H19/let-7/LIN28 reciprocal negative regulatory circuit promotes breast cancer stem cell maintenance

LincRNA-H19 ( H19 ), an imprinted oncofetal gene, plays a central role in carcinogenesis. Hitherto, the mechanism by which H19 regulates cancer stem cells (CSCs) 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 ma mmosphere-forming ability. Conversely, silencing of H19 represses these BCSC properties. In concordance, knockdown of H19 dramatically inhibits tumor growth an d suppresses tumorigenesis in nude mice. Mechanistically, we found that H19 functions as a competing endogenous RNA (ceRNA) to sponge miRNA let-7, leading to an increase in expression of a let-7 target, the core pluripotency factor LIN28, wh ich is enriched in BCSC populations and breast patient samples. Intriguingly, this gain of LIN28 expression can also feedback to reverse the H19 loss-mediated suppre ssion 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 carcino mas. Collectively, these findings reveal that lincRNA H19, miRNA let-7 and transcriptional factor LIN28 form a double negative feedback loop, which plays a cr itical role in the maintenance of BCSCs. Consequently, disrupting this pathway provid es a novel therapeutic strategy for breast cancer