Epimorphin deletion protects mice from inflammation-induced colon carcinogenesis and alters stem cell niche myofibroblast secretion

Abstract

Epithelial-mesenchymal interactions regulate normal gut epithelial homeostasis and have a putative role in inflammatory bowel disease and colon cancer pathogenesis. Epimorphin is a mesenchymal and myofibroblast protein with antiproliferative, promorphogenic effects in intestinal epithelium. We previously showed that deletion of epimorphin partially protects mice from acute colitis, associated with an increase in crypt cell proliferation. Here we explored the potential therapeutic utility of modulating epimorphin expression by examining the effects of epimorphin deletion on chronic inflammation-associated colon carcinogenesis using the azoxymethane/dextran sodium sulfate (AOM/DSS) model. We found that mice in which epimorphin expression was absent had a marked reduction in incidence and extent of colonic dysplasia. Furthermore, epimorphin deletion in myofibroblasts altered the morphology and growth of cocultured epithelial cells. Loss of epimorphin affected secretion of soluble mesenchymal regulators of the stem cell niche such as Chordin. Importantly, IL-6 secretion from LPS-treated epimorphin-deficient myofibroblasts was completely inhibited, and stromal IL-6 expression was reduced in vivo. Taken together, these data show that epimorphin deletion inhibits chronic inflammation-associated colon carcinogenesis in mice, likely as a result of increased epithelial repair, decreased myofibroblast IL-6 secretion, and diminished IL-6-induced inflammation. Furthermore, we believe that modulation of epimorphin expression may have therapeutic benefits in appropriate clinical settings.

Embelin Reduces Colitis-Associated Tumorigenesis through Limiting IL-6/STAT3 Signaling

“…To determine BrdUrd incorporation, sections were stained using a BrdUrd In Situ Detection Kit (BD Pharmingen) according to the manufacturer's recommendations. Cell proliferation was assessed as described previously (19).…”

Isolation of Myofibroblasts from Mouse and Human Esophagus

“…The technique described has been successfully used by the authors to establish primary murine colonic myofibroblasts 7 and further adapted for establishment of murine 6 and human myofibroblast-like esophageal stromal cells.…”

Epimorphin deletion inhibits polyposis in theApcmin/+mouse model of colon carcinogenesis via decreased myofibroblast HGF secretion

“…To better understand the role of myofibroblasts in regulating proliferation and carcinogenesis of the gut epithelium, we have studied epimorphin (Epim), a member of the syntaxin family of vesicle-docking proteins expressed in gut myofibroblasts (10,33,35). Syntaxins are SNARE complex structural proteins that are required for membrane fusion events.…”

“…One of the best studied, syntaxin 1, functions as part of a target or t-SNARE complex to mediate neurotransmitter release in synapses (11). We have shown that Epim, or syntaxin 2, plays a role in regulating myofibroblast secretion of growth factors and cytokines (33). Epim is also unique among the syntaxins; in addition to its intracellular function as a vesicle-docking protein that regulates cellular secretion, it also has an extracellular location (6,12,29).…”

“…We previously generated Epim Ϫ/Ϫ mice and showed that Epim deletion results in partial protection from colitis (35) and from inflammation-induced carcinogenesis in an azoxymethane/dextran sodium sulfate model (33). Epim plays a role in carcinogenesis in other epithelial organs; for example, ectopic overexpression of Epim in hepatocellular carcinoma cells results in increased invasion and metastasis in an orthotopic liver implantation model, associated with increased MMP-9 expression (14).…”