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The clinical and biological significance of MIR-224 expression in colorectal cancer metastasis
journal contributionposted on 2020-08-20, 16:39 authored by Hui Ling, Karen Pickard, Cristina Ivan, Claudio Isella, Mariko Ikuo, Richard Mitter, Riccardo Spizzo, Marc D Bullock, Cornelia Braicu, Valentina Pileczki, Kimberly Vincent, Martin Pichler, Verena Stiegelbauer, Gerald Hoefler, Maria I Almeida, Annie Hsiao, Xinna Zhang, John N Primrose, Graham K Packham, Kevin Liu, Krishna Bojja, Roberta Gafà, Lianchun Xiao, Simona Rossi, Jian H Song, Ivan Vannini, Francesca Fanini, Scott Kopetz, Patrick Zweidler-McKay, Xuemei Wang, Calin Ionescu, Alexandru Irimie, Muller Fabbri, Giovanni Lanza, Stanley R Hamilton, Ioana Berindan-Neagoe, Enzo Medico, Alex H Mirnezami, George A Calin, Milena S Nicoloso
OBJECTIVE: MicroRNA (miRNA) expression profile can be used as prognostic marker for human cancers. We aim to explore the significance of miRNAs in colorectal cancer (CRC) metastasis. DESIGN: We performed miRNA microarrays using primary CRC tissues from patients with and without metastasis, and validated selected candidates in 85 CRC samples by quantitative real-time PCR (qRT-PCR). We tested metastatic activity of selected miRNAs and identified miRNA targets by prediction algorithms, qRT-PCR, western blot and luciferase assays. Clinical outcomes were analysed in six sets of CRC cases (n=449), including The Cancer Genome Atlas (TCGA) consortium and correlated with miR-224 status. We used the Kaplan-Meier method and log-rank test to assess the difference in survival between patients with low or high levels of miR-224 expression. RESULTS: MiR-224 expression increases consistently with tumour burden and microsatellite stable status, and miR-224 enhances CRC metastasis in vitro and in vivo. We identified SMAD4 as a miR-224 target and observed negative correlation (Spearman Rs=-0.44, p<0.0001) between SMAD4 and miR-224 expression in clinical samples. Patients with high miR-224 levels display shorter overall survival in multiple CRC cohorts (p=0.0259, 0.0137, 0.0207, 0.0181, 0.0331 and 0.0037, respectively), and shorter metastasis-free survival (HR 6.51, 95% CI 1.97 to 21.51, p=0.0008). In the TCGA set, combined analysis of miR-224 with SMAD4 expression enhanced correlation with survival (HR 4.12, 95% CI 1.1 to 15.41, p=0.0175). CONCLUSIONS: MiR-224 promotes CRC metastasis, at least in part, through the regulation of SMAD4. MiR-224 expression in primary CRC, alone or combined with its targets, may have prognostic value for survival of patients with CRC.
COLORECTAL CANCERLIVER METASTASESMICROSATELLITE INSTABILITYMOLECULAR GENETICSRNA EXPRESSIONAdenocarcinomaAdultAgedAged, 80 and overAnimalsAustriaBiomarkers, TumorColorectal NeoplasmsFemaleGene Expression Regulation, NeoplasticHumansIn Vitro TechniquesItalyKaplan-Meier EstimateMaleMiceMicroRNAsMiddle AgedNeoplasm InvasivenessPredictive Value of TestsRomaniaSensitivity and SpecificityUnited KingdomCB1103 Clinical Sciences1114 Paediatrics and Reproductive MedicineGastroenterology & Hepatology