Inhibition of Wnt signaling induces cell apoptosis and suppresses cell proliferation in cholangiocarcinoma cells

Zhang, Kunsong; Zhou, Qi; Wang, Ya-Feng; Liu, Liang

doi:10.3892/or.2013.2560

Cited by 34 publications

(29 citation statements)

References 25 publications

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“…The Wnt pathway can be activated aberrantly not only by mutations in APC but also by CTNNB1 gene encoding b-catenin, leading to ligand-independent Wnt signaling [8, 9]. However, increasing evidence suggests that dysregulation of Wnt signaling by secreted antagonists on the cell surface is also associated with tumorigenesis [10–15]; for example, the low expression induced by promoter methylation of Wnt antagonists genes SFRP1 and WIF1 may induce ligand-dependent Wnt signaling activity [16–19]. …”

Section: Main Textmentioning

confidence: 99%

Coexpression of SFRP1 and WIF1 as a Prognostic Predictor of Favorable Outcomes in Patients with Colorectal Carcinoma

Huang

Zhong

Gao

et al. 2014

BioMed Research International

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Colorectal tumorigenesis is ascribed to the activity of Wnt signaling pathway in a ligand-independent manner mainly through APC and CTNNB1 gene mutations and in a ligand-dependent manner through low expression of Wnt inhibitors such as WNT inhibitory factor 1 (WIF1) and secreted frizzled related protein 1 (SFRP1). In this study we found that WIF1 protein expression was increased and SFRP1 was decreased significantly in CRC tissue versus normal tissue, and high expression of WIF1 was associated with big tumor diameters and deep invasion, and loss of SFRP1 expression was associated with the left lesion site, deep invasion, and high TNM stage. Among the four expression patterns (WIF+/SFRP1+, WIF+/SFRP1−, WIF−/SFRP1+, and WIF−/SFRP1−) only coexpression of WIF1 and SFRP1 (WIF+/SFRP1+) was associated with favorable overall survival, together with low TNM stage, as an independent prognostic factor as shown in a multivariate survival model. The results indicated that WIF1 seemed to play an oncogenic role, while SFRP1 seemed to play an oncosuppressive role although both of them are secreted Wnt antagonists. Coexpression of SFRP1 and WIF1, rather than SFRP1 or WIF1 alone, could be used, together with low TNM stage, as a prognostic predictor of favorable outcomes in CRC.

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Section: Main Textmentioning

confidence: 99%

Coexpression of SFRP1 and WIF1 as a Prognostic Predictor of Favorable Outcomes in Patients with Colorectal Carcinoma

Huang

Zhong

Gao

et al. 2014

BioMed Research International

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“…Although RNF43 mutations and alterations in APC and CTNNB1 are absent in sporadic CC (7,8), we hypothesized that sporadic CC may require activation of WNT signaling akin to that of fluke-associated CC and that, in the absence of mutations in APC or CTNNB1, may remain sensitive to ligand or receptor inhibitors.…”

Section: Introductionmentioning

confidence: 99%

WNT signaling drives cholangiocarcinoma growth and can be pharmacologically inhibited

Boulter¹,

Guest²,

Kendall³

et al. 2015

J. Clin. Invest.

233

242

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“…Loss of cell-cell communication in the HTM may also lead to apoptosis and reduced cellularity. Indeed, sustained inhibition of Wnt can induce apoptosis (Bodine et al, 2005; Zhang et al, 2013) and can act as a mediator of senescence (Elzi et al, 2012). Both apoptosis and senescence have been hypothesized to play a role in progression of glaucoma.…”

mentioning

confidence: 99%

Wnt inhibition induces persistent increases in intrinsic stiffness of human trabecular meshwork cells

Morgan

Raghunathan

Chang

et al. 2015

Experimental Eye Research

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Wnt antagonism has been linked to glaucoma and intraocular pressure regulation, as has increased stiffness of human trabecular meshwork (HTM) tissue. We have shown culturing HTM cells on substrates that mimic the elevated stiffness of glaucomatous tissue leads to elevated expression of the Wnt antagonist secreted frizzled related protein 1 (SFRP1), suggesting a linkage between SFRP1 and HTM mechanobiology. In this study, we document biomechanical consequences of Wnt antagonism on HTM cells. Cells were treated with the Wnt antagonists (SFRP1, KY02111, and LGK-974) for 8 days and allowed to recover for 4 days. After recovery, intrinsic cell stiffness and activation of the Wnt pathway via β-catenin staining and blotting were assayed. Basal cell stiffness values were 3.71±0.37, 4.33±3.07, and 3.07± kPa (median±S.D.) for cells derived from 3 donors. Cell stiffness increased after 0.25 μg/mL (4.32±5.12, 8.86±8.51, 4.84±3.15 kPa) and 0.5 μg/mL (16.75±5.59, 13.18±7.99, and 8.54±5.77 kPa) SFRP1 treatment. Stiffening was observed after 10μM KY02111 (10.72±5.63 and 6.57±5.53 kPa) as well as LGK-974 (9.60±7.41 and 11.40±9.24 kPa) treatment compared with controls (3.79±1.01 and 5.16±2.14 kPa). Additionally, Wnt inhibition resulted in decreased β-catenin staining and increased phosphorylation at threonine 41 after recovery. In conclusion, this work demonstrates a causal relationship between Wnt inhibition and cell stiffening. Additionally, these findings suggest transient Wnt inhibition resulted in durable modulation of the mechanical phenotype of HTM cells. When placed in context with previous results, these findings provide a causal link between Wnt antagonism and cell stiffness and suggest a feedback loop contributing to glaucoma progression.

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Inhibition of Wnt signaling induces cell apoptosis and suppresses cell proliferation in cholangiocarcinoma cells

Cited by 34 publications

References 25 publications

Coexpression of SFRP1 and WIF1 as a Prognostic Predictor of Favorable Outcomes in Patients with Colorectal Carcinoma

Coexpression of SFRP1 and WIF1 as a Prognostic Predictor of Favorable Outcomes in Patients with Colorectal Carcinoma

WNT signaling drives cholangiocarcinoma growth and can be pharmacologically inhibited

Wnt inhibition induces persistent increases in intrinsic stiffness of human trabecular meshwork cells

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