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NDRG1 overexpression promotes the progression of esophageal squamous cell carcinoma through modulating Wnt signaling pathway

View Article: PubMed Central - PubMed

ABSTRACT

N-myc down-regulated gene 1 (NDRG1) has been shown to regulate tumor growth and metastasis in various malignant tumors and also to be dysregulated in esophageal squamous cell carcinoma (ESCC). Here, we show that NDRG1 overexpression (91.9%, 79/86) in ESCC tumor tissues is associated with poor overall survival of esophageal cancer patients. When placed in stable transfectants of the KYSE 30 ESCC cell line generated by lentiviral transduction with the ectopic overexpression of NDRG1, the expression of transducin-like enhancer of Split 2 (TLE2) was decreased sharply, however β−catenin was increased. Mechanistically, NDRG1 physically associates with TLE2 and β−catenin to affect the Wnt pathway. RNA interference and TLE2 overexpression studies demonstrate that NDRG1 fails to active Wnt pathway compared with isogenic wild-type controls. Strikingly, NDRG1 overexpression induces the epithelial mesenchymal transition (EMT) through activating the Wnt signaling pathway in ESCC cells, decreased the expression of E-cadherin and enhanced the expression of Snail. Our study elucidates a mechanism of NDRG1-regulated Wnt pathway activation and EMT via affecting TLE2 and  β-catenin expression in esophageal cancer cells. This indicates a pro-oncogenic role for NDRG1 in esophageal cancer cells whereby it modulates tumor progression.

No MeSH data available.


Related in: MedlinePlus

Illustration showing the mechanism by which NDRG1 mediates activation of the Wnt signaling pathway. Overexpression of NDRG1 results in decreased TLE2 expression and increased β-catenin levels, which may then switch to β-catenin/TCF complex assembly and initiation of Wnt signaling pathway activation, promoting EMT in esophageal tumor cells.
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f0006: Illustration showing the mechanism by which NDRG1 mediates activation of the Wnt signaling pathway. Overexpression of NDRG1 results in decreased TLE2 expression and increased β-catenin levels, which may then switch to β-catenin/TCF complex assembly and initiation of Wnt signaling pathway activation, promoting EMT in esophageal tumor cells.

Mentions: In conclusion, our results demonstrate the upregulation of NDRG1 in ESCC and its association with poor overall median survival. We also demonstrate a critical role for NDRG1 in inducing EMT in ESCC cells, upregulating mesenchymal markers, and activating the Wnt signaling pathway via decreased TLE2 and increased β-catenin in ESCC. These results suggest that NDRG1 mediates the regulation of TLE2 and β-catenin levels and thereby affects the Wnt pathway and promotes EMT in ESCC cells (Fig. 6). These results indicate a pivotal pro-oncogenic role for NDRG1 in ESCC through which it modulates tumor progression. Further studies of the molecular mechanisms involving NDRG1 may lead to the development of novel therapeutic targets for esophageal cancer.Figure 6.


NDRG1 overexpression promotes the progression of esophageal squamous cell carcinoma through modulating Wnt signaling pathway
Illustration showing the mechanism by which NDRG1 mediates activation of the Wnt signaling pathway. Overexpression of NDRG1 results in decreased TLE2 expression and increased β-catenin levels, which may then switch to β-catenin/TCF complex assembly and initiation of Wnt signaling pathway activation, promoting EMT in esophageal tumor cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5036407&req=5

f0006: Illustration showing the mechanism by which NDRG1 mediates activation of the Wnt signaling pathway. Overexpression of NDRG1 results in decreased TLE2 expression and increased β-catenin levels, which may then switch to β-catenin/TCF complex assembly and initiation of Wnt signaling pathway activation, promoting EMT in esophageal tumor cells.
Mentions: In conclusion, our results demonstrate the upregulation of NDRG1 in ESCC and its association with poor overall median survival. We also demonstrate a critical role for NDRG1 in inducing EMT in ESCC cells, upregulating mesenchymal markers, and activating the Wnt signaling pathway via decreased TLE2 and increased β-catenin in ESCC. These results suggest that NDRG1 mediates the regulation of TLE2 and β-catenin levels and thereby affects the Wnt pathway and promotes EMT in ESCC cells (Fig. 6). These results indicate a pivotal pro-oncogenic role for NDRG1 in ESCC through which it modulates tumor progression. Further studies of the molecular mechanisms involving NDRG1 may lead to the development of novel therapeutic targets for esophageal cancer.Figure 6.

View Article: PubMed Central - PubMed

ABSTRACT

N-myc down-regulated gene 1 (NDRG1) has been shown to regulate tumor growth and metastasis in various malignant tumors and also to be dysregulated in esophageal squamous cell carcinoma (ESCC). Here, we show that NDRG1 overexpression (91.9%, 79/86) in ESCC tumor tissues is associated with poor overall survival of esophageal cancer patients. When placed in stable transfectants of the KYSE 30 ESCC cell line generated by lentiviral transduction with the ectopic overexpression of NDRG1, the expression of transducin-like enhancer of Split 2 (TLE2) was decreased sharply, however β−catenin was increased. Mechanistically, NDRG1 physically associates with TLE2 and β−catenin to affect the Wnt pathway. RNA interference and TLE2 overexpression studies demonstrate that NDRG1 fails to active Wnt pathway compared with isogenic wild-type controls. Strikingly, NDRG1 overexpression induces the epithelial mesenchymal transition (EMT) through activating the Wnt signaling pathway in ESCC cells, decreased the expression of E-cadherin and enhanced the expression of Snail. Our study elucidates a mechanism of NDRG1-regulated Wnt pathway activation and EMT via affecting TLE2 and  β-catenin expression in esophageal cancer cells. This indicates a pro-oncogenic role for NDRG1 in esophageal cancer cells whereby it modulates tumor progression.

No MeSH data available.


Related in: MedlinePlus