Wnt signaling induces epithelial differentiation during cutaneous wound healing

Fathke, Carrie; Wilson, Lynne; Shah, Kavita V.; Kim, Brian; Hocking, Anne M.; Moon, Randall T.; Isik, F. Frank

doi:10.1186/1471-2121-7-4

Cited by 132 publications

(56 citation statements)

References 35 publications

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“…On the other hand, immortalized keratinocytes HHK respond to neutral-pepsin (pH 7.0) by minimal activation of NF- κ B (Figs 3A, 4A and 5Ba). We also note that HHK responds to weakly acidic-pepsin by an increase in wnt5α, but without co-activation of NF- κ B, TNF-α, STAT3, EGFR or Tp53 and Tp63, supporting a wnt5α function in this setting as an important key molecule toward epithelial differentiation rather than oncogenesis [49]. …”

Section: Discussionmentioning

confidence: 98%

The In Vitro Effect of Acidic-Pepsin on Nuclear Factor KappaB Activation and Its Related Oncogenic Effect on Normal Human Hypopharyngeal Cells

Sasaki¹,

Toman²,

Vageli³

2016

PLoS ONE

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BackgroundExtra-esophageal carcinogenesis has been widely discussed in relation to the chronic effects of laryngopharyngeal reflux and most prominently with pepsin historically central to this discussion. With refluxate known to include gastric (pepsin) and duodenal (bile) fluids, we recently demonstrated the mechanistic role of NF-κB in mediating the preneoplastic effects of acidic-bile. However, the role of pepsin in promoting hypopharyngeal premalignant events remains historically unclear. Here, we investigate the in vitro effect of acidic-pepsin on the NF-κB oncogenic pathway to better define its potential role in hypopharyngeal neoplasia.MethodsHuman hypopharyngeal primary cells (HHPC) and keratinocytes (HHK) were repetitively exposed to physiologic pepsin concentrations (0.1 mg/ml) at pH 4.0, 5.0 and 7.0. Cellular localization of phospho-NF-κB and bcl-2 was determined using immunofluorescence and western blotting. NF-κB transcriptional activity was tested by luc reporter and qPCR. Analysis of DNA content of pepsin treated HHK and HHPC was performed using Fluorescence-activated-cell sorting assay. To explore a possible dose related effect, pepsin concentration was reduced from 0.1 to 0.05 and 0.01 mg/ml.ResultsAt physiologic concentration, acidic-pepsin (0.1 mg/ml at pH 4.0) is lethal to most normal hypopharyngeal cells. However, in surviving cells, no NF-κB transcriptional activity is noted. Acidic-pepsin fails to activate the NF-κB or bcl-2, TNF-α, EGFR, STAT3, and wnt5α but increases the Tp53 mRNAs, in both HHPC and HHK. Weakly acidic-pepsin (pH 5.0) and neutral-pepsin (pH 7.0) induce mild activation of NF-κB with increase in TNF-α mRNAs, without oncogenic transcriptional activity. Lower concentrations of pepsin at varying pH do not produce NF-κB activity or transcriptional activation of the analyzed genes.ConclusionOur findings in vitro do not support the role of acidic-pepsin in NF-κB related hypopharyngeal carcinogenesis.

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Section: Discussionmentioning

confidence: 98%

The In Vitro Effect of Acidic-Pepsin on Nuclear Factor KappaB Activation and Its Related Oncogenic Effect on Normal Human Hypopharyngeal Cells

Sasaki¹,

Toman²,

Vageli³

2016

PLoS ONE

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“…WNT genes are required for blastema formation (Kawakami et al, 2006; Stoick-Cooper et al, 2007). In addition, several studies have linked WNT signaling to tissue repair and wound healing, including in skin and bone (Chen et al, 2007; Chua et al, 2011; Fathke et al, 2006; Lim et al, 2013; Whyte et al, 2013). It is tempting to speculate that the observed requirement for WNT signaling during the induction of the pluripotent state represents a cell culture equivalent to these in vivo regenerative processes.…”

Section: Discussionmentioning

confidence: 99%

A Rare Human Syndrome Provides Genetic Evidence that WNT Signaling Is Required for Reprogramming of Fibroblasts to Induced Pluripotent Stem Cells

et al. 2014

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SUMMARY WNT signaling promotes the reprogramming of somatic cells to an induced pluripotent state. We provide genetic evidence that WNT signaling is a requisite step during the induction of pluripotency. Fibroblasts from individuals with Focal Dermal Hypoplasia (FDH), a rare genetic syndrome caused by mutations in the essential WNT processing enzyme PORCN, fail to reprogram using standard methods. This blockade in reprogramming is overcome by ectopic WNT signaling and by PORCN overexpression, thus demonstrating that WNT signaling is essential for reprogramming. The rescue of reprogramming is critically dependent on the level of WNT signaling: steady baseline activation of the WNT pathway yields karyotypically normal iPS cells, whereas daily stimulation with Wnt3a produces FDH-iPS cells with severely abnormal karyotypes. Therefore, although WNT signaling is required for cellular reprogramming, inappropriate activation of WNT signaling induces chromosomal instability, highlighting the precarious nature of ectopic WNT activation, and its tight relationship with oncogenic transformation.

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“…Cutaneous wound healing studies in mice show that β-catenin signaling is indeed activated as a consequence of wounding [10 •• ,11] and forced activation of β-catenin using a stabilized mutant that resists ubiquitin-mediated degradation (Catnb ex3 ) is sufficient to drive hyperplastic wounds and exuberant collagen synthesis, mimicking aggressive fibromatoses in humans [12]. Conversely, removal of β-catenin using Cre-loxP technology resulted in smaller wounds [13].…”

Section: Evidence For Wnt Signaling In Fibrosis: Lessons From Skinmentioning

confidence: 99%

β-catenin signaling

Lam

Gottardi

2011

Current Opinion in Rheumatology

166

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Purpose of review The Wnt/β-catenin signaling pathway plays a critical role in development and adult tissue homeostasis. Recent investigations implicate Wnt/β-catenin signaling in abnormal wound repair and fibrogenesis. The purpose of this review is to highlight recent key studies that support a role for Wnt/β-catenin signaling in fibrosis. Recent findings Studies of patients with fibrotic diseases have demonstrated changes in components of the Wnt/β-catenin pathway. In animal models, perturbations in Wnt/β-catenin signaling appear to aggravate or ameliorate markers of injury and fibrosis in a variety of different tissues. Studies also suggest that fibroblasts from different tissue sources may have markedly divergent responses to Wnt/β-catenin signaling. Cross-talk between Wnt/β-catenin and transforming growth factor-β pathways is complex and context-dependent, and may promote fibrogenesis through coregulation of fibrogenic gene targets. High throughput screening has identified several novel chemical inhibitors of Wnt/β-catenin signaling that may be of therapeutic potential. Summary Wnt/β-catenin signaling appears important in normal wound healing and its sustained activation is associated with fibrogenesis. The mechanism by which Wnt/β-catenin signaling may modify the response to injury is cell-type and context-dependent. Better understanding of this signaling pathway may provide a promising new therapeutic approach for human fibrotic diseases.

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Wnt signaling induces epithelial differentiation during cutaneous wound healing

Cited by 132 publications

References 35 publications

The In Vitro Effect of Acidic-Pepsin on Nuclear Factor KappaB Activation and Its Related Oncogenic Effect on Normal Human Hypopharyngeal Cells

The In Vitro Effect of Acidic-Pepsin on Nuclear Factor KappaB Activation and Its Related Oncogenic Effect on Normal Human Hypopharyngeal Cells

A Rare Human Syndrome Provides Genetic Evidence that WNT Signaling Is Required for Reprogramming of Fibroblasts to Induced Pluripotent Stem Cells

β-catenin signaling

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