β连环蛋白/LEF1对调节Wnt/β连环蛋白信号通路的microRNA-371-373簇的转录激活

Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory for Biocontrol, Sun Yat-Sen University, Guangzhou, China

The microRNA-371-373 (miR-371-373) cluster is specifically expressed in human embryonic stem cells (ESCs) and is thought to be involved in stem cell maintenance. Recently, microRNAs (miRNAs) of this cluster were shown to be frequently upregulated in several human tumors. However, the regulatory mechanism for the involvement of the miR-371-373 cluster in human ESCs or cancer cells remains unclear. In this study, we explored the relationship between this miRNA cluster and the Wnt/β-catenin-signaling pathway, which has been shown to be involved in both stem cell maintenance and tumorigenesis. We show that miR-371-373 expression is induced by lithium chloride and is positively correlated with Wnt/β-catenin-signaling activity in several human cancer cell lines. Mechanistically, three TCF/LEF1-binding elements (TBEs) were identified in the promoter region and shown to be required for Wnt-dependent activation of miR-371-373. Interestingly, we also found that miR-372&373, in turn, activate Wnt/β-catenin signaling. In addition, four protein genes related to the Wnt/β-catenin-signaling pathway were identified as direct targets of miR-372&373, including Dickkopf-1 (DKK1), a well-known inhibitor of Wnt/β-catenin signaling. Using a lentiviral system, we showed that overexpression of miR-372 or miR-373 promotes cell growth and the invasive activity of tumor cells as knockdown of DKK1. Taken together, our study demonstrates a novel β-catenin/LEF1-miR-372&373-DKK1 regulatory feedback loop, which may have a critical role in regulating the activity of Wnt/β-catenin signaling in human cancer cells. © 2012 Macmillan Publishers Limited All rights reserved.

Qu, L.-H.; Key Laboratory of Gene Engineering of the Ministry of Education, School of Life Sciences, Sun Yat-Sen University, 135 Xingangxi Road, Guangzhou 510275, China; email: lssqlh@mail.sysu.edu.cn