Wnt signaling through β-catenin and the lymphoid-enhancing factor 1/T-cell factor (LEF1/TCF) family of transcription factors maintains stem cell properties in both normal and malignant tissues; however, the underlying molecular pathway involved in this process has not been completely defined. Using a microRNA microarray screening assay, we identified the let-7 miRNAs as downstream targets of Wnt/β-catenin pathway. Expression studies indicated that Wnt/β-catenin pathway suppresses mature let-7 miRNAs but not the primary transcripts, which suggests a posttranscriptional regulation of repression. Furthermore, we identified Lin28, a negative let-7 biogenesis regulator, as a novel direct downstream target of Wnt/β-catenin pathway. Loss of function of Lin28 impairs the Wnt/β-catenin pathway-mediated let-7 inhibition and breast cancer stem cell expansion; enforced expression of let-7 blocks the Wnt/β-catenin pathway-stimulated breast cancer stem cell phenotype. Finally, we demonstrated that Wnt/β-catenin pathway induces Lin28 upregulation and let-7 downregulation in both cancer samples and mouse tumour models. Moreover, the delivery of a modified lin28 siRNA or a let-7a agomir into the premalignant mammary tissues of MMTV-wnt-1 mice resulted in a complete rescue of the stem cell phenotype driven by Wnt/β-catenin pathway. These findings highlight a pivotal role for Lin28/let-7 in Wnt/β-catenin pathway mediated cellular phenotypes. Thus, Wnt/β-catenin pathway, Lin28, and let-7 miRNAs, three of the most crucial stem cell regulators, connect in one signal cascade.
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