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Gastrointestinal Cancer: Targets and Therapy Volume 4, 2014 - Issue
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Review

Esophageal cancer-related gene 4 at the interface of injury, inflammation, infection, and malignancy

Andrew BairdDivision of Trauma, Burn, and Acute Critical Care, Department of Surgery, University of California San Diego Health Sciences, San Diego, CA, USACorrespondence[email protected]
,
Jisook LeeDivision of Trauma, Burn, and Acute Critical Care, Department of Surgery, University of California San Diego Health Sciences, San Diego, CA, USA
,
Sonia PodvinDivision of Trauma, Burn, and Acute Critical Care, Department of Surgery, University of California San Diego Health Sciences, San Diego, CA, USA
,
Arwa KurabiDivision of Trauma, Burn, and Acute Critical Care, Department of Surgery, University of California San Diego Health Sciences, San Diego, CA, USA
,
Xitong DangDivision of Trauma, Burn, and Acute Critical Care, Department of Surgery, University of California San Diego Health Sciences, San Diego, CA, USA
,
Raul CoimbraDivision of Trauma, Burn, and Acute Critical Care, Department of Surgery, University of California San Diego Health Sciences, San Diego, CA, USA
,
Todd CostantiniDivision of Trauma, Burn, and Acute Critical Care, Department of Surgery, University of California San Diego Health Sciences, San Diego, CA, USA
,
Vishal BansalDivision of Trauma, Burn, and Acute Critical Care, Department of Surgery, University of California San Diego Health Sciences, San Diego, CA, USA
&
Brian P EliceiriDivision of Trauma, Burn, and Acute Critical Care, Department of Surgery, University of California San Diego Health Sciences, San Diego, CA, USA
 show all
Pages 131-142 | Published online: 24 Oct 2014

Figures & data

Figure 1 The ECRG4 gene and the ECRG4 promoter.

Notes: Located on human chromosome 2, the ECRG4 gene is composed of four exons and predicted to be regulated by multiple potential transcription factors as well as DNA methylation. The consensus binding sites and the density of methylate-able CpG islands were derived from sequences mapped using Gene ToolsCitation66, Promoter Prediction ServerCitation67, and FPROMCitation68. Binding sites are illustrated in the 5′ region of the gene, and the density of methylate-able CpG islands is shown as vertical hash marks.
Abbreviations: DNA, deoxyribonucleic acid; ECRG4, esophageal cancer-related gene 4.
Figure 1 The ECRG4 gene and the ECRG4 promoter.

Table 1 Homology of ECRG4 in different species

Figure 2 ECRG4 protein, processing, and secretion by the cell.

Notes: (A) ECRG4 is a highly conserved protein. The primary amino acid sequences from various species were mined from ENSEMBLCitation69 and sequences were compared to that of human ECRG4 by alignment of amino acids using Clustal Omega.Citation70 Conserved amino acid sequences are highlighted to show similarity between species. The gene and protein identifications, respectively, were: human (ENSG00000119147.6 and ENSP00000238044); chimpanzee (ENSPTRG00000012317 and ENTRP00000021098); rhesus (ENSMMUG0000001697 and ENSMMUP00000002269.2); mouse (ENSMUSG00000026051 and ENSMUSP00000027217); rat (ENSRNOG00000023576 and ENSRNOP00000030526); bat (ENSPVAG000000977 and ENSPVAP00000000925.1); dog (ENSCAFG0000002098 and ENSCAFP0000003083); cow (ENSBTAG00000012637 and ENSMUSP00000027217); chicken (ENSGALG00000016800 and ENSGALP00000027071.4); zebrafish A (ENSDARG00000056087 and ENSDARP00000072984.3); and zebrafish B (ENSDARG00000088717 and ENSDARP00000105276.1). Amino acid sequences for all 57 known orthologs to the human c2orf40 gene can be found at http://uswest.ensembl.org/Homo_sapiens/Gene/Compara_Ortholog?db=core;g=ENSG00000119147;r=2:106063294-106078155;t=ENST00000409944. (B) Cell surface processing by PC1/PC2 and furin convertases generates multiple peptide candidates. ECRG4 (left) encodes a noncanonical hydrophobic leader sequence that assists in tethering ECRG4 to the cell surface.Citation45 As predicted by Mirabeau et al,Citation3 ECRG4 processing at consensus protease substrate sequences for protein convertases like PC1/2, furin, or thrombin (large jagged lines) have the potential to yield several peptides (labeled 1–9) depending on the presence or absence of different proteases with differential activities. The effects of serine proteases like ECRG1 that have been shown to interact with ECRG4Citation52 are illustrated by the smaller jagged lines, which can process ECRG4 to even more potentially active peptides, making experimental analyses difficult.
Abbreviation: ECRG4, esophageal cancer-related gene 4.
Figure 2 ECRG4 protein, processing, and secretion by the cell.

Figure 3 Injury-induced downregulation of ECRG4.

Notes: Mining a gene chip microarray prepared from mouse mucosal epithelium of mice after infection (solid line) there is a time-dependent decrease ECRG4 mRNA. The decrease was compared to the thickness of the ME mucosa (dashed line) and mouse ECRG4 expression was downregulated within 12 hours, with mucosal hyperplasia increasing shortly thereafter. ECRG4 expression recovers just prior to the return of mucosa to normal thickness. Most importantly, if the decrease in ECRG4 gene expression is circumvented by preinjecting adenovirus encoding ECRG4, the hyperplastic response is blocked. These data imply that the scope of the mucosal response depends on the levels of “resting” ECRG4 on the epithelial surface. +indicates statistically different changes from control (P<0.05). Adapted from Kurabi A, Pak K, Dang X, et al. Ecrg4 attenuates the inflammatory proliferative response of mucosal epithelial cells to infection. PLoS One. 2013;8(4):e61394.Citation39
Abbreviations: ECRG4, esophageal cancer-related gene 4; mRNA, messenger ribonucleic acid.
Figure 3 Injury-induced downregulation of ECRG4.

Figure 4 A model for the action of ECRG4 in cancer and the response to injury.

Notes: In quiescent tissues (A), ECRG4 is present on the cell surface of both epithelial cellsCitation35,Citation38–Citation40 and circulating leukocytes.Citation37 This cell surface ECRG4 is thought to play a “sentinel” function that monitors homeostasis, gauges the proinflammatory response to injury and infection,Citation35,Citation39,Citation40 and thereby maintains quiescence. Upon infection or inflammation (B), protease activation and priming of these cells release processed forms of ECRG4 from the cell surfaceCitation37,Citation44,Citation45 and ECRG4 gene expression is downregulated,Citation35,Citation39,Citation40 taking a cancer genotype.Citation4–Citation6,Citation11–Citation14,Citation16–Citation22,Citation52,Citation53,Citation55,Citation63 The release of smaller processed ECRG4 peptides have intrinsic activities that recruit, inhibit, and activate both inflammatory and epithelial cells.Citation37,Citation44 The now reactive epithelial cells (C) are characterized by downregulated ECRG4 gene expression and a loss of ECRG4 on the cell surface, enabling responsiveness to autocrine, paracrine, and endocrine growth promoting factors (D) that result in cell expansion through increased migration, proliferation, and lost differentiation. A gauged return of the intact ECRG4 to the cell surface in a protease-free (or neutralized) milieu, which is dependent on the methylation of the ECRG4 promoter, inhibits reactivity and helps restore quiescence. In cancer, a continuous downregulation of ECRG4 through hypermethylation and the failure to restore ECRG4 to the cell surface compromises normal immune cell surveillance (A), and displays a continuous inflammation phenotype (B) that enables constitutive reactivity (C) and responsiveness of the cell to mediators of inflammation. The hypermethylation of ECRG4 prevents its ultimate return to the cell surface, thereby interfering with normal immunosurveillance.
Abbreviations: ECRG4, esophageal cancer-related gene 4; PMN, polymorphonuclear cells.
Figure 4 A model for the action of ECRG4 in cancer and the response to injury.

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