β-Catenin/LEF1 transactivates the microRNA-371-373 cluster that modulates the Wnt/β-catenin-signaling pathway

Abstract

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.

Reactivation of epigenetically silenced miR-512 and miR-373 sensitizes lung cancer cells to cisplatin and restricts tumor growth

“…26 Furthermore, miR-373 and miR-372 can engage in an oncogenic feedback loop with members of the Wnt/β-catenin pathway. 20 However, although these reports imply that miR-371-373 possess oncogenic activities, other studies reveal that they can display tumorsuppressive features, 22,27,44,49 as observed also here. This dichotomous behavior of miR-373 and other chromosome 19 miRs is not unusual.…”

“…19 The miR 371-373 cluster, expressed in human embryonic stem cells, is involved in stem cell pluripotency. 20 We subsequently chose to focus on one representative of each cluster: miR-512-5p (miR-512), belonging to the C19MC cluster, and miR-373. qRT-PCR analysis confirmed that miR-512 and miR-373, both nearly undetectable in A549 cells, were highly induced by 5′ aza+TSA (Figures 2c and d).…”

Downregulation of MicroRNA-152 contributes to high expression of DKK1 in multiple myeloma

“…Previous studies have shown that other oncogenic miRNAs such as miR-372, 373 and 29a can directly target DKK1 promoting oncogenesis and chemoresistance in other cancers. 45,46 Of note, we also show that melphalan in the presence of miR-152 mimic sensitized MM cells to a more pronounced apoptotic cell death. Melphalan has been demonstrated to induce apoptosis either alone or in combination with other drugs through various canonical mechanisms.…”

Potential for pharmacological manipulation of human embryonic stem cells

“…The AXIN/GSK3b/APC complex normally promotes the proteolytic degradation of b-catenin, and so if this 'b-catenin destruction complex' is inhibited, b-catenin can accumulate, stabilize and enter the nucleus and then interact with the TCF/LEF family transcription factors, which promote specific gene expression. Recent studies linking WNT signalling and pluripotency have shown that the human NANOG gene is regulated through a TCF/LEF element within an enhancer (Kim et al, 2011a), while a pluripotency-associated micro-RNA (miRNA) cluster (miR-371-373) (Wang et al, 2008;Judson et al, 2009) was found to be positively regulated by WNT/b-catenin signalling activity in several human cancer cell lines (Zhou et al, 2011). Lithium chloride (LiCl)-mediated inhibition of GSK3 and b-catenin ubiquitination (Klein and Melton, 1996) stimulated WNT/bcatenin activity and subsequently stimulated the expression of the miRNA cluster through direct binding of b-catenin/ LEF1 to the miRNA promoter.…”