title: The FOXO1-miR27 tandem regulates myometrial invasion in endometrioid endometrial adenocarcinoma.
abstract: Micro-RNA (miRNA) signatures influence the prognosis of cancer, but little is known about their role in myometrial invasion in endometrioid endometrial adenocarcinoma (EEC). We studied miRNA expression signatures in noninvasive and invasive EEC focusing on the alteration of miR-27 and its main target, FOXO1 as well as their relationship with the clinicopathological parameters and other genetic alterations such as PIK3CA mutations. In 25 tumors and 5 normal endometria, unsupervised hierarchical clustering analysis showed that normal endometria and noninvasive EEC were grouped together and separately from invasive and advanced stage tumors. Of the 20 miRNAs differentially expressed in noninvasive (stage IA) and myoinvasive adenocarcinomas (stage IB and IC), miR27 was overexpressed in invasive adenocarcinomas, and its expression increased linearly according to stage. Results were validated by quantitative real-time reverse transcription polymerase chain reaction in an independent series of 44 EEC. By in situ hybridization, miR-27 expression was limited to the stroma. Using quantitative real-time reverse transcription polymerase chain reaction, the expression of proapoptotic transcription factor FOXO1 was down-regulated in invasive compared with noninvasive tumors. Furthermore, we found that the expression of active caspase 3 was higher in noninvasive than invasive EEC. When stratified by PIK3CA mutations, all invasive tumors down-regulated FOXO1, but only nonmutated adenocarcinomas showed miR-27 overexpression. In conclusion, we propose that the miR27-FOXO1 tandem inhibits apoptosis and represents an alternative pathway for tumor cell survival in PIK3CA-nonmutated EEC.
authors.affiliation: Department of Pathology, IIB-Sant Pau, Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, Barcelona, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Mozos
authors.affiliation: Department of Pathology, IIB-Sant Pau, Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, Barcelona, Spain.
authors.forename: Lluis
authors.initials: L
authors.lastname: Catasús
authors.affiliation: Department of Pathology, IIB-Sant Pau, Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, Barcelona, Spain.
authors.forename: Emanuela
authors.initials: E
authors.lastname: D'Angelo
authors.affiliation: Biobanco IIB Sant Pau, IIB-Sant Pau, Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, Barcelona, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Serrano
authors.affiliation: Department of Pathology, IIB-Sant Pau, Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, Barcelona, Spain.
authors.forename: Iñigo
authors.initials: I
authors.lastname: Espinosa
authors.affiliation: Department of Pathology, IIB-Sant Pau, Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, Barcelona, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Ferrer
authors.affiliation: Department of Pathology, IIB-Sant Pau, Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, Barcelona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Pons
authors.affiliation: Department of Pathology, IIB-Sant Pau, Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, Barcelona, Spain. Electronic address: jprat@santpau.cat.
authors.forename: Jaime
authors.initials: J
authors.lastname: Prat
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018269:Carcinoma, Endometrioid / Q000235:genetics* / Q000473:pathology; D053148:Caspase 3 / Q000096:biosynthesis; D058534:Class I Phosphatidylinositol 3-Kinases; D015536:Down-Regulation; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000502:physiology*; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000503:physiopathology*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics
chemical_list: C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C531388:MIRN27 microRNA, human; D035683:MicroRNAs; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D053148:Caspase 3
keywords: Endometrioid endometrial cancer; FOXO1; PIK3CA; miR27; miRNA