학술논문
The clinical and biological significance of MIR-224 expression in colorectal cancer metastasis
Document Type
Academic Journal
Author
Ling, Hui; Pickard, Karen; Ivan, Cristina; Isella, Claudio; Ikuo, Mariko; Mitter, Richard; Spizzo, Riccardo; Bullock, Marc D; Braicu, Cornelia; Pileczki, Valentina; Vincent, Kimberly; Pichler, Martin; Stiegelbauer, Verena; Hoefler, Gerald; Almeida, Maria I; Hsiao, Annie; Zhang, Xinna; Primrose, John N; Packham, Graham K; Liu, Kevin; Bojja, Krishna; Gafà, Roberta; Xiao, Lianchun; Rossi, Simona; Song, Jian H; Vannini, Ivan; Fanini, Francesca; Kopetz, Scott; Zweidler-McKay, Patrick; Wang, Xuemei; Ionescu, Calin; Irimie, Alexandru; Fabbri, Muller; Lanza, Giovanni; Hamilton, Stanley R; Berindan-Neagoe, Ioana; Medico, Enzo; Mirnezami, Alex H; Calin, George A; Nicoloso, Milena S
Source
Gut. Jun 01, 2016 65(6):977-989
Subject
Language
English
ISSN
0017-5749
Abstract
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.