PCR assays. PTEN loss of expression was assessed in the same endometrial tissues by immunohistochemistry. Expression of five miRNAs (miR-182, 183, 200a, 200c and 205) was significantly higher in endometrial carcinoma (CA) when compared with complex atypical hyperplasia (CAH), simple hyperplasia (SH) and normal endometrial tissue (Po0.05, respectively). Considering the likelihood ratio and number of parameters, the composite panel of six miRNAs was the best marker, revealing a sensitivity of 91% and a specificity of 94% in differentiating endometrial CA from endometrial hyperplasia or normal endometrium while the individual miRNAs exhibited 64-77% sensitivity and 66-91% specificity. Interestingly, in distinguishing endometrial CA from CAH, the composite panel of four miRNAs (miR-182, 183, 200a, 200c) was the best marker, producing 95% sensitivity and 91% specificity. The percentage of PTEN loss was significantly higher in endometrial CA compared with SH (68% vs 24%, Po0.05), and it was also higher in CAH compared with SH (71% vs 24%, Po005). Aberrant expression of miRNAs and loss of PTEN expression are common in endometrial hyperplasia and CA. They might serve to increase the diagnostic reproducibility and improve discrimination, especially, between CAH and CA by miRNA expression profiles and between simple and complex hyperplasia through PTEN expression patterns. Those expression profiles of biomarkers also might be used to predict the potential for progression from endometrial hyperplasia to invasive CA.

Identification of microRNA expression profile related to lymph node status in women with early-stage grade 1–2 endometrial cancer

“…48 We focused our analysis on postoperative FFPE EC primary tumors since it is known that FFPE specimens can be used for real-time PCR-based quantitative miRNA expression studies. 16 This meant we could draw on the entire specimen collection of the Pathology Department containing samples taken between 2003 and 2012, and select samples to form two groups fully respecting the matching criteria. However, to provide a diagnostic tool, this analysis should be validated on preoperative samples.…”

“…15 However, there are few data about nodal status-associated miRNA regulation in EC, especially in women at low and intermediate risk. miRNAs, with their remarkable stability, can be studied in formalin-fixed paraffin-embedded (FFPE) specimens 16 and are promising biomarkers for tumor staging.…”

PTEN, PAX2 and PINCH protein expression in normal endometrium, endometrial hyperplasia, and endometrioid adenocarcinomas

“…Akiyama-Abe et al reported that expression of PTEN was lost in 56 endometrial carcinoma patients (25%) [17]. Heejeong et al showed that PTEN loss was significantly higher in endometrial carcinoma compared with simple hyperplasia (68% vs. 24%), and it was also higher in complex atypical hyperplasia compared with simple hyperplasia (71% vs. 24%) [18]. In our study, PTEN expression in endometrioid carcinomas was similar to that in atypical hyperplasias (p=0.14), suggesting that alterations in PTEN occur at a relatively early stage in endometrial tumorigenesis.…”

Androgen actions via androgen receptor promote PTEN inactivation induced uterine cancer

“…PTEN functions as a phosphatase and inhibits the growth factor signals transduced through PI3K by inhibiting AKT phosphorylation (Li et al 1998). Pten mutations are observed in 30-80% of type 1 ECs and in 20-70% of complex atypical hyperplasia, a premalignant stage of EC (Tashiro et al 1997, Levine et al 1998, Lee et al 2012. Global homozygous PTEN inactivation is embryo lethal and the mice die between gestation days 6.5 and 9.5 .…”