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

Boisteau, Émeric; Posseme, Céline; Modugno, Federico Di; Edeline, Julien; Coulouarn, Cédric; Hrstka, Roman; Martisova, Andrea; Delom, Frédéric; Eriksson, Leif A.; Chevet, Éric; Lièvre, Astrid; Ogier–Denis, Éric

doi:10.1038/s41388-022-02452-1

Cited by 11 publications

(18 citation statements)

References 112 publications

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“…AGR proteins including AGR1, AGR2, and AGR3 are members of the PDI family involved in oxidative protein folding in the ER (14)(15)(16). AGR proteins play a critical role in embryonic development, tissue regeneration, and tumor development and progression (14)(15)(16).…”

Section: Discussionmentioning

confidence: 99%

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Over-expression of Anterior Gradient 3 Is Associated With Tumor Progression and Poor Survival in Gastric Cancer

Lee

Park

et al. 2023

In Vivo

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Background/Aim: Anterior gradient (AGR) proteins, including AGR1, AGR2, and AGR3, which are members of the protein disulfide isomerase family, have been reported as biomarkers for various carcinogenesis processes. Although AGR2 and AGR1 have been demonstrated to be associated with gastric cancer (GC) progression and poor survival, the effect of AGR3 on the progression and prognosis of GC remains unknown. Therefore, our study aimed to examine the expression and prognostic significance of AGR3 in patients with GC. Patients and Methods: We investigated 271 GC patients receiving curative surgery. Formalin-fixed and paraffin-embedded tissue blocks were obtained, and long-term survival analysis was performed. The expression of AGR3 in GC tissues was investigated by quantitative reverse transcription-polymerase chain reaction, western blotting, and immunohistochemistry. Results: AGR3 was overexpressed in GC tissue compared with paired normal tissue at the mRNA and protein levels. AGR3 over-expression was significantly associated with larger tumor size, deeper tumor invasion, lymph node metastasis, and advanced tumor stage. The overall survival of patients with positive AGR3 expression was significantly lower than that of patients without positive AGR3 expression. Multivariate analysis demonstrated that AGR3 and age were independent prognostic factors associated with overall survival. Conclusion: Over-expression of AGR3 was significantly associated with tumor progression and poor survival of GC patients. Therefore, AGR3 may be a novel biomarker and prognostic factor for GC.Gastric cancer (GC) is one of the most prevalent cancer types and the leading cause of cancer-related mortality worldwide, especially in East Asia. Despite recent advances in therapeutic modalities, patients with advanced GC experience rapid disease progression with high morbidity, mortality, and poor survival (1-3). Early diagnosis is crucial to improve the prognosis of GC. Therefore, the search for reliable and practical molecular biomarkers for the early detection and prediction of cancer progression in GC has attracted much attention among clinicians.The protein disulfide isomerase (PDI) family includes thiol oxidoreductase, which mediates the formation, folding, and structural maturation of several substrate proteins in the endoplasmic reticulum (ER) (4-7). Its expression is elevated in a variety of cancers, which is closely related to the invasion and oncogenic phenotypes of tumor cells, and plays a significant role in the progression and prognosis of cancers (8-13).Anterior gradient (AGR) proteins are members of the PDI family involved in secretory and transmembrane proteostasis in the ER (14-16). AGR proteins are composed of three PDIlike proteins including AGR1, AGR2, and AGR3 (14-16). Several studies have suggested that AGR proteins exhibit various cellular functions (e.g., cell migration, differentiation, and proliferation) and pro-oncogenic functions in different types of cancers (14-16).AGR2 is the most described PDI family member and is s...

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Section: Discussionmentioning

confidence: 99%

“…AGR 3 is a highly related homolog of pro-oncogenic AGR2 and belongs to the PDI family (14)(15)(16). It is overexpressed in several cancers including breast, ovary, prostate, and liver cancers (19)(20)(21)(22)(23).…”

Section: Agr3 Expression In Gastric Cancer Tissue Analyzed By (A) Qua...mentioning

confidence: 99%

Over-expression of Anterior Gradient 3 Is Associated With Tumor Progression and Poor Survival in Gastric Cancer

Lee

Park

et al. 2023

In Vivo

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“…5 6 Moreover, AGR2 is strongly expressed in endodermderived organs (lung stomach, colon prostate, intestine) and as such, is almost exclusively expressed in mucosal epithelial cells. 1 Its overexpression has been associated with tumour aggressiveness in various cancers. 1 Tian et al claim that in CRC, AGR2 is only produced by tumour-infiltrating neutrophils (TANs) which impacts on the migration of CRC cells through the activation of signalling pathways depending on CD98hc-cCT and Rho GTPases.…”

mentioning

confidence: 99%

“…1 Its overexpression has been associated with tumour aggressiveness in various cancers. 1 Tian et al claim that in CRC, AGR2 is only produced by tumour-infiltrating neutrophils (TANs) which impacts on the migration of CRC cells through the activation of signalling pathways depending on CD98hc-cCT and Rho GTPases. Although this result is interesting, it is surprising that no expression of AGR2 is detected in tumour epithelial cells.…”

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confidence: 99%

“…AGR2 and AGR3 can be secreted in the extracellular milieu to trigger cell migration,2 and for AGR2 only, epithelial-to-mesenchymal transition,3 chemoattraction of monocytes4 and myofibroblast activation 5 6. Moreover, AGR2 is strongly expressed in endoderm-derived organs (lung stomach, colon prostate, intestine) and as such, is almost exclusively expressed in mucosal epithelial cells 1. Its overexpression has been associated with tumour aggressiveness in various cancers 1…”

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AGR2 protein expression in colorectal tumour epithelialcompartment

Chevet

Bassal

Beq

et al. 2022

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Characterization of the AGR2-NPM3 axis uncovers the AGR2 involvement in PD-L1 regulation in colorectal cancer

Martisova,

Faktor,

Sosolikova

et al. 2024

Sci Rep

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Despite extensive research, the molecular role of AGR2 in the progression and metastasis of colorectal cancer (CRC) has not been fully characterized. We used quantitative mass spectrometry (SWATH MS) to identify differentially expressed proteins in paired CRC cell models of the SW480 and SW620 cell lines in response to AGR2 protein level manipulation. Relying on the results from SWATH MS and subsequent immunochemical validation, we selected NMP3 as the top candidate protein associated with AGR2 in CRC tumour cells in our screen. RT‒qPCR and immunochemical analysis confirmed the involvement of AGR2-mediated regulation of NPM3 at the transcriptional and posttranscriptional levels. Since PD-L1 is a constituent of the NPM3 regulatory axis, we aimed to correlate the changes in PD-L1 to the differential expression of AGR2 in our cell models. We found that AGR2 positively regulates PD-L1 levels in both SW480 and SW620 cell lines; additionally, several different CRC patient transcriptome cohorts confirmed the association of AGR2 with PD-L1. Our work reveals a new AGR2-NPM3 regulatory axis and the involvement of AGR2 in the regulation of PD-L1, which paves the way for the association of AGR2 with immune evasion in CRC cells.

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

Cited by 11 publications

References 112 publications

Over-expression of Anterior Gradient 3 Is Associated With Tumor Progression and Poor Survival in Gastric Cancer

Over-expression of Anterior Gradient 3 Is Associated With Tumor Progression and Poor Survival in Gastric Cancer

AGR2 protein expression in colorectal tumour epithelialcompartment

Characterization of the AGR2-NPM3 axis uncovers the AGR2 involvement in PD-L1 regulation in colorectal cancer

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