Secretion of pro-oncogenic AGR2 protein in cancer

Abstract

Anterior gradient-2 (AGR2) protein mediates the formation, breakage and isomerization of disulphide bonds during protein maturation in the endoplasmic reticulum (ER) and contributes to the homoeostasis of the secretory pathway. AGR2 promotes tumour development and metastasis and its elevated expression is almost completely restricted to malignant tumours. Interestingly, this supposedly ER-resident protein can be localised to other compartments of cancer cells and can also be secreted into the extracellular milieu. There are emerging evidences that describe the gain-of-function activities of the extracellular AGR2, particularly in cancer development. Here, we reviewed studies detailing the expression, pathological and physiological roles associated with AGR2 and compared the duality of localization, intracellular and extracellular, with special emphasis on the later. We also discussed the possible mechanisms of AGR2 secretion as well as deliberating the functional impacts of AGR2 in cancer settings. Last, we deliberate the current therapeutic strategies and posit the potential use AGR2, as a prognosis and diagnosis marker in cancer.

Keywords: Biochemistry; Cancer; Cancer research; Cell biology; Enzymology; Molecular biology; Oncology; PDI; Protein folding; Protein secretion; Secretory pathway; UPR.

Figure 1

AGR2 protein architecture. (A) Schematic illustrating structure of the full-length AGR2 protein. The panel highlights the functional motifs human AGR2; signal peptide, an N-terminal intrinsically disordered region predicted using PSIPRED v3.3; a dimerization motif (green); a thioredoxin motif (brown), peptide-docking site (red) and ER retention motif (blue). (B) Solution structure of dimeric AGR2 (PDB code:2LNS). One monomer is represented as surface representation and the other monomer represented as a cartoon. The functional motifs in color-coded based on (A).

Figure 2

AGR2 genomic alterations in large cancer genomic studies. Genomic alterations in AGR2 was queried using cBioPortal (https://www.cbioportal.org/) that contains 10953 patients in 32 cancer studies [49, 50]. The abbreviations of cancer studies are labelled according to TCGA studies [114].

Figure 3

AGR2 and its splice variants mRNA expression in normal and cancer tissues. (A) Dot plots showing AGR2 mRNA expression in tumour and normal tissue samples extracted from the GEPIA2 web tool [115]. Cancer types highlighted in red have significant upregulation of AGR2 expression whereas those highlighted in green have reduced AGR2 expression compared to their normal counterparts. (B) Bar-plot showing the annotated AGR2 isoforms expression across the TCGA Pan-cancer analysis.

Figure 4

Emerging roles of iAGR2 and eAGR2 in normal and cancer conditions. AGR2 normally resides in the ER predominantly in its dimeric form and involves in the ER proteostasis through its protein disulphide isomerase activity. In a normal condition, AGR2 engages in the goblet differentiation that is responsible for secreting mucus in the respiratory and intestinal tracts that protects them from pathogenic infection. AGR2 is also essential for milk production during normal mammary gland development as well as receptor maturation and trafficking. In cancer cells, ER protein synthesis machinery is challenged with high mutant protein folding demands causing an ER stress that in turns activates UPR. In this context, AGR2 is actively regulated by the UPR pathways possibly via the IRE1α and ATF6 arms that can impact on AGR2 functions and export from the ER. There could also be an interplay of UPR/ERAD/Autophagy pathways. AGR2 can also escape the ER and be secreted into the extracellular environment in cancer. The presence of eAGR2 in the extracellular environment can contribute to the hallmarks of cancers such as enhancing cell proliferation, metastasis and dissemination, inflammation and angiogenesis. The mechanisms of AGR2 secretion are beginning to be elucidated. These include, among others, the association of its structure-function variants, possible PTMs and dimeric-monomeric regulations.