期刊
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
卷 573, 期 -, 页码 86-92出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2021.08.028
关键词
Extracellular AGR2; Tumor microenvironment; Fibroblasts; beta-catenin; 18A4
资金
- National Natural Science Foundation of China [81373319, 81872790]
- Shanghai International Science and Technology Commission Foundation [184907411400]
- Postdoctoral Science Foundation of China [2020M681312]
AGR2 is often overexpressed in several types of cancer, and it can translocate into the cytoplasm through endocytosis when secreted by tumor cells or externally added. Extracellular AGR2 can bind to beta-catenin and promote its nuclear accumulation in fibroblasts and cancer cells, even in the presence of an EGFR inhibitor, suggesting an alternative pathway for beta-catenin regulation. The effects of extracellular AGR2 on beta-catenin were confirmed to be caused solely by AGR2 through experiments using a monoclonal antibody against AGR2.
Anterior gradient 2 (AGR2) is often overexpressed in several types of cancer. AGR2 is cytoplasmic or secreted as an extracellular signal. Intracellular AGR2 properties and role in cancer have been well studied, but its extracellular function is largely unclear. It has been shown that extracellular AGR2 activates endothelial cells and fibroblasts in culture, but the mechanism of AGR2 signaling is not well elucidated. Here, we report that tumor secreted or externally added AGR2 translocates into cytoplasm by endocytosis, binds to beta-catenin and further co-translocates to the nucleus in NIH3T3 fibroblasts. Externally added AGR2 also increased beta-catenin expression, stability, and accumulation in the nucleus in both fibroblasts and cancer cells. External AGR2 rescued the expression of fi-catenin, which was suppressed by EGFR inhibitor AG1478 indicating an alternative pathway to regulate beta-catenin independent of EGFR signal. These effects were abolished when a monoclonal antibody against AGR2 was added to the experiments, confirming the effects are caused by AGR2 only. Putting together, our results show that extracellular AGR2 signaling pathway involves endocytosis mediated cellular translocation, direct binding and regulating beta-catenin nuclear accumulation. It is also a target against tumor initiated AGR2 signaling to form and maintain tumor microenvironment. (C) 2021 Elsevier Inc. All rights reserved.
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