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Secretion of protein disulphide isomerase AGR2 confers tumorigenic properties

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ABSTRACT

The extracellular matrix (ECM) plays an instrumental role in determining the spatial orientation of epithelial polarity and the formation of lumens in glandular tissues during morphogenesis. Here, we show that the Endoplasmic Reticulum (ER)-resident protein anterior gradient-2 (AGR2), a soluble protein-disulfide isomerase involved in ER protein folding and quality control, is secreted and interacts with the ECM. Extracellular AGR2 (eAGR2) is a microenvironmental regulator of epithelial tissue architecture, which plays a role in the preneoplastic phenotype and contributes to epithelial tumorigenicity. Indeed, eAGR2, is secreted as a functionally active protein independently of its thioredoxin-like domain (CXXS) and of its ER-retention domain (KTEL), and is sufficient, by itself, to promote the acquisition of invasive and metastatic features. Therefore, we conclude that eAGR2 plays an extracellular role independent of its ER function and we elucidate this gain-of-function as a novel and unexpected critical ECM microenvironmental pro-oncogenic regulator of epithelial morphogenesis and tumorigenesis.

Doi:: http://dx.doi.org/10.7554/eLife.13887.001

No MeSH data available.


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Extracellular AGR2 disrupts cell-cell adhesion.Confocal cross-sections of HBEC organoids in the presence (+eAGR2) or absence (-eAGR2) of AGR2 in the ECM stained with E-Cadherin (A), β-catenin (B), or Laminin-V (C), and DAPI (blue) for nucleus. Scale bars, 50 μm.DOI:http://dx.doi.org/10.7554/eLife.13887.014
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fig8: Extracellular AGR2 disrupts cell-cell adhesion.Confocal cross-sections of HBEC organoids in the presence (+eAGR2) or absence (-eAGR2) of AGR2 in the ECM stained with E-Cadherin (A), β-catenin (B), or Laminin-V (C), and DAPI (blue) for nucleus. Scale bars, 50 μm.DOI:http://dx.doi.org/10.7554/eLife.13887.014

Mentions: Confocal microscopy analysis of non-tumorigenic HBEC organoids was then used to further evaluate the impact of eAGR2 on cell-cell adhesion. We investigate the possibility that eAGR2 disrupts tissue organization by affecting cell-cell adhesion. The HBEC organoids were stained with the following cell-cell adhesion markers E-cadherin (Figure 8A), β-catenin (Figure 8B) and laminin-V (Figure 8C). E-cadherin, β-catenin and Laminin-V relocalized from the basal side of the organoids to cell cytoplasm (Figure 8A–B). Thus, eAGR2 in the ECM, resulted in a disruption of cell-cell contact, of non-tumorigenic organoids.10.7554/eLife.13887.014Figure 8.Extracellular AGR2 disrupts cell-cell adhesion.


Secretion of protein disulphide isomerase AGR2 confers tumorigenic properties
Extracellular AGR2 disrupts cell-cell adhesion.Confocal cross-sections of HBEC organoids in the presence (+eAGR2) or absence (-eAGR2) of AGR2 in the ECM stained with E-Cadherin (A), β-catenin (B), or Laminin-V (C), and DAPI (blue) for nucleus. Scale bars, 50 μm.DOI:http://dx.doi.org/10.7554/eLife.13887.014
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Related In: Results  -  Collection

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fig8: Extracellular AGR2 disrupts cell-cell adhesion.Confocal cross-sections of HBEC organoids in the presence (+eAGR2) or absence (-eAGR2) of AGR2 in the ECM stained with E-Cadherin (A), β-catenin (B), or Laminin-V (C), and DAPI (blue) for nucleus. Scale bars, 50 μm.DOI:http://dx.doi.org/10.7554/eLife.13887.014
Mentions: Confocal microscopy analysis of non-tumorigenic HBEC organoids was then used to further evaluate the impact of eAGR2 on cell-cell adhesion. We investigate the possibility that eAGR2 disrupts tissue organization by affecting cell-cell adhesion. The HBEC organoids were stained with the following cell-cell adhesion markers E-cadherin (Figure 8A), β-catenin (Figure 8B) and laminin-V (Figure 8C). E-cadherin, β-catenin and Laminin-V relocalized from the basal side of the organoids to cell cytoplasm (Figure 8A–B). Thus, eAGR2 in the ECM, resulted in a disruption of cell-cell contact, of non-tumorigenic organoids.10.7554/eLife.13887.014Figure 8.Extracellular AGR2 disrupts cell-cell adhesion.

View Article: PubMed Central - PubMed

ABSTRACT

The extracellular matrix (ECM) plays an instrumental role in determining the spatial orientation of epithelial polarity and the formation of lumens in glandular tissues during morphogenesis. Here, we show that the Endoplasmic Reticulum (ER)-resident protein anterior gradient-2 (AGR2), a soluble protein-disulfide isomerase involved in ER protein folding and quality control, is secreted and interacts with the ECM. Extracellular AGR2 (eAGR2) is a microenvironmental regulator of epithelial tissue architecture, which plays a role in the preneoplastic phenotype and contributes to epithelial tumorigenicity. Indeed, eAGR2, is secreted as a functionally active protein independently of its thioredoxin-like domain (CXXS) and of its ER-retention domain (KTEL), and is sufficient, by itself, to promote the acquisition of invasive and metastatic features. Therefore, we conclude that eAGR2 plays an extracellular role independent of its ER function and we elucidate this gain-of-function as a novel and unexpected critical ECM microenvironmental pro-oncogenic regulator of epithelial morphogenesis and tumorigenesis.

Doi:: http://dx.doi.org/10.7554/eLife.13887.001

No MeSH data available.


Related in: MedlinePlus