scholarly journals Downregulation of the Canonical WNT Signaling Pathway by TGFβ1 Inhibits Photoreceptor Differentiation of Adult Human Müller Glia with Stem Cell Characteristics

2016 ◽  
Vol 25 (1) ◽  
pp. 1-12 ◽  
Author(s):  
Angshumonik Angbohang ◽  
Na Wu ◽  
Thalis Charalambous ◽  
Karen Eastlake ◽  
Yuan Lei ◽  
...  
Keyword(s):  
Stem Cell ◽  
Wnt Signaling ◽  
Signaling Pathway ◽  
Wnt Signaling Pathway ◽  
Muller Glia ◽  
Müller Glia ◽  
Canonical Wnt Signaling ◽  
Adult Human ◽  
Canonical Wnt

Downregulation of Cancer Stemness by Novel Diterpenoid Ovatodiolide Inhibits Hepatic Cancer Stem Cell-Like Traits by Repressing Wnt/β-Catenin Signaling

2018 ◽  
Vol 46 (04) ◽  
pp. 891-910 ◽  
Author(s):  
Mingche Liu ◽  
Oluwaseun Adebayo Bamodu ◽  
Kuang-Tai Kuo ◽  
Wei-Hwa Lee ◽  
Yen-Kuang Lin ◽  
...  
Keyword(s):  
Stem Cell ◽  
Wnt Signaling ◽  
Signaling Pathway ◽  
Anticancer Agents ◽  
Target Therapy ◽  
Wnt Signaling Pathway ◽  
Tumor Evolution ◽  
Canonical Wnt Signaling ◽  
Differentiation Potential ◽  
Canonical Wnt

The hierarchical tumor propagation or cancer stem cells (CSCs) model of carcinogenesis postulates that like physiologic adult stem cell (ASC), the CSCs positioned at the apex of any tumor population form the crux of tumor evolution with a constitutive regenerative capacity and differentiation potential. The propagation and recurrence of the characteristically heterogeneous and therapy-resistant hepatocellular carcinoma (HCC), adds to accumulating evidence to support this CSCs model. Based on the multi-etiologic basis of HCC formation which among others, focuses on the disruption of the canonical Wnt signaling pathway, this study evaluated the role of cembrane-type phytochemical, Ovatodiolide, in the modulation of the Wnt/[Formula: see text]-catenin pathway, and its subsequent effect on liver CSCs’ activities. Our fluorescence-activated cell sorting (FACS) and quantitative RT-PCR analyses of side population (SP) indicated that CD133+ cells were [Formula: see text]-catenin-overexpressing, more aggressive, and resistant to the conventional anticancer agents, Cisplatin and Doxorubicin, when compared to [Formula: see text]-catenin-downregulated group. We demonstrated that marked upregulation of [Formula: see text]-catenin and its downstream targets effectively enhanced hepatosphere formation, with an associated induction of CD133, OCT4 and Sox2 expression and also caused an significant enhancement of HCC proliferation. However, treatment with Ovatodiolide induced downregulation of [Formula: see text]-catenin and its downstream effector genes, abolished hepatosphere formation and reversed the [Formula: see text]-catenin-associated enhancement of HCC growth. In summary, we demonstrated for the first time that Ovatodiolide suppressed the canonical Wnt signaling pathway, and inhibited the generation of liver CSCs; Thus, projecting Ovatodiolide as a putatively effective therapeutic agent for anti-HCC target therapy.

scholarly journals Cirmtuzumab Inhibits Non-Canonical Wnt Signaling without Enhancing Canonical Wnt/β-Catenin Signaling in Chronic Lymphocytic Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2652-2652
Author(s):  
Han Zhang ◽  
Suping Zhang ◽  
Emanuela M. Ghia ◽  
Michael Y. Choi ◽  
Jieyu Zhang ◽  
...  
Keyword(s):  
Stem Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Wnt Signaling ◽  
Signaling Pathway ◽  
Wnt Signaling Pathway ◽  
Lymphocytic Leukemia ◽  
Canonical Wnt Signaling ◽  
Gene Set Enrichment ◽  
Canonical Wnt ◽  
Cell Stem Cell

Abstract ROR1 is a receptor tyrosine kinase-like orphan receptor for Wnt5a that is expressed by cells during embryogenesis and by the neoplastic cells of a variety of cancers, including chronic lymphocytic leukemia (CLL). ROR1 can induce activation of β-catenin-independent non-canonical Wnt-signaling. Studies reveal a cross-talk between the non-canonical Wnt-signaling pathway and the β-catenin-dependent canonical Wnt-signaling pathway, which we previously found was also activated in CLL (Lu D, et al, PNAS 101:31118-3123, 2004). Prior studies indicated that silencing a related Wnt5a receptor, ROR2, could augment canonical Wnt-signaling induced by Wnt3a. In this study, we examined whether genetic silencing of ROR1 or inhibition of ROR1-signaling also could influence canonical Wnt signaling. To inhibit ROR1 signaling we used the humanized anti-ROR1 mAb cirmtuzumab, which is being evaluated in patients with CLL (Choi MY, et al, Cell Stem Cell, 22:951, 2018). Surprisingly, we found that CRISPR/Cas9 deletion of ROR1 in 293T cells also could enhance the capacity of Wnt3a to activate canonical Wnt-signaling, albeit to a lesser extent than CRISPR/Cas9 deletion of ROR2; conversely, re-introduction of ROR1 into ROR1-deleted 293T cells suppressed Wnt3a-induced activation of canonical Wnt-signaling. In contrast, treatment of wildtype 293T cells with cirmtuzumab did not enhance Wnt3a-induced activation of canonical Wnt-signaling, but nonetheless suppressed ROR1-dependent non-canonical signaling induced by Wnt5a. We examined the influence of ROR1 on canonical Wnt-signaling in CLL. First, we examined whether the relative expression of ROR1 influenced the relative levels of genes induced by activation of the canonical Wnt-signaling pathway. Gene set enrichment analysis (GSEA) of gene-expression data on CLL cells of different patients (n=448, GSE13204) revealed that CLL cells with low-level expression of ROR1 (ROR1Low) did not have increased levels of genes induced by activation of canonical Wnt-signaling relative to those noted in CLL cells with high-level expression of ROR1 (ROR1Hi). Nonetheless, ROR1Hi CLL cells did have increased levels of genes induced by activation of non-canonical Wnt signaling compared to ROR1Low CLL cells. As in 293T cells, siRNA-mediated knockdown of ROR1 in ROR1Hi CLL cells could enhance the capacity of Wnt3a to increase the levels of genes induced by canonical Wnt-signaling (e.g. MYC, CCND1). However, treatment of the same CLL cells with cirmtuzumab did not enhance the levels of such genes in response to Wnt3a, even at concentrations that exceeded those required to inhibit Wnt5a-induced ROR1-dependent non-canonical Wnt-signaling. We examined whether these findings also applied to CLL cells treated with cirmtuzumab in vivo. For this, we performed gene-set enrichment analyses on the transcriptomes of CLL cells collected from patients before and after treatment with cirmtuzumab in a recently completed phase I clinical trial (Choi MY, et al, Cell Stem Cell, 22:951, 2018). Although treatment with cirmtuzumab repressed expression of genes induced by activation of non-canonical Wnt signaling, we did not observe changes in the levels of genes induced by activation of the canonical Wnt signaling pathway. Collectively, this study demonstrates that cirmtuzumab can inhibit non-canonical Wnt signaling without enhancing canonical Wnt signaling in CLL, in contrast to what we observed in CLL cells silenced for ROR1. As such, treatment with cirmtuzumab may represent a more selective approach to suppressing non-canonical Wnt5a signaling than strategies aimed at genetic down-modulation or silencing of ROR1. Disclosures Choi: Rigel: Consultancy; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Gilead: Speakers Bureau; AbbVie, Inc: Consultancy, Speakers Bureau; Genentech: Speakers Bureau.

AB0070 Wnt and wisp1 expression in the synovium induces cartilage damage by skewing of tgf-beta signaling via the canonical wnt signaling pathway

2013 ◽  
Vol 72 (Suppl 3) ◽  
pp. A807.1-A807
Author(s):  
M. H. van den Bosch ◽  
A. B. Blom ◽  
P. L. van Lent ◽  
H. M. van Beuningen ◽  
F. A. van de Loo ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Signaling Pathway ◽  
Cartilage Damage ◽  
Wnt Signaling Pathway ◽  
Tgf Beta ◽  
Canonical Wnt Signaling ◽  
Canonical Wnt

scholarly journals KCTD1 Suppresses Canonical Wnt Signaling Pathway by Enhancing β-catenin Degradation

PLoS ONE ◽  
2014 ◽  
Vol 9 (4) ◽  
pp. e94343 ◽  
Author(s):  
Xinxin Li ◽  
Cheng Chen ◽  
Fangmei Wang ◽  
Wenhuan Huang ◽  
Zhongheng Liang ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Signaling Pathway ◽  
Wnt Signaling Pathway ◽  
Canonical Wnt Signaling ◽  
Canonical Wnt
Sign in / Sign up

Export Citation Format

Share Document