Inhibition of nuclear Wnt signalling: challenges of an elusive target for cancer therapy

Lyou, Yung; Habowski, Amber N.; Chen, George T.; Waterman, Marian L.

doi:10.1111/bph.13963

Cited by 50 publications

(53 citation statements)

References 90 publications

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“…It has been previously reported that LEF1 is associated with the signal transduction of Wnt/β-catenin downstream molecules. Previous studies have revealed that LEF1 binds to β-catenin to form a β-catenin/LEF complex, thereby promoting the expression of Wnt signaling pathway downstream molecules, including c-Myc and Cyclin D1 (23,24). LEF1 tumor expression was also mediated by miRNAs, including miR-218, miR-181a and miR-227 (23,25,26).…”

Section: Discussionmentioning

confidence: 99%

MicroRNA‑6852 suppresses glioma A172 cell proliferation and invasion by targeting LEF1

et al. 2019

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microRNA (miR)-6852 has been demonstrated to suppress the progression of gastric, colorectal and cervical cancer. The mechanism by which miR-6852 regulates glioma cells is yet to be elucidated. In the present study, reverse transcription-quantitative PCR analysis was used and the results demonstrated that miR-6852 expression was reduced in glioma tissues and cells. Cell counting kit-8 and transwell assay analysis indicated that proliferation, migration and invasion of A172 cells in the miR-6852 mimic group were lower than in the miR-NC group. Compared with the Inh-NC group, A172 cells of the Inh-miR-6852 group exhibited higher proliferation, migration and invasion. Additionally, the results indicated that lymphoid enhancer binding factor 1 (LEF1) was directly inhibited by miR-6852 and LEF1 expression was negatively correlated with miR-6852 expression in glioma tissues. Furthermore, the restoration of LEF1 reversed the effects of the miR-6852 mimics. The present findings suggested that miR-6852 inhibited glioma cells proliferation, migration and invasion by targeting the suppression of LEF1. Recently, miR-6852 has been demonstrated to be associated with the development of tumors, including those in gastric, colorectal and cervical cancer (9-11). The association of miR-6852 with glioma remains undetermined. Therefore, the present study aimed to assess miR-6852 expression in glioma, and further determine the effect of miR-6852 in the regulation of glioma progression. Materials and methodsGlioma tissue collection. A total of 32 pairs of glioma tissues (14 males and 18 females; age range, 31-56 years old; median age, 47 years old) and corresponding normal tissues were collected during biopsy from Affiliated Hospital of Hebei University (Hebei, China) between October 2014 and October 2016 for the current study. Normal tissues were derived from the temporal lobes and saddle area 2 cm away from tumor tissues. All glioma tissues were obtained from patients upon first diagnosis of glioma. Among these patients, 18 cases were high-grade and 14 cases were low-grade. All patients did not recieve radiotherapy or chemotherapy prior to surgery. Patients

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Section: Discussionmentioning

confidence: 99%

MicroRNA‑6852 suppresses glioma A172 cell proliferation and invasion by targeting LEF1

et al. 2019

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“…Importantly, BCL9/9L and PYGO proteins were found to significantly contribute to the malignant traits typical of Wnt-induced CRCs (Deka et al, 2010;Gay et al, 2019;Jiang et al, 2020;Mani et al, 2009;Mieszczanek et al, 2019;Moor et al, 2015;Talla and Brembeck, 2016). These observations provided impetus to consider the BCL9/PYGO axis as relevant "targetable" unit in CRC (Lyou et al, 2017;Mieszczanek et al, 2019;Talla and Brembeck, 2016;Zimmerli et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

TBX3 acts as tissue-specific component of the Wnt/β-catenin enhanceosome

Zimmerli

Borrelli

Jauregi-Miguel

et al. 2020

Preprint

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BCL9 and PYGO are b-catenin cofactors that enhance the transcription of Wnt target genes. They have been proposed as therapeutic targets to diminish Wnt signalling output in intestinal malignancies. Here we find that, in colorectal cancer cells and in developing mouse forelimbs, BCL9 proteins sustain the action of b-catenin in a largely PYGO-independent manner. Our genetic analyses implied that BCL9 necessitates other interaction partners in mediating its transcriptional output. We identified the transcription factor TBX3 as a candidate tissue-specific member of the b-catenin transcriptional complex. In developing forelimbs, TBX3 and BCL9 co-occupy a large number of Wnt-responsive regulatory elements, genome-wide. Moreover, mutations in Bcl9 affect the expression of TBX3 targets in vivo, and modulation of TBX3 abundance impacts on Wnt target genes transcription in a b-catenin-and TCF/LEF-dependent manner. Finally, TBX3 overexpression exacerbates the metastatic potential of Wntdependent human colorectal cancer cells. Our work implicates TBX3 as a new, context-dependent component of the Wnt/b-catenin-dependent enhanceosome.

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“…During active Wnt signaling, the cytosolic β-catenin is transported to the nucleus and by binding to the T-cell factor/lymphoid enhancer-binding factor, transcription of the Wnt target genes is initiated. The PNU 74654 binds beta-catenin and hinders its interaction with TCF/LEF and thereby inhibits the Wnt signaling 23 . The Notch receptors 1 to 4 are associated with a mammalian signaling system where the ligand binding to the receptors initiates the cleavage of the intracellular domain of receptor by γ-secretase.…”

Section: Discussionmentioning

confidence: 99%

Exploitation of fibrin-based signaling niche for deriving progenitors from human adipose-derived mesenchymal stem cells towards potential neural engineering applications

Chandrababu

Senan

Krishnan

2020

Sci Rep

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Adipose-derived mesenchymal stem cells (hADMSC) retaining proliferation and multi-differentiation potential may support the central nervous system (CNS) regeneration. Multipotency of MSC may result in both desirable and undesirable cells, post-transplantation. A better strategy to attain desired cells may be in vitro commitment of hADMSCs to uni-/bi-potent neural progenitor cells (NPCs), prior to transplantation. Derivation of stable NPCs may require a suitable niche eliciting proliferation and differentiation signals. The present study designed a biomimetic niche comprising insoluble fibrin supported adhesion matrix and exogenously added growth factors (GFs) for deriving different neural cells and established the role of Notch and Wnt signals for proliferation and differentiation of hADMSCs, respectively. The stable transformation of hADMSCs into neurospheres (NS) comprising Nestin +ve NPCs was achieved consistently. Slight modifications of niche enable differentiation of NS to NPCs; NPCs to neurons; NPCs to oligodendrocyte progenitor cells (OPCs); and OPCs to oligodendrocytes (OLG). Fibrin plays a crucial role in the conversion of hADMSC to NS and NPCs to OPCs; but, not essential for OPC to OLG maturation. Co-survival and cell-cell interaction of NPC derived neurons and OPCs promoting OLG maturation is illustrated. The designed biomimetic niche shows the potential for directing autologous ADMSCs to neural cells for applications in regenerative medicine.The injured central nervous system (CNS) tissue shows limited and slothful ability to regenerate. This may be because of the inadequate number of endogenous neural progenitor cells (NPC) and the development of unfavorable micro-environment post-injury, affecting cell homing and differentiation. The stem cell transplantation is considered as a prospective therapy for CNS injury, considering the trophic support and its potential to differentiate into specific cells in the injured region 3 . The injury-associated and other degenerating diseases affecting CNS require glial and neuronal cells for its regeneration into fully functional tissue. Therefore, the exploitation of multi-potent hADMSCs may aim generation of NPCs and oligodendrocyte progenitor cell (OPC) with proliferation/differentiation potential starting from the same source of hADMSC, for mixed cell transplantation. Differentiation into each cell type may require specific niche conditions consisting of adhesive protein and growth factors (GF).Several advantages of the fibrin-based niche in stem cell growth and differentiation have been reported. Polymerized fibrin network constitutes several other adhesive proteins including fibronectin(FN) and laminin(La) playing a prominent role in eliciting signals for proliferation, survival, and differentiation. A previous study reported that both FN and La are responsible for stimulating Nestin +ve progenitors in peripheral blood mononuclear cells (PBMNC) directing differentiation to neurons 4,5 . The heparin-binding domains of the FN can immobilize GFs like PDGF, FGF...

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Inhibition of nuclear Wnt signalling: challenges of an elusive target for cancer therapy

Abstract: This article is part of a themed section on WNT Signalling: Mechanisms and Therapeutic Opportunities. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.24/issuetoc.

Cited by 50 publications

References 90 publications

MicroRNA‑6852 suppresses glioma A172 cell proliferation and invasion by targeting LEF1

MicroRNA‑6852 suppresses glioma A172 cell proliferation and invasion by targeting LEF1

TBX3 acts as tissue-specific component of the Wnt/β-catenin enhanceosome

Exploitation of fibrin-based signaling niche for deriving progenitors from human adipose-derived mesenchymal stem cells towards potential neural engineering applications

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