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Anterior gradient proteins in gastrointestinal cancers: from cell biology to pathophysiology
Emeric Boisteau1,2, Céline Posseme1,3, Federico Di Modugno1,3
1INSERM U1242, University of Rennes, Rennes, France.
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.
Insights
Anterior gradient (AGR) proteins, particularly AGR2, are crucial in digestive tract health and disease. Their roles in inflammation and cancer suggest potential as therapeutic targets for digestive disorders.
Area of Science:
- Cell Biology
- Gastroenterology
- Oncology
Background:
- Secretory epithelia in the digestive tract rely on specialized molecular machines.
- Anterior gradient (AGR) proteins (AGR1, AGR2, AGR3) are part of the protein disulfide isomerase family.
- These proteins are vital for secretory and transmembrane protein biogenesis in the endoplasmic reticulum.
Purpose of the Study:
- To review the known roles and mechanisms of AGR proteins in digestive diseases.
- To examine AGR protein expression in healthy digestive tracts and digestive cancers.
- To discuss the diagnostic and therapeutic implications of AGR protein biology.
Main Methods:
- Literature review of existing research on AGR proteins.
- Analysis of AGR protein expression patterns in healthy and diseased digestive tissues.
- Synthesis of data on AGR protein functions in inflammation and oncogenesis.
Main Results:
- AGR proteins are highly expressed in digestive tract epithelia.
- AGR2 is extensively studied, showing diverse subcellular localizations and pro-oncogenic functions.
- AGR2 overexpression correlates with poor prognosis in digestive cancers and plays a role in gut inflammation and homeostasis.
Conclusions:
- AGR2 is implicated in both inflammation and oncogenesis within the digestive system.
- Dysregulation of AGR proteins contributes to digestive diseases.
- AGR proteins represent promising targets for future diagnostic and therapeutic strategies in gastroenterology and oncology.
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