miRNAs Regulate Myometrial Invasion in Endometrioid Endometrial Carcinoma
Ana Mozos, Emanuela D´Angelo, Cristina Rivera, Elena Serrano, Inigo Espinosa, Luis Catasus, Jaime Prat. Hospital de la Santa Creu i Sant Pau. Institute of Biomedical Research (IIB Sant Pau). Autonomous University of Barcelona, Barcelona, Spain
Background: Recently, distinct miRNA expressions signatures have been identified in different stages of endometrioid endometrial carcinoma (EEC). The PTEN/AKT pathway is activated in EEC and induces deregulation of various FOXO proteins, a family of transcription factors that controls cell fate. FOXO1 which is involved in cell cycle regulation, apoptosis, and cell differentiation, is also controlled by miRNAs. For the first time, we study the expression of miRNA signatures and FOXO1 in a series of non-invasive and invasive EEC.
Design: miRNA expression signatures were studied in a series of 25 EEC and 5 normal endometria. Results, were validated in a series of 41 additional EEC by quantitative PCR for miR-27 and FOXO1, and immunohistochemistry for FOXO1 and active Caspase 3. Also PIK3CA and PTEN gene mutations were assessed by sequencing analysis for exons 9 and 20 of PIK3CA, and exons 1-9 of PTEN genes.
Results: In unsupervised hierarchical clustering analysis, normal endometria and non-invasive EEC were grouped together and separately from invasive and advanced stage tumors. A signature of 20 miRNAs was found to be differentially expressed in invasive and non invasive tumors (adjusted p value <0.001). One of them, miR27, was overexpressed in invasive carcinomas when compared to non invasive EEC (p=0.0013) and its expression increased linearly in each stage (p=0.001). Differences between non-invasive and invasive EEC were also observed in the validation group (p=0.045). Moreover, FOXO1, the main target of miR27, was downregulated in invasive tumors when compared to non-invasive tumors (p=0.033). Accordingly, we found that expression of active caspase 3 was higher in non-invasive than in invasive EEC (p=0.023). By immunohistochemistry, all tumors lacked FOXO1 immunoreaction whereas normal endometria were immunoreactive. In invasive tumors, miR27 overexpression (p=0.032) and FOXO1 downregulation (p=0.014) also occurred in unmutated PIK3CA tumors (n=27).
Conclusions: Different miRNA signatures were found in invasive and non invasive EEC. The miR27-FOXO1 tandem inhibits apoptosis and represents an alternative mechanism of tumor cell survival in unmutated PIK3CA cases.
Category: Gynecologic & Obstetrics
Monday, March 19, 2012 8:30 AM
Platform Session: Section E, Monday Morning