Abstract
Engrailed-2 (EN2) is a homeodomain-containing transcription factor that has roles in boundary formation and neural guidance in early development, but which is also expressed in a range of cancers. In addition to transcriptional regulation, it is secreted by cells and taken up by others through a mechanism that is yet to be fully elucidated. In this study, the distribution of EN2 protein in cells was evaluated using immunofluorescence with a set of antibodies raised against overlapping epitopes across the protein, and through the use of an EN2-GFP construct. MX2 expression in primary prostate tumors was evaluated using immunohistochemistry. We showed that EN2 protein is present in the cell membrane and within microvesicles that can be secreted from the cell and taken up by others. When taken up by normal cells from the stroma EN2 induces the expression of MX2 (MxB), a protein that has a key role in the innate immune response to viruses. Our findings indicate that EN2 secretion by tumors may be a means of preventing viral-mediated immune invasion of tissue immediately adjacent to the tumor.
Highlights
Punia N, Primon M, Simpson GR et al (2019) Membrane insertion and secretion of the Engrailed-2 (EN2) transcription factor by prostate cancer cells may induce antiviral activity in the stroma
We show that EN2 is present in the membrane of cancer cells and that it is secreted through an active mechanism that is dependent on vesicle formation, and that cells that take up exogenous EN2 protein undergo distinct changes in behavior that could profoundly influence tumor development through modification of the tumor microenvironment
In order to do this, a series of antibodies were raised in sheep using 20 amino acid peptides that overlapped each other by 10 amino acids, and which together covered the whole length of the EN2 protein
Summary
Punia N, Primon M, Simpson GR et al (2019) Membrane insertion and secretion of the Engrailed-2 (EN2) transcription factor by prostate cancer cells may induce antiviral activity in the stroma. There is evidence that EN2 can be secreted from cells in a process that is dependent on a peptide sequence within the DNA-binding homeodomain region[11,12,13,14], and that in the developing brain this gives rise to an extracellular gradient of EN2 protein that can be taken up by temporal retina and nasal axons resulting in attraction and repulsion, respectively[15] These effects on axonal migration appear to be mediated at the level of translational regulation exerted by the internalized EN2 protein[15]
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