The clinical and biological significance of MIR-224 expression in colorectal cancer metastasis.
The clinical and biological significance of MIR-224 expression in colorectal cancer metastasis.
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miR-224表达在结直肠癌转移中的临床和生物学意义。
DOI：
10.1136/gutjnl-2015-309372
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发表时间：
2016-06
期刊：
影响因子：
24.5
通讯作者：
Nicoloso MS
中科院分区：
文献类型：
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作者：
Ling H;Pickard K;Ivan C;Isella C;Ikuo M;Mitter R;Spizzo R;Bullock M;Braicu C;Pileczki V;Vincent K;Pichler M;Stiegelbauer V;Hoefler G;Almeida MI;Hsiao A;Zhang X;Primrose J;Packham G;Liu K;Bojja K;Gafà R;Xiao L;Rossi S;Song JH;Vannini I;Fanini F;Kopetz S;Zweidler-McKay P;Wang X;Ionescu C;Irimie A;Fabbri M;Lanza G;Hamilton SR;Berindan-Neagoe I;Medico E;Mirnezami A;Calin GA;Nicoloso MS
microRNA（miRNA）表达谱可作为人类癌症的预后标志物。我们的目的是探讨miRNAs在结直肠癌（CRC）转移中的意义。我们使用来自有和没有转移的患者的原发性CRC组织进行了miRNA微阵列，并通过qRT-PCR在85个CRC样本中验证了所选择的候选者。我们测试了所选miRNA的转移活性，并通过预测算法、qRT-PCR、蛋白质印迹和荧光素酶测定来鉴定miRNA靶点。分析了包括癌症基因组图谱联盟在内的六组CRC病例（n=449）的临床结果，并与miR-224状态相关。我们使用Kaplan-Meier方法和log-rank检验来评估miR-224表达水平低或高的患者之间的生存差异。miR-224表达的增加与肿瘤负荷和微卫星稳定（MSS）状态一致，并且miR-224在体外和体内增强CRC转移。我们将SMAD 4确定为miR-224靶点，并观察到临床样本中SMAD 4和miR-224表达之间的负相关性（斯皮尔曼Rs=-0.44，p<0.0001）。在多个CRC队列中，高miR-224水平的患者显示出较短的总生存期（分别为p=0.0259、0.0137、0.0207、0.0181、0.0331和0.0037）和较短的无转移生存期（风险比6.51，95%CI 1.97-21.51，p=0.0008）。在TCGA组中，miR-224与SMAD 4表达的联合分析增强了与生存期的相关性（风险比4.12，95% CI 1.1-15.41，p=0.0175）。miR-224至少部分地通过调节SMAD 4促进CRC转移。miR-224在原发性CRC中的表达，单独或与其靶点组合，可能对CRC患者的生存具有预后价值。
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. We performed miRNA microarrays using primary CRC tissues from patients with and without metastasis, and validated selected candidates in 85 CRC samples by 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 analyzed in six sets of CRC cases (n=449) including The Cancer Genome Atlas 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. MiR-224 expression increases consistently with tumor burden and microsatellite stable (MSS) 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 (hazard ratio 6.51, 95% CI 1.97-21.51, p=0.0008). In the TCGA set, combined analysis of miR-224 with SMAD4 expression enhanced correlation with survival (hazard ratio 4.12, 95% CI 1.1-15.41, p=0.0175). 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 CRC patient survival.