Iet-7 regulates self renewal and tumorigenicity of breast cancer cells
Iet-7 regulates self renewal and tumorigenicity of breast cancer cells
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Iet-7调节乳腺癌细胞的自我更新和致瘤性
DOI：
10.1016/j.cell.2007.10.054
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发表时间：
2007-12-14
期刊：
影响因子：
64.5
通讯作者：
Song, Erwei
中科院分区：
文献类型：
--
作者：
Yu, Fengyan;Yao, Herui;Song, Erwei
癌症可能由罕见的自我更新肿瘤起始细胞（T-IC）引起。然而，T-IC自我更新，多能分化和致瘤性是如何维持的仍然不清楚。由于miRNA可以调节细胞命运决定，我们比较了来自乳腺癌细胞系的自我更新和分化细胞以及来自1度乳腺癌的乳腺T-IC（BT-IC）和非BT-IC中的miRNA表达。Iet-7 miRNAs在BT-IC中显著减少，并随着分化而增加。用Iet-7慢病毒感染BT-IC可降低体外增殖、乳腺球形成和未分化细胞的比例以及NOD/SCID小鼠中肿瘤的形成和转移，而通过反义寡核苷酸拮抗Iet-7可增强非T-IC的体外自我更新。增加的Iet-7可降低H-RAS和HMGA 2，这是已知的Iet-7靶点。在富含BT-IC的细胞系中沉默H-RAS降低了自我更新，但对分化没有影响，而沉默HMGA 2增强了分化，但不影响自我更新。因此，Iet-7通过沉默一个以上的靶点来调节多种BT-IC干细胞样特性。
Cancers may arise from rare self-renewing tumor- initiating cells (T-IC). However, how T-IC self renewal, multipotent differentiation, and tumorigenicity are maintained remains obscure. Because miRNAs can regulate cell-fate decisions, we compared miRNA expression in self-renewing and differentiated cells from breast cancer lines and in breast T-IC (BT-IC) and non-BT-IC from 1 degrees breast cancers. Iet-7 miRNAs were markedly reduced in BT-IC and increased with differentiation. Infecting BT-IC with Iet-7-lentivirus reduced proliferation, mammosphere formation, and the proportion of undifferentiated cells in vitro and tumor formation and metastasis in NOD/SCID mice, while antagonizing Iet-7 by antisense oligonucleotides enhanced in vitro self renewal of non-T-IC. Increased Iet-7 paralleled reduced H-RAS and HMGA2, known Iet-7 targets. Silencing H-RAS in a BT-IC-enriched cell line reduced self renewal but had no effect on differentiation, while silencing HMGA2 enhanced differentiation but did not affect self renewal. Therefore Iet-7 regulates multiple BT-IC stem cell-like properties by silencing more than one target.