Insights into the role of ERp57 in cancer

Abstract

Endoplasmic reticulum resident protein 57 (ERp57) has a molecular weight of 57 kDa, belongs to the protein disulfide-isomerase (PDI) family, and is primarily located in the endoplasmic reticulum (ER). ERp57 functions in the quality control of nascent synthesized glycoproteins, participates in major histocompatibility complex (MHC) class I molecule assembly, regulates immune responses, maintains immunogenic cell death (ICD), regulates the unfolded protein response (UPR), functions as a 1,25-dihydroxy vitamin D₃ (1,25(OH)₂D₃) receptor, regulates the NF-κB and STAT3 pathways, and participates in DNA repair processes and cytoskeletal remodeling. Recent studies have reported ERp57 overexpression in various human cancers, and altered expression and aberrant functionality of ERp57 are associated with cancer growth and progression and changes in the chemosensitivity of cancers. ERp57 may become a potential biomarker and therapeutic target to combat cancer development and chemoresistance. Here, we summarize the available knowledge of the role of ERp57 in cancer and the underlying mechanisms.

Keywords: DNA repair.; ERp57/PDIA3; cancer; immune response; immunogenic cell death; unfolded protein response.

Figure 1

Schematic representation of the structural features of ERp57. ERp57 has four thioredoxin-like site domains—termed a, b, b', and a'—and an acidic C-terminal tail. The C-terminus contains a QEDL sequence that serves as an ER retention signal. The redox-active catalytic sites in the a and a' domains are shown in red, while the redox-inactive catalytic sites in the b and b' domains are shown in blue. The redox-active catalytic sites involve a CGHC sequence. The a' domain has DNA-binding activity, and the b' domain has peptide-binding activity.

Figure 2

The amino acid sequence of ERp57 and the functional domains. ERp57 has a total of 505 amino acids including four thioredoxin-like site domains, two redox-active catalytic sites, two redox-inactive catalytic sites, and a C-terminal ER retention signal. The redox-active catalytic sites are shown with a red background, while the redox-inactive catalytic sites are shown with a blue background. The C-terminus contains a QEDL sequence shown in purple.

Figure 3

ERp57 expression in normal samples and tumor samples in the TCGA (UALCAN). ERp57 expression is significantly different between tumor samples and tumor samples (P < 0.05) according to TCGA genomics data for a wide variety of cancers. The difference in mRNA expression was assessed by Student's t-test.

Figure 4

The biological functions of ERp57 in cancer. ERp57 regulates diverse signal transduction pathways: ERp57 is associated with CRT and CNX, participates in MHC class I molecule assembly, inhibits T cell-mediated immune responses, regulates the UPR, functions as a receptor for 1,25(OH)₂D₃, binds to STAT3 and NF-κB, enhances MMC-induced DNA cross-linking, and participates in DNA repair processes and cytoskeletal remodeling.