Abstract
Effective diagnostic, prognostic and therapeutic biomarkers can help in tracking disease progress, predict patients’ survival, and considerably affect the drive for successful clinical management. The present review aims to determine how the metastatic-linked protein anterior gradient homologue 2 (AGR2) operates to affect cancer progression, and to identify associated potential diagnostic, prognostic and therapeutic biomarkers, particularly in central nervous system (CNS) tumors. Studies that show a high expression level of AGR2, and associate the protein expression with the resilience to chemotherapeutic treatments or with poor cancer survival, are reported. The primary protein structures of the seven variants of AGR2, including their functional domains, are summarized. Based on experiments in various biological models, this review shows an orchestra of multiple molecules that regulate AGR2 expression, including a feedback loop with p53. The AGR2-associated molecular functions and pathways including genomic integrity, proliferation, apoptosis, angiogenesis, adhesion, migration, stemness, and inflammation, are detailed. In addition, the mechanisms that can enable the rampant oncogenic effects of AGR2 are clarified. The different strategies used to therapeutically target AGR2-positive cancer cells are evaluated in light of the current evidence. Moreover, novel associated pathways and clinically relevant deregulated genes in AGR2 high CNS tumors are identified using a meta-analysis approach.
Highlights
The anterior gradient homolog 2 protein (AGR2) is considered a member of the protein disulphide isomerase (PDI) superfamily
The results showed that the anterior gradient homologue 2 (AGR2) overexpression had a negative effect on the overall survival (OS) and time to tumor progression (TTP)
A study showed that the AGR2 protein expression level in the samples from breast cancer patients, who were previously treated with tamoxifen, was higher than that in those who had not been treated with tamoxifen [103]
Summary
The anterior gradient homolog 2 protein (AGR2) is considered a member of the protein disulphide isomerase (PDI) superfamily. The clinical relevance of AGR2 overexpression in cancer progression was emphasized when the human AGR2 protein was shown to attenuate the p53 activity following DNA damage through the suppression of phosphorylated p53 [8]. The AGR2 gene was identified later in a gene expression profiling study in the MDA-MB-231 breast cancer cell line to promote survival and invasion under stressed and hypoxic conditions [13]. Gene expression signatures have shown that AGR2 is overexpressed in many tumors. The analysis for breast cancer patients found the AGR2 overexpression to be significantly associated with poor OS and TTP [22]. Using a meta-analysis approach, the identified signal transduction pathways modulated in the CNS tumors overexpressing AGR2 are shown
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