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Anterior gradient proteins in gastrointestinal cancers: from cell biology to pathophysiology

Abstract

Most of the organs of the digestive tract comprise secretory epithelia that require specialized molecular machines to achieve their functions. As such anterior gradient (AGR) proteins, which comprise AGR1, AGR2, and AGR3, belong to the protein disulfide isomerase family, and are involved in secretory and transmembrane protein biogenesis in the endoplasmic reticulum. They are generally expressed in epithelial cells with high levels in most of the digestive tract epithelia. To date, the vast majority of the reports concern AGR2, which has been shown to exhibit various subcellular localizations and exert pro-oncogenic functions. AGR2 overexpression has recently been associated with a poor prognosis in digestive cancers. AGR2 is also involved in epithelial homeostasis. Its deletion in mice results in severe diffuse gut inflammation, whereas in inflammatory bowel diseases, the secretion of AGR2 in the extracellular milieu participates in the reshaping of the cellular microenvironment. AGR2 thus plays a key role in inflammation and oncogenesis and may represent a therapeutic target of interest. In this review, we summarize the already known roles and mechanisms of action of the AGR family proteins in digestive diseases, their expression in the healthy digestive tract, and in digestive oncology. At last, we discuss the potential diagnostic and therapeutic implications underlying the biology of AGR proteins.

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Fig. 1: The mammalian AGR proteins: structural aspects.
Fig. 2: Subcellular functions of AGR proteins: structural aspects.
Fig. 3: Expression of AGR family members in the normal gastrointestinal tract.
Fig. 4: Expression of AGR family members in gastrointestinal cancers.

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Acknowledgements

We thank the Immuno-histopathology platform H2P2 for their expertise and work (https://histopathologie.univ-rennes1.fr/) and Raphael Pineau for his technical help. This work was funded by grants from INCa (PRT-K20-136) to CC and JE, INCa (PLBIO) to EC, La Ligue Contre le Cancer to EO-D and AL and from La Ligue Contre le Cancer Gironde and from the Site de recherche intégrée sur le cancer de Bordeaux (SIRIC Brio) to FD. LAE acknowledges funding from the Swedish research council (grant no 2019-3684) and the Swedish Cancer Foundation (grant no 21-1447 Pj). EB was funded by an “année-recherche” grant from the ministry of health.

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EB, EC, EO-D, and CP wrote the first draft of the manuscript, made the figures, and finalized the document. LAE carried out the structural analyses presented in Fig. 1. CP, FDM, JE, RH, AM, CC, FD, XT, LAE, and AL critically read the manuscript and worked on it.

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Correspondence to Eric Chevet, Astrid Lièvre or Eric Ogier-Denis.

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EO-D, XT, and EC are founders of Thabor Therapeutics.

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According to the French regulation, patients did not oppose to the analysis, and the study was approved by the Rennes Ethics Committee (Avis no. 21.122).

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Boisteau, E., Posseme, C., Di Modugno, F. et al. Anterior gradient proteins in gastrointestinal cancers: from cell biology to pathophysiology. Oncogene 41, 4673–4685 (2022). https://doi.org/10.1038/s41388-022-02452-1

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