期刊
CELL DEATH & DISEASE
卷 8, 期 -, 页码 -出版社
SPRINGERNATURE
DOI: 10.1038/cddis.2016.438
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资金
- National Natural Science Foundation of China [81573025, 81630005, 81201686]
- Liaoning [NSF2014029102]
- Dalian high-level talent innovation program [2016RD12]
- Natural Science Foundation of Liaoning [2015020264]
- CRUK [A12011]
- Breast Cancer Now [2012MayPR070, 2012NovPhD016]
- Biotechnology and Biological Sciences Research Council [BBS/B/03785] Funding Source: researchfish
- Cancer Research UK [12011] Funding Source: researchfish
- Engineering and Physical Sciences Research Council [1234732] Funding Source: researchfish
- Medical Research Council [MR/N012097/1] Funding Source: researchfish
- MRC [MR/N012097/1] Funding Source: UKRI
Long noncoding RNA-H19 (H19), an imprinted oncofetal gene, has a central role in carcinogenesis. Hitherto, the mechanism by which H19 regulates cancer stem cells, remains elusive. Here we show that breast cancer stem cells (BCSCs) express high levels of H19, and ectopic overexpression of H19 significantly promotes breast cancer cell clonogenicity, migration and mammosphereforming ability. Conversely, silencing of H19 represses these BCSC properties. In concordance, knockdown of H19 markedly inhibits tumor growth and suppresses tumorigenesis in nude mice. Mechanistically, we found that H19 functions as a competing endogenous RNA to sponge miRNA let-7, leading to an increase in expression of a let-7 target, the core pluripotency factor LIN28, which is enriched in BCSC populations and breast patient samples. Intriguingly, this gain of LIN28 expression can also feedback to reverse the H19 loss-mediated suppression of BCSC properties. Our data also reveal that LIN28 blocks mature let-7 production and, thereby, de-represses H19 expression in breast cancer cells. Appropriately, H19 and LIN28 expression exhibits strong correlations in primary breast carcinomas. Collectively, these findings reveal that lncRNA H19, miRNA let-7 and transcriptional factor LIN28 form a double-negative feedback loop, which has a critical role in the maintenance of BCSCs. Consequently, disrupting this pathway provides a novel therapeutic strategy for breast cancer.
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