MicroRNAs related to angiogenesis are dysregulated in endometrioid endometrial cancer

Abstract

STUDY QUESTIONWhich is the role of microRNAs (miRNAs) related to several angiogenesis regulators such as VEGF-A (Vascular endothelial growth factor-A) and TSP-1 (Thrombospondin-1) in endometrial cancer? SUMMARY ANSWERA dysregulated expression of miRNAs related to angiogenesis and an increase in the VEGF-A levels were observed in endometrial cancer in comparison with control. The different expression of miRNAs could modulate the expression of angiogenic and antiangiogenic factors, which may play an important role in the pathogenesis of endometrial cancer. WHAT IS KNOWN ALREADYDysregulated miRNA expression has been previously evaluated in endometrial adenocarcinoma. To the best of our knowledge, there are no studies on the relationship between angiogenic factors and miRNAs in endometrial cancer. STUDY DESIGN, SIZE, DURATIONCasecontrol study: 41 patients with histologically proven endometrioid endometrial cancer and 56 women without endometrial cancer. PARTICIPANTS/MATERIALS, SETTING, METHODSRNAs isolated from tissue samples were analyzed using the GeneChip miRNA 2.0 Array platform (Affymetrix). TaqMan qRTPCR was used to assess the expression of the selected miRNAs related to angiogenesis (miR-15b,-16,-17-5p,-20a,-21,-125a,- 200b,-210,-214 (*),-221,-222 and-424), and VEGF-A and TSP-1 mRNAs were assessed by qRTPCR using SYBR Green. Protein levels were quantified by ELISAs. MAIN RESULTS AND THE ROLE OF CHANCECompared with the miRNAs in the control endometrium, eight miRNAs (miR-15b,-17-5p,-20a,-125a,-214 (*),-221,-222 and-424) were significantly down-regulated and two miRNAs (miR-200b and-210) were significantly up-regulated in the cancerous endometrium. A significant increase in VEGF-A mRNA and protein expression and in TSP-1 protein levels (P <0.01) was observed in endometrial cancer. Moreover, significant inverse correlations between VEGF-A protein levels and miR-20a,-125a,-214 (*),-221,-222 and-424 were detected. In contrast, a positive correlation was observed between VEGF-A and miR-200b and-210. Furthermore, stage IB endometrial cancer was associated with a higher VEGF-A protein/mRNA ratio and lower miR-214 (*),-221 and-222 expression in comparison with stage IA. LIMITATIONS, REASONS FOR CAUTIONFuture functional studies (e.g. miRNA inhibition or ectopic overexpression) in cell culture models are needed to confirm the VEGF targeting by the miRNAs found in the present study. WIDER IMPLICATIONS OF THE FINDINGSThe findings of the present study have potential implications for diagnostics and therapeutics of endometrial carcinoma. STUDY FUNDING/COMPETING INTEREST(S)This work was supported by research grants from the Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica (Instituto de Salud Carlos III, Fondo de Investigación Sanitaria, PI080185, PI0110091) and Red RECAVA (RD06/0014/0004), by Consellería de Sanidad (AP-141/11) and Consellería de Educación (PROMETEO/2011/027), Generalitat Valenciana, by Beca Fibrinolisis 2009 and Becario 2010, 2011 from Fundación Española de Trombosis y Hemostasia and by the Fundación Investigación Hospital La Fe, Spain. None of the authors have any conflicts of interest. © 2012 The Author.