MicroRNA-451 Is Involved in the Self-renewal, Tumorigenicity, and Chemoresistance of Colorectal Cancer Stem Cells
MicroRNA-451 Is Involved in the Self-renewal, Tumorigenicity, and Chemoresistance of Colorectal Cancer Stem Cells
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DOI：
10.1002/stem.741
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发表时间：
2011-11-01
期刊：
影响因子：
5.2
通讯作者：
Garcia-Foncillas, Jesus
中科院分区：
文献类型：
--
作者：
Bitarte, Nerea;Bandres, Eva;Garcia-Foncillas, Jesus
许多抗肿瘤疗法影响快速分裂的细胞。然而，肿瘤增殖可能是由癌症干细胞（CSC）驱动的，癌症干细胞分裂缓慢，对细胞毒性药物具有相对抗性。因此，许多肿瘤可能会进展，因为CSC对治疗不敏感。在这项工作中，我们寻找靶基因的表达参与CSCs的增殖和化疗耐药性。这两个过程可以同时由细胞调节因子如microRNA（miRNAs）控制。因此，从不同的结肠癌细胞中获得具有CSC性质的结肠球，并进行miRNA谱分析。结果显示，与亲本细胞相比，miR-451在结肠球中下调。令人惊讶的是，miR-451的表达导致结肠球的自我更新、致瘤性和对伊立替康的化学抗性降低。我们鉴定了环氧化酶-2（考克斯-2）作为参与球体生长的间接miR-451靶基因。我们的研究结果表明，miR-451下调允许直接靶基因巨噬细胞移动抑制因子的表达，参与考克斯-2的表达。反过来，考克斯-2允许Wnt活化，这对于CSC生长是必需的。此外，miR-451恢复降低ATP结合盒药物转运蛋白ABCB 1的表达，并导致伊立替康致敏。这些发现与在对基于伊立替康的一线治疗无反应的患者中观察到的miR-451表达较低密切相关。我们的数据表明，miR-451是避免结直肠癌复发和耐药性的一种新候选药物，并可用作预测结肠癌患者对伊立替康反应的标志物。干细胞2011;29：1661-1671
Many antitumor therapies affect rapidly dividing cells. However, tumor proliferation may be driven by cancer stem cells (CSCs), which divide slowly and are relatively resistant to cytotoxic drugs. Thus, many tumors may progress because CSCs are not sensitive to the treatment. In this work, we searched for target genes whose expression is involved in proliferation and chemoresistance of CSCs. Both of these processes could be controlled simultaneously by cell regulators such as microRNAs (miRNAs). Therefore, colonospheres with properties of CSCs were obtained from different colon carcinoma cells, and miRNA profiling was performed. The results showed that miR-451 was downregulated in colonspheres versus parental cells. Surprisingly, expression of miR-451 caused a decrease in self-renewal, tumorigenicity, and chemoresistance to irinotecan of colonspheres. We identified cyclooxygenase-2 (COX-2) as an indirect miR-451 target gene involved in sphere growth. Our results indicate that miR-451 downregulation allows the expression of the direct target gene macrophage migration inhibitory factor, involved in the expression of COX-2. In turn, COX-2 allows Wnt activation, which is essential for CSC growth. Furthermore, miR-451 restoration decreases expression of the ATP-binding cassette drug transporter ABCB1 and results in irinotecan sensitization. These findings correlate well with the lower expression of miR-451 observed in patients who did not respond to irinotecan-based first-line therapy compared with patients who did. Our data suggest that miR-451 is a novel candidate to circumvent recurrence and drug resistance in colorectal cancer and could be used as a marker to predict response to irinotecan in patients with colon carcinoma. STEM CELLS 2011;29:1661-1671