Circulating miR-200c as a diagnostic and prognostic biomarker for gastric cancer

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MicroRNAs are aberrantly expressed and correlate with tumourigenesis and the progression of solid tumours. The miR-200 family determines the epithelial phenotype of cancer cells and regulates invasiveness and migration. Thus, we hypothesised that the quantitative detection of the miR-200 family as epithelial-specific microRNAs in the blood could be a useful clinical biomarker for gastric cancer (GC). Methods We initially validated the expression levels of miR-200a, 200b, 200c and 141 in GC cell lines (n = 2) and blood from healthy controls (n = 19) using real-time quantitative reverse transcription PCR (qRT-PCR). The microarray expression profiles of the miR-200 family in 160 paired samples of non-tumour gastric mucosae and GC were downloaded through ArrayExpress and analysed. MiR-200c was selected for clinical validation. The qRT-PCR prospective assessment of miR-200c was performed using 67 blood samples (52 stage I-IV GC patients and 15 controls); the area under the receiver operating characteristic curve (AUC-ROC) was estimated. The Kaplan-Meier and Breslow-Wilcoxon tests were used to assess the correlation of miR-200c with overall and progression-free survival (OS and PFS). Multivariate analyses were performed using the Cox model. Results The miR-200c blood expression levels in GC patients were significantly higher than in normal controls ( p = 0.018). The AUC-ROC was 0.715 ( p = 0.012). The sensitivity, specificity and accuracy rates of 65.4%, 100% and 73.1%, respectively, were observed. The levels of miR-200c in the blood above the cutoff defined by the ROC curve was found in 17.6% of stage I-II GC patients, 20.6% of stage III patients and 67.7% of stage IV patients ( p < 0.001). The miR-200c expression levels were not associated with clinical or pathological characteristics or recent surgical procedures. There was a correlation ( p = 0.016) with the number of lymph node metastases and the increased expression levels of miR-200c in blood were significantly associated with a poor OS (median OS, 9 vs 24 months; p = 0.016) and PFS (median PFS, 4 vs 11 months; p = 0.044). Multivariate analyses confirmed that the upregulation of miR-200c in the blood was associated with OS (HR = 2.24; p = 0.028) and .

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Publié le 01 janvier 2012
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ValladaresAyerbeset al. Journal of Translational Medicine2012,10:186 http://www.translationalmedicine.com/content/10/1/186
R E S E A R C HOpen Access Circulating miR200c as a diagnostic and prognostic biomarker for gastric cancer 1,2* 22 3 Manuel ValladaresAyerbes, Margarita Reboredo , Vanessa MedinaVillaamil , Pilar IglesiasDíaz , 3 22 24 2 Maria José LorenzoPatiño , Mar Haz , Isabel Santamarina , Moisés Blanco , Juan FernándezTajes , Maria Quindós , 2 22,5 2 Alberto Carral , Angélica Figueroa , Luis Miguel AntónAparicioand Lourdes Calvo
Abstract Background:MicroRNAs are aberrantly expressed and correlate with tumourigenesis and the progression of solid tumours. The miR200 family determines the epithelial phenotype of cancer cells and regulates invasiveness and migration. Thus, we hypothesised that the quantitative detection of the miR200 family as epithelialspecific microRNAs in the blood could be a useful clinical biomarker for gastric cancer (GC). Methods:We initially validated the expression levels of miR200a, 200b, 200c and 141 in GC cell lines (nand= 2) blood from healthy controls (n= 19)using realtime quantitative reverse transcription PCR (qRTPCR). The microarray expression profiles of the miR200 family in 160 paired samples of nontumour gastric mucosae and GC were downloaded through ArrayExpress and analysed. MiR200c was selected for clinical validation. The qRTPCR prospective assessment of miR200c was performed using 67 blood samples (52 stage IIV GC patients and 15 controls); the area under the receiver operating characteristic curve (AUCROC) was estimated. The KaplanMeier and BreslowWilcoxon tests were used to assess the correlation of miR200c with overall and progressionfree survival (OS and PFS). Multivariate analyses were performed using the Cox model. Results:The miR200c blood expression levels in GC patients were significantly higher than in normal controls (p =0.018). The AUCROC was 0.715 (p= 0.012).The sensitivity, specificity and accuracy rates of 65.4%, 100% and 73.1%, respectively, were observed. The levels of miR200c in the blood above the cutoff defined by the ROC curve was found in 17.6% of stage III GC patients, 20.6% of stage III patients and 67.7% of stage IV patients (p <0.001). The miR200c expression levels were not associated with clinical or pathological characteristics or recent surgical procedures. There was a correlation (pwith the number of lymph node metastases and the increased= 0.016) expression levels of miR200c in blood were significantly associated with a poor OS (median OS, 9vs24 months; p =0.016) and PFS (median PFS, 4vs11 months;p =0.044). Multivariate analyses confirmed that the upregulation of miR200c in the blood was associated with OS (HR= 2.24;p == 2.27;0.028) and PFS (HRp =0.028), independent of clinical covariates. Conclusions:These data suggest that increased miR200c levels are detected in the blood of gastric cancer patients. MiR200c has the potential to be a predictor of progression and survival. Keywords:Gastric cancer, MicroRNA, miR200, Blood, Biomarker, Prognostic factors
* Correspondence: manuel.valladares@ayerbes@sergas.es 1 Medical Oncology Department, La Coruña University Hospital, Servicio Galego de Saúde (SERGAS), As Xubias, 84, La Coruña, PC 15006, Spain 2 Translational Cancer Research Lab, Biomedical Research Institute (INIBIC), Carretera del Pasaje, s/n, La Coruña, PC 15006, Spain Full list of author information is available at the end of the article
© 2012 ValladaresAyerbes et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.