title: The Wnt-β-catenin pathway represses let-7 microRNA expression through transactivation of Lin28 to augment breast cancer stem cell expansion.
abstract: Wnt signalling 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 let-7 miRNAs as downstream targets of the Wnt-β-catenin pathway. Expression studies indicated that the Wnt-β-catenin pathway suppresses mature let-7 miRNAs but not the primary transcripts, which suggests a post-transcriptional regulation of repression. Furthermore, we identified Lin28, a negative let-7 biogenesis regulator, as a novel direct downstream target of the Wnt-β-catenin pathway. Loss of function of Lin28 impairs 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 the 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 the Wnt-β-catenin pathway. These findings highlight a pivotal role for Lin28/let-7 in Wnt-β-catenin-pathway-mediated cellular phenotypes. Thus, the Wnt-β-catenin pathway, Lin28 and let-7 miRNAs, three of the most crucial stem cell regulators, connect in one signal cascade.
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, China.
authors.forename: Wang-Yu
authors.initials: WY
authors.lastname: Cai
authors.forename: Tong-Zhen
authors.initials: TZ
authors.lastname: Wei
authors.forename: Qi-Cong
authors.initials: QC
authors.lastname: Luo
authors.forename: Qiu-Wan
authors.initials: QW
authors.lastname: Wu
authors.forename: Qing-Feng
authors.initials: QF
authors.lastname: Liu
authors.forename: Meng
authors.initials: M
authors.lastname: Yang
authors.forename: Guo-Dong
authors.initials: GD
authors.lastname: Ye
authors.forename: Jia-Fa
authors.initials: JF
authors.lastname: Wu
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Chen
authors.forename: Guang-Bin
authors.initials: GB
authors.lastname: Sun
authors.forename: Yun-Jia
authors.initials: YJ
authors.lastname: Liu
authors.forename: Wen-Xiu
authors.initials: WX
authors.lastname: Zhao
authors.forename: Zhi-Ming
authors.initials: ZM
authors.lastname: Zhang
authors.forename: Bo-An
authors.initials: BA
authors.lastname: Li
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics*; D015533:Transcriptional Activation; D051155:Wnt1 Protein / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: C495270:CTNNB1 protein, human; C000715187:Lin28A protein, human; D035683:MicroRNAs; D016601:RNA-Binding Proteins; C495247:WNT1 protein, human; D051155:Wnt1 Protein; D051176:beta Catenin; C487931:mirnlet7 microRNA, human; D008156:Luciferases
keywords: Breast cancer; Let-7; Lin28; Stem cell; Wnt–β-catenin pathway