TY - JOUR
T1 - The clinical and biological significance of MIR-224 expression in colorectal cancer metastasis
AU - Ling, Hui
AU - Pickard, Karen
AU - Ivan, Cristina
AU - Isella, Claudio
AU - Ikuo, Mariko
AU - Mitter, Richard
AU - Spizzo, Riccardo
AU - Bullock, Marc D.
AU - Braicu, Cornelia
AU - Pileczki, Valentina
AU - Vincent, Kimberly
AU - Pichler, Martin
AU - Stiegelbauer, Verena
AU - Hoefler, Gerald
AU - Almeida, Maria I.
AU - Hsiao, Annie
AU - Zhang, Xinna
AU - Primrose, John N.
AU - Packham, Graham K.
AU - Liu, Kevin
AU - Bojja, Krishna
AU - Gafà, Roberta
AU - Xiao, Lianchun
AU - Rossi, Simona
AU - Song, Jian H.
AU - Vannini, Ivan
AU - Fanini, Francesca
AU - Kopetz, Scott
AU - Zweidler-McKay, Patrick
AU - Wang, Xuemei
AU - Ionescu, Calin
AU - Irimie, Alexandru
AU - Fabbri, Muller
AU - Lanza, Giovanni
AU - Hamilton, Stanley R.
AU - Berindan-Neagoe, Ioana
AU - Medico, Enzo
AU - Mirnezami, Alex H.
AU - Calin, George A.
AU - Nicoloso, Milena S.
N1 - Publisher Copyright:
© 2016, BMJ Publishing Group. All rights reserved.
PY - 2016/6/1
Y1 - 2016/6/1
N2 - 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.
AB - 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.
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U2 - 10.1136/gutjnl-2015-309372
DO - 10.1136/gutjnl-2015-309372
M3 - Article
C2 - 25804630
AN - SCOPUS:84929589715
SN - 0017-5749
VL - 65
SP - 977
EP - 989
JO - Gut
JF - Gut
IS - 6
ER -