Comparative microRNA profiling of prostate carcinomas with increasing tumor stage by deep-sequencing
Menée sur 40 paires d'échantillons de tissu tumoral et de tissu sain prélevés sur des patients atteints d'un carcinome de la prostate à divers stades de la maladie, cette étude met en évidence des anomalies d'expression de plusieurs micro-ARNs
Résumé en anglais
MicroRNAs (miRNAs) post-transcriptionally regulate gene expression and are important in tumorigenesis. Previous deep-sequencing identified the miRNA profile of prostate carcinoma (PCa) vs. non-malignant prostate tissue. Here, we generated by deep sequencing miRNA expression profiles of PCa with increasing tumor stage relative to corresponding non-malignant and healthy prostate tissue and detected clearly changed miRNA expression patterns. The miRNA profiles of the healthy and non-malignant tissues were consistent with our previous findings, indicating a high fidelity of the method employed. In the tumors, quantitative RT-PCR analysis of 40 paired samples of PCa vs. normal tissue revealed significant upregulation of miR-20a, miR-148a, miR-200b and miR-375 and downregulation of miR-143 and miR-145. Hereby, miR-375 increased from normal to organ-confined tumors (pT2 pN0), slightly decreased in tumors with extra-capsular growth (pT3 pN0) but was then expressed again at higher levels in lymph node metastasizing (pN1) tumors. The sequencing data for miR-375 were confirmed by Northern blotting and qRT-PCR. The regulation for other selected miRNAs could, however, not be confirmed by qRT-PCR in individual tumor stages. MiR-200b, in addition to miR-200c and miR-375 reduced the expression of Sec23a. Interestingly, miR-375 found up-regulated by us and others in tumor vs. normal tissue and miR-15a found induced by sequencing pT2 and pT3 but not in the metastasizing tumors, target the phosphatases PHLPP1 and PHLPP2, respectively. PHLPP1 and PHLPP2 dephosphorylate members of the AKT-family of signal transducers thereby inhibiting cell growth. Co-expression of miR-15a and miR-375 resulted in down-regulation of PHLPP1/2 and strongly increased PCa cell growth. Implications: These genomic data reveal relevant miRNAs in prostate cancer that may have biomarker and therapeutic potential.
