Dysadherin can enhance tumorigenesis by conferring properties of stem-like cells to hepatocellular carcinoma cells

Park, Jeong-Ran; Kim, Ran-Ju; Lee, Yoo-Kyung; Kim, Chang Woo; Roh, Kyung-Jin; Oh, Seung Hyun; Kang, Kyung‐Sun; Nam, Jeong‐Seok

doi:10.1016/j.jhep.2010.06.026

Cited by 31 publications

(25 citation statements)

References 40 publications

(58 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast, little is known about the mechanism involved in the disruption of cell junctions by FXYD5. FXYD5 is expressed in normal and cancer cells (Gabrielli et al, 2011; Park et al, 2011;Shimada et al, 2004). In normal cells, FXYD5 increases the Na,K-ATPase activity (Lubarski et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…FXYD5 is unique in the FXYD family as it possesses an extended extracellular O-glycosylated domain (Ino et al, 2002;Tsuiji et al, 2003). Elevated levels of FXYD5 in tumors of patients with different types of cancer correlate with a poor prognosis (Lee et al, 2012;Maehata et al, 2011;Mitselou et al, 2010;Park et al, 2011;Shimada et al, 2004), and overexpression of FXYD5 in various cell types results in the impairment of intercellular adhesion (Ino et al, 2002;Lubarski et al, 2011;Shimamura et al, 2004;Tsuiji et al, 2003). It has been suggested that overexpression of FXYD5 downregulates E-cadherin levels, promoting metastasis (Batistatou et al, 2007a;Ino et al, 2002;Shimamura et al, 2004;Tamura et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

“…It has been suggested that overexpression of FXYD5 downregulates E-cadherin levels, promoting metastasis (Batistatou et al, 2007a;Ino et al, 2002;Shimamura et al, 2004;Tamura et al, 2005). However, E-cadherinindependent mechanisms have been also described, including the activation of the NF-κB pathway, leading to increased production of the tumor-promoting chemokine CCL2 (Lubarski et al, 2011;Nam et al, 2007;Park et al, 2011;Stamatovic et al, 2009). Moreover, FXYD5 is expressed in normal lung, kidney and gut epithelium (Lubarski et al, 2005), although the functional role of this protein in normal tissues is unclear.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The O-glycosylated ectodomain of FXYD5 impairs adhesion by disrupting cell–cell trans-dimerization of Na,K-ATPase β1 subunits

Tokhtaeva

Sun

Deiss-Yehiely

et al. 2016

Journal of Cell Science

View full text Add to dashboard Cite

FXYD5 (also known as dysadherin), a regulatory subunit of the Na,K-ATPase, impairs intercellular adhesion by a poorly understood mechanism. Here, we determined whether FXYD5 disrupts the transdimerization of Na,K-ATPase molecules located in neighboring cells. Mutagenesis of the Na,K-ATPase β 1 subunit identified four conserved residues, including Y199, that are crucial for the intercellular Na,K-ATPase trans-dimerization and adhesion. Modulation of expression of FXYD5 or of the β 1 subunit with intact or mutated β 1 -β 1 binding sites demonstrated that the anti-adhesive effect of FXYD5 depends on the presence of Y199 in the β 1 subunit. Immunodetection of the plasma membrane FXYD5 was prevented by the presence of O-glycans. Partial FXYD5 deglycosylation enabled antibody binding and showed that the protein level and the degree of O-glycosylation were greater in cancer than in normal cells. FXYD5-induced impairment of adhesion was abolished by both genetic and pharmacological inhibition of FXYD5 O-glycosylation. Therefore, the extracellular O-glycosylated domain of FXYD5 impairs adhesion by interfering with intercellular β 1 -β 1 interactions, suggesting that the ratio between FXYD5 and α 1 -β 1 heterodimer determines whether the Na,K-ATPase acts as a positive or negative regulator of intercellular adhesion.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The O-glycosylated ectodomain of FXYD5 impairs adhesion by disrupting cell–cell trans-dimerization of Na,K-ATPase β1 subunits

Tokhtaeva

Sun

Deiss-Yehiely

et al. 2016

Journal of Cell Science

View full text Add to dashboard Cite

show abstract

“…Dysadherin positive cell populations have high cell proliferation rates and show anti-apoptotic properties (Park et al 2011). Parallel to their findings, in this study we observed that while dysadherin expression decreased, apoptosis increased in HT-29 and Caco-2 cells depending on the HYP concentration.…”

Section: Resultsmentioning

confidence: 99%

Alterations in dysadherin expression and F-actin reorganization: a possible mechanism of hypericin-mediated photodynamic therapy in colon adenocarcinoma cells

2014

View full text Add to dashboard Cite

Dysadherin is a recently found anti-adhesion molecule, therefore detection and down regulation of its expression is promising in cancer treatment. The up-regulation of dysadherin contributes to colon cancer recurrence and metastasis. Dysadherin also has connections with cytoskeletal proteins and it can cause alterations in the organisation of filamentous actin (Factin) in metastatic cancers. In this study, hypericin (HYP)-mediated photodynamic therapy (PDT) was performed in two different grade colon adenocarcinoma cell lines HT-29 (Grade I) and Caco-2 (Grade II). Cells were treated with 0.04, 0.08 or 0.15 lM HYP concentrations and irradiated with (4 J/cm 2 ) fluorescent lamps. The effects of HYP was examined 16 and 24 h after the activation. We investigated for the first time the effect of HYP-mediated PDT on the expression of dysadherin and F-actin organisation. According to the results, HYP mediated PDT caused a decrease in gene expression and immunofluorescence staining of dysadherin and an increase in actin stress fibers and actin aggregates in HT-29 and Caco-2 cell lines. Besides, cytotoxicity, number of floating cells and apoptotic index changed depending on the cell type, HYP concentration and incubation time. We have demonstrated for the first time that dysadherin and F-actin could be target molecules for HYP-

show abstract

“…This family contains seven integral membrane proteins that interact with the Na,K-ATPase and regulate its function in a tissue-specific manner (27, 28). FXYD5, also known as dysadherin, is not only involved in the regulation of Na,K-ATPase activity (29, 30) but also acts as a tumorigenic protein when overexpressed (31, 32). Its expression is elevated in metastatic tumors, suggesting FXYD5 as an oncogenic marker (32–38).…”

Section: Introductionmentioning

confidence: 99%

FXYD5 Is an Essential Mediator of the Inflammatory Response during Lung Injury

et al. 2017

View full text Add to dashboard Cite

The alveolar epithelium secretes cytokines and chemokines that recruit immune cells to the lungs, which is essential for fighting infections but in excess can promote lung injury. Overexpression of FXYD5, a tissue-specific regulator of the Na,K-ATPase, in mice, impairs the alveolo-epithelial barrier, and FXYD5 overexpression in renal cells increases C-C chemokine ligand-2 (CCL2) secretion in response to lipopolysaccharide (LPS). The aim of this study was to determine whether FXYD5 contributes to the lung inflammation and injury. Exposure of alveolar epithelial cells (AEC) to LPS increased FXYD5 levels at the plasma membrane, and FXYD5 silencing prevented both the activation of NF-κB and the secretion of cytokines in response to LPS. Intratracheal instillation of LPS into mice increased FXYD5 levels in the lung. FXYD5 overexpression increased the recruitment of interstitial macrophages and classical monocytes to the lung in response to LPS. FXYD5 silencing decreased CCL2 levels, number of cells, and protein concentration in bronchoalveolar lavage fluid (BALF) after LPS treatment, indicating that FXYD5 is required for the NF-κB-stimulated epithelial production of CCL2, the influx of immune cells, and the increase in alveolo-epithelial permeability in response to LPS. Silencing of FXYD5 also prevented the activation of NF-κB and cytokine secretion in response to interferon α and TNF-α, suggesting that pro-inflammatory effects of FXYD5 are not limited to the LPS-induced pathway. Furthermore, in the absence of other stimuli, FXYD5 overexpression in AEC activated NF-κB and increased cytokine production, while FXYD5 overexpression in mice increased cytokine levels in BALF, indicating that FXYD5 is sufficient to induce the NF-κB-stimulated cytokine secretion by the alveolar epithelium. The FXYD5 overexpression also increased cell counts in BALF, which was prevented by silencing the CCL2 receptor (CCR2), or by treating mice with a CCR2-blocking antibody, confirming that FXYD5-induced CCL2 production leads to the recruitment of monocytes to the lung. Taken together, the data demonstrate that FXYD5 is a key contributor to inflammatory lung injury.

show abstract

Dysadherin can enhance tumorigenesis by conferring properties of stem-like cells to hepatocellular carcinoma cells

Cited by 31 publications

References 40 publications

The O-glycosylated ectodomain of FXYD5 impairs adhesion by disrupting cell–cell trans-dimerization of Na,K-ATPase β1 subunits

The O-glycosylated ectodomain of FXYD5 impairs adhesion by disrupting cell–cell trans-dimerization of Na,K-ATPase β1 subunits

Alterations in dysadherin expression and F-actin reorganization: a possible mechanism of hypericin-mediated photodynamic therapy in colon adenocarcinoma cells

FXYD5 Is an Essential Mediator of the Inflammatory Response during Lung Injury

Contact Info

Product

Resources

About