Micro-RNA signature of the epithelial–mesenchymal transition in endometrial carcinosarcoma

9 páginas, 3 figuras, 2 tablas.-- et al.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.This study was supported by grants from the Instituto de Salud Carlos III (ISCIII; Grant Nos PI07/90324 and PI 080971) and the Ministerio de Ciencia e Innovación (ISCIII), co-financed by the European Development Regional Fund, ‘A way to achieve Europe’ ERDF (Grant No. RD06/0020/0013), the Junta de Andalucía (Consejería de Salud; Grant No. PI-0384/2007) and the Consejería de Innovación (Proyecto de Excelencia, Grant No. P07-CVI-03100) to JP. Partial support from the MICINN (SAF2007-63051; Consolider Grant No. CDS2007-00017 to AC; Grant No. SAF2007-63065 to GM-B), by grants from the Fundación Mutua Madrileña to GMB (2007) and AC (2009) is also acknowledged. MÁC is a postdoctoral researcher funded by the ISCIII (Grant No. RD06/0020/0013); LR-P is a graduate student (PFIS; Grant No. F109/00193); MB is a researcher funded by the Asociación de padres de niños oncológicos (Andex); MÁL-G is the recipient of a research grant from the Fondo de Investigaciones Sanitarias (Grant No. CM06/00163) and is partially funded by the Breakthrough Breast Cancer Research Centre (UK) and the Red Temática de Investigación Cooperativa en Cáncer (RTICC), Fondo Europeo de Desarrollo Regional (FEDER).Peer reviewe