let-7 Regulates Self Renewal and Tumorigenicity of Breast Cancer Cells
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 c...
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Veröffentlicht in: | Cell 2007-12, Vol.131 (6), p.1109-1123 |
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Sprache: | eng |
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Zusammenfassung: | 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° breast cancers.
let-7 miRNAs were markedly reduced in BT-IC and increased with differentiation. Infecting BT-IC with
let-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
let-7 by antisense oligonucleotides enhanced in vitro self renewal of non-T-IC. Increased
let-7 paralleled reduced H-RAS and HMGA2, known
let-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
let-7 regulates multiple BT-IC stem cell-like properties by silencing more than one target. |
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ISSN: | 0092-8674 1097-4172 |
DOI: | 10.1016/j.cell.2007.10.054 |