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The human AGR2 (Anterior gradient 2) gene is located on chromosome 7p21.3. The AGR2 gene shares two mRNAs, both of which contain 8 exons and 7 introns. The AGR2 protein has 175 amino acids and a molecular weight of approximately 19979.2 Da. AGR2 mRNA is mainly expressed in endodermal-derived organs containing mucus-secreting cells. The transcription factor FOXa-1, FOXa-2, which is a typical mucous cell such as goblet cells, has an AGR2 promoter activity. It was found that AGR2 protein is involved in promoting the formation of disulfide bonds by cysteine in mucin2. Some scholars transplanted normal mammary epithelium and stroma into female nude mice and treated with estrogen to find that AGR2 mRNA was up-regulated, which proved that estrogen up-regulated AGR2 gene expression, and later found that there was an ER binding site on AGR2 promoter.
Under normal conditions, the AGR2 protein is mainly localized in the lumen of the endoplasmic reticulum, assisting the endoplasmic reticulum glucoamary transfer of the nascent peptide. In addition to the endoplasmic reticulum, AGR2 is present in a variety of cellular structures, such as the nucleus, cell surface, and extracellular fluid. It belongs to a family of protein disulfide isomerases and contains a classical "-CXXC-" domain. Its function in the endoplasmic reticulum promotes redox reactions between proteins, transport of secreted proteins, and reconstruction of sulfur bonds and promotion of the formation of disulfide isomerization and the like.
The AGR2 gene was found to be involved in the growth factor EGF receptor pathway in lung adenocarcinoma studies. The AGR2 protein can induce the expression of AREG (bidirectional regulatory protein). AREG acts as a ligand to activate the EGF receptor signaling pathway, promoting tumor cell growth and proliferation. The AGR2 gene is also involved in the PDPK/AKT signaling pathway. Estrogen binds to ER after transmembrane and forms an activated complex ER-E, which directly activates the expression of the AGR2 gene as a transcription factor. ERB2 dimerization can also be achieved through the ERB2 /PI3K/AKT signaling pathway, further triggering AKT kinase phosphorylation. Duction of EMT induced AGR2 resulted in a mesenc activated AKT acts as a transcription factor to activate the downstream AGR2 gene. In turn, it promotes the formation of ER-E complexes. Sommerova et al. found that AGR2 reduction and EMT induction induced AGR2, which resulted in a mesenchymal phenotype that returned to the epithelial phenotype and regained epithelial markers. The activated Smad and Erk signaling cascades are considered to be complementary pathways that promote TGF-β mediated AGR2 inhibition.
Figure 1. AGR2 biological pathways. (Chevet, et al. 2013).
AGR2 and Tumor
Initial studies have shown that the AGR2 gene is overexpressed in ER-positive breast cancer cells, and the prognosis of AGR2 gene expression is poor. Guo et al. analyzed 69 samples from the Gene Expression Omnibus database and found that AGR2 expression in non-triple negative breast cancer tissues was significantly higher than that in normal tissues and triple-negative breast cancer groups, and AGR2 could be considered as a presumptive prognosis biomarkers for breast cancer. Lacambra et al. found that the prognostic impact of AGR2 expression may be related to the therapeutic outcome of estrogen receptor-positive breast cancer and/or its metastatic effect. In addition, overexpression of the AGR2 gene in vivo also promotes the metastasis of breast cancer. Hypoxia-inducible factor-1α (HIF-1α) is associated with chemoresistance in human breast cancer. Li et al. found that AGR2, as a breast cancer biomarker, regulates hypoxia-induced doxorubicin resistance through the binding and stabilizing effects of HIF-1α. This provides a possible explanation for changes in chemoresistance levels in breast cancer and further validates that AGR2 is a potential anti-breast cancer therapeutic target.
Neeb and other studies have confirmed that AGR2mRNA and protein are obviously up-regulated in prostate cancer, and AGR2 protein is also detected in the urine of patients with prostate cancer. Over expression of AGR2 protein not only causes cell cycle arrest but also promotes metastasis. In addition, E2 is the only estrogen in prostate cancer that induces AGR2 gene expression by activating AR. In vivo and in vitro tests confirm that EBP1 attenuated tumor invasiveness by inhibiting the expression of AGR2. FOXa1 and FOXa2 activate the promoter of AGR2 gene in prostate cancer, while EBP1 attenuated the transcriptional activation of AGR2 gene by FOXa1 and FOXa2.
In addition to the above tumors, AGR2 is also abnormally expressed in other tumors. Barrett's esophagus is a precancerous lesion that progresses to Barrett's esophageal adenocarcinoma. The AGR2 gene was highly expressed in Barrett's esophageal intestinal metaplasia and Barrett's esophageal adenocarcinoma, and it was on the rise. In esophageal adenocarcinoma, AGR2 protein induces AREG expression and enhances the survival and proliferation of esophageal adenocarcinoma cells. AGR2 is also abnormally elevated in most primary and metastatic fibroblastic liver cancers. AGR2 gene showed polymorphism but no significant mutation was found. It was negative in hepatocellular carcinoma and hepatic adenoma. In pancreatic intraepithelial neoplasia and pancreatic adenocarcinoma, AGR2 expression is elevated. In addition, AGR2 protein levels are elevated in pancreatic epithelial neoplasia and pancreatic juice in patients with intraductal papillary mucinous adenocarcinoma of the pancreas. In gastrointestinal cancer, AGR2 mRNA can be used as a special marker for circulating cancer cells, and the AGR2 gene is highly expressed in colon cancer cell lines. Ma et al. found that in vitro knockdown of TGFBR1 in the head and neck squamous cell carcinoma (HNSCC) cell line increased AGR2 expression. These results suggest that AGR2 is involved in the self-renewal of EMT and CSC and may provide potential therapeutic targets for HNSCC. Alavi et al. found that almost all non-small cell lung cancer (NSCLC) tumors showed AGR2 expression. The expression of AGR2 in lung cancer has prognostic value in young patients.