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.
Highlights
It is well established that proper organization, maintenance, and function of the epithelial organs are largely ascribed to cell-cell adhesion and polarization of epithelium and its interaction with extracellular matrix (ECM)
To further confirm that anterior gradient-2 (AGR2) is essential for cancer tumorigenesis, we investigated the effects of overexpressing AGR2 in non-tumorigenic human bronchial epithelial cell (HBEC) using lentivirus-mediated infection with either empty vector (HBEC-EV) (Figure 4A, top panels) or AGR2 containing vector (HBEC-AGR2) (Figure 4A, bottom panels)
Since AGR2 has been correlated as potentially involved in Epithelial–Mesenchymal Transition (EMT) (Mizuuchi et al, 2015; Ma et al, 2015) and that EMT is characterized by a reduction of cell-cell adhesion and loss of apico-basolateral polarity (Thiery, 2002), we examined whether Extracellular AGR2 (eAGR2) might regulate EMT in non-tumorigenic HBEC organoids
Summary
It is well established that proper organization, maintenance, and function of the epithelial organs are largely ascribed to cell-cell adhesion and polarization of epithelium and its interaction with extracellular matrix (ECM). IAGR2 overexpression could represent a mechanistic intermediate between endoplasmic reticulum quality control (ERQC) and tumor development (Higa et al, 2011; Chevet et al, 2013) In such model, increased iAGR2 expression could enhance ER protein homeostasis/proteostasis thereby allowing tumor cells to cope with abnormal protein production and secretion and contributing to the aggressiveness of cancer (Higa et al, 2011). The latter was demonstrated using both in vitro and in vivo approaches (Chevet et al, 2013). For the first time, 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
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