ESE1/AGR2 axis antagonizes TGF‐β‐induced epithelial‐mesenchymal transition in low‐grade pancreatic cancer

Abstract

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

AGR2: The Covert Driver and New Dawn of Hepatobiliary and Pancreatic Cancer Treatment

“…Elevated mucin expression can enhance cancer cell invasion and impact patient prognosis in ICC [36]. The role of AGR2 in elevating mucin levels to influence cancer invasion has been observed in various cancers, including pancreatic [37], colon [38], and breast cancers.…”

“…The expression of AGR2 is intricately regulated by various proteins, predominantly through protein-protein interactions that influence its function [48]. ESE1, identified as a robust activator of the AGR2 promoter in tumors, is regulated by transforming growth factor (TGF)-β [37]. AGR2 is a novel transcriptional target of ESE1, positively correlating with AGR2 to maintain epithelial cellular uniformity.…”

“…AGR2 is a novel transcriptional target of ESE1, positively correlating with AGR2 to maintain epithelial cellular uniformity. Conversely, TGF-β acts as an antagonist to this process [37], inhibiting AGR2 expression [49]. Additionally, the protein ZEB1 exhibits a negative correlation with AGR2 expression, with increased ZEB1 levels leading to reduced AGR2 expression [50].…”

“…The connection between AGR2 and EMT across various cancer types remains unclear. For instance, in lung adenocarcinoma and pancreatic ductal adenocarcinoma, TGF-β downregulates AGR2 expression to promote EMT [37,52], while in colon and head and neck squamous cell carcinomas, AGR2 overexpression plays a role in EMT promotion [53,54]. Both ZEB1 and TGF-β are involved in inducing EMT, but the role of AGR2 in this process is still unclear.…”

The Role of the Transforming Growth Factor-β Signaling Pathway in Gastrointestinal Cancers

“…Epithelium-specific ETS transcription factor 1 (ESE1) belongs to the ETS-domain transcription factor superfamily. In PC, an ESE1/anterior gradient protein 2 axis negatively interacts with TGF-β signaling to mediate the EMT phenotype by functioning with EMT drivers such as ZEB1/2 [66]. In addition, TGF-β1 upregulates acyl-CoA synthetases 3, leading to promoting ATP and suppressing NADPH, thereby maintaining redox homeostasis and facilitating the EMT and metastasis of CRC cells [67].…”