Dual‐specificity phosphatase 6 deletion protects the colonic epithelium against inflammation and promotes both proliferation and tumorigenesis
Journal of Cellular Physiology
Published online on October 01, 2018
Abstract
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- "\nAbstract\nThe Ras/mitogen‐activated protein kinase (MAPK) pathway controls fundamental
cellular processes such as proliferation, differentiation, and apoptosis. The dual‐specificity
phosphatase 6 (DUSP6) regulates cytoplasmic MAPK signaling by dephosphorylating
and inactivating extracellular signal‐regulated kinase (ERK1/2) MAPK. To determine
the role of DUSP6 in the maintenance of intestinal homeostasis, we characterized
the intestinal epithelial phenotype of \nDusp6 knockout (KO) mice under normal,
oncogenic, and proinflammatory conditions. Our results show that loss of Dusp6 increased
crypt depth and epithelial cell proliferation without altering colonic architecture.
Crypt regeneration capacity was also enhanced, as revealed by ex vivo \nDusp6 KO
organoid cultures. Additionally, loss of Dusp6 induced goblet cell expansion without
affecting enteroendocrine and absorptive cell differentiation. Our data also demonstrate
that \nDusp6 KO mice were protected from acute dextran sulfate sodium‐induced colitis,
as opposed to wild‐type mice. In addition, \nDusp6 gene deletion markedly enhanced
tumor load in \nApc\nMin/+ mice. Decreased DUSP6 expression by RNA interference
in HT29 colorectal cancer cells enhanced ERK1/2 activation levels and promoted both
anchorage‐independent growth in soft agar as well as invasion through Matrigel.
Finally, \nDUSP6 mRNA expression in human colorectal tumors was decreased in advanced
stage tumors compared with paired normal tissues. These results demonstrate that
DUSP6 phosphatase, by controlling ERK1/2 activation, regulates colonic inflammatory
responses, and protects the intestinal epithelium against oncogenic stress."
- Journal of Cellular Physiology, EarlyView.