INSERM U1242, University of Rennes, Rennes, France.
Department of Gastroenterology, University Hospital Pontchaillou, University of Rennes, Rennes, France.
Oncogene. 2022 Oct;41(42):4673-4685. doi: 10.1038/s41388-022-02452-1. Epub 2022 Sep 6.
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.
大多数消化道器官由分泌上皮组成，这些上皮需要专门的分子机器来实现其功能。因此，属于蛋白二硫键异构酶家族的前沿梯度（AGR）蛋白，包括 AGR1、AGR2 和 AGR3，参与内质网中分泌和跨膜蛋白的生物发生。它们通常在具有高表达水平的上皮细胞中表达，在大多数消化道上皮细胞中均有表达。迄今为止，绝大多数报告都涉及 AGR2，已经证明它具有各种亚细胞定位并发挥致癌功能。最近发现 AGR2 的过表达与消化道癌症的预后不良有关。AGR2 还参与上皮细胞稳态。在小鼠中敲除其基因会导致严重的弥漫性肠道炎症，而在炎症性肠病中，AGR2 在细胞外环境中的分泌参与了细胞微环境的重塑。因此，AGR2 在炎症和致癌作用中起着关键作用，可能是一个有治疗前景的靶点。在这篇综述中，我们总结了 AGR 家族蛋白在消化道疾病中的已知作用和作用机制，以及它们在健康消化道和消化道肿瘤学中的表达。最后，我们讨论了 AGR 蛋白生物学的潜在诊断和治疗意义。
