Wnt/β-catenin pathway represses let-7 microRNAs expression via transactivation of Lin28 to augment breast cancer stem cell expansion

• Published in: Journal of cell science
• Main Authors: Cai, Wang-Yu, Wei, Tong-Zhen, Luo, Qi-Cong, Wu, Qiu-Wan, Liu, Qing-Feng, Yang, Meng, Ye, Guo-Dong, Wu, Jia-Fa, Chen, Yuan-Yuan, Sun, Guang-Bin, Liu, Yun-Jia, Zhao, Wen-Xiu, Zhang, Zhi-Ming, Li, Bo-An
• Format: Journal Article
• Language: English
• Published: 01.01.2013
• ISSN: 0021-9533; 1477-9137
• DOI: 10.1242/jcs.123810

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.