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The clinical and biological significance of MIR-224 expression in colorectal cancer metastasis

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journal contribution
posted on 20.08.2020 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.