Micro-RNA signature of the epithelial-mesenchymal transition in endometrial carcinosarcoma.
Endometrial carcinosarcomas (ECSs) undergo a true epithelial-mesenchymal transition (EMT). The molecular determinants of the EMT in vivo are unclear, although a role for some miRNAs, mainly involving the miR-200 family, was recently suggested from in vitro cellular models. We analysed the microRNA (miRNA) signatures associated to EMT in human carcinosarcomas, and determined their relationships with EMT markers and repressors of E-cadherin transcription. The expression of E-, P- and N-cadherin, cadherin-11, p120, vimentin, SPARC, fascin and caveolin-1 was studied in a group of 76 ECS by immunohistochemistry. In addition, real-time PCR was used to measure the differences in the expression of 384 miRNAs, E-cadherin, cadherin-11, SPARC, SNAIL, ZEB1, ZEB2, TWIST-1, TCF4, TGFβ1 and TGFβ2 between the epithelial and mesenchymal components of 23 ECSs. A loss of epithelial characteristics, including cadherin switching and the acquisition of a mesenchymal phenotype, was accompanied by changes in the profile of miRNA expression and the up-regulation of all the E-cadherin repressors analysed. A greater than five-fold difference in the expression of 14 miRNAs between both neoplastic components was seen. Members of the miR-200 family were down-regulated in the mesenchymal part of the ECS. In addition, miR-23b and miR-29c, which are involved in the inhibition of mesenchymal markers, and miR-203, which is involved in the inhibition of cell stemness, were also down-regulated. Up-regulated miRNAs included miR-155, miR-369-5p, miR-370, miR-450a and miR-542-5p. These data suggest that in human ECS, the interplay between transcriptional repressors of E-cadherin and miRNAs provides a link between EMT-activation and the maintenance of stemness.
Department of Pathology, Hospital Universitario Virgen del Rocío-IBIS, Instituto de Biomedicina de Sevilla, Sevilla, Spain.
María Ángeles
MÁ
Castilla
Gema
G
Moreno-Bueno
Laura
L
Romero-Pérez
Koen
K
Van De Vijver
Michele
M
Biscuola
María Ángeles
MÁ
López-García
Jaime
J
Prat
Xavier
X
Matías-Guiu
Amparo
A
Cano
Esther
E
Oliva
José
J
Palacios
D015820:Cadherins / Q000378:metabolism; D002296:Carcinosarcoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D035683:MicroRNAs / Q000235:genetics; D009363:Neoplasm Proteins / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D012334:RNA, Neoplasm / Q000235:genetics; D012097:Repressor Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D014157:Transcription Factors / Q000378:metabolism; D000074165:Zinc Finger E-box Binding Homeobox 2; D000071799:Zinc Finger E-box-Binding Homeobox 1
D015820:Cadherins; D018398:Homeodomain Proteins; D035683:MicroRNAs; D009363:Neoplasm Proteins; D012334:RNA, Neoplasm; D012097:Repressor Proteins; D014157:Transcription Factors; C486307:ZEB1 protein, human; C492363:ZEB2 protein, human; D000074165:Zinc Finger E-box Binding Homeobox 2; D000071799:Zinc Finger E-box-Binding Homeobox 1