Epimorphin deletion protects mice from inflammation-induced colon carcinogenesis and alters stem cell niche myofibroblast secretion.
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.
Shaker
Anisa
A
Department of Internal Medicine, Washington University School of Medicine, Saint Louis, Missouri, USA.
Swietlicki
Elzbieta A
EA
Wang
Lihua
L
Jiang
Shujun
S
Onal
Birce
B
Bala
Shashi
S
DeSchryver
Katherine
K
Newberry
Rodney
R
Levin
Marc S
MS
Rubin
Deborah C
DC
D000818:Animals; D001397:Azoxymethane / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D003110:Colonic Neoplasms / Q000150:complications / Q000235:genetics / Q000473:pathology*; D016264:Dextran Sulfate / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D017384:Sequence Deletion
D015850:Interleukin-6; D016264:Dextran Sulfate; D001397:Azoxymethane
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