823 A20 Restricts Canonical Wnt Signaling in Intestinal Epithelial Cells and Suppresses Colon Carcinogenesis

The pathogenesis of Crohn’s disease-associated fibrostenosis and fistulas imply the epithelial-to-mesenchymal transition (EMT) process. As succinate and its receptor (SUCNR1) are involved in intestinal inflammation and fibrosis, we investigated their relevance in EMT and Crohn’s disease (CD) fistulas. Succinate levels and SUCNR1-expression were analyzed in intestinal resections from non-Inflammatory Bowel Disease (non-IBD) subjects and CD patients with stenosing-B2 or penetrating-B3 complications and in a murine heterotopic-transplant model of intestinal fibrosis. EMT, as increased expression of Snail1, Snail2 and vimentin and reduction in E-cadherin, was analyzed in tissues and succinate-treated HT29 cells. The role played by SUCNR1 was studied by silencing its gene. Succinate levels and SUCNR1 expression are increased in B3-CD patients and correlate with EMT markers. SUCNR1 is detected in transitional cells lining the fistula tract and in surrounding mesenchymal cells. Grafts from wild type (WT) mice present increased succinate levels, SUCNR1 up-regulation and EMT activation, effects not observed in SUCNR1−/− tissues. SUCNR1 activation induces the expression of Wnt ligands, activates WNT signaling and induces a WNT-mediated EMT in HT29 cells. In conclusion, succinate and its receptor are up-regulated around CD-fistulas and activate Wnt signaling and EMT in intestinal epithelial cells. These results point to SUCNR1 as a novel pharmacological target for fistula prevention.

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P.05.5 MICRORNA-155 IS DOWN-REGULATED IN APC-MUTANT SETTINGS AND MODULATES CANONICAL WNT SIGNALING IN COLON CARCINOGENESIS

Digestive and Liver Disease ◽

10.1016/s1590-8658(18)30496-1 ◽

2018 ◽

Vol 50 (2) ◽

pp. e166-e167 ◽

Cited By ~ 1

Author(s):

A. Prossomariti ◽

G. Piazzi ◽

L. D'Angelo ◽

S. Miccoli ◽

D. Turchetti ◽

...

Keyword(s):

Wnt Signaling ◽

Colon Carcinogenesis ◽

Canonical Wnt Signaling ◽

Canonical Wnt

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Protein kinase Cι is required for Ras transformation and colon carcinogenesis in vivo

The Journal of Cell Biology ◽

10.1083/jcb.200311011 ◽

2004 ◽

Vol 164 (6) ◽

pp. 797-802 ◽

Cited By ~ 102

Author(s):

Nicole R. Murray ◽

Lee Jamieson ◽

Wangsheng Yu ◽

Jie Zhang ◽

Yesim Gökmen-Polar ◽

...

Keyword(s):

Protein Kinase ◽

Epithelial Cells ◽

Intestinal Epithelial Cells ◽

Colon Carcinogenesis ◽

Ras Signaling ◽

Intestinal Epithelial ◽

Anchorage Independent Growth ◽

Oncogenic Ras ◽

Constitutively Active

Protein kinase C ι (PKCι) has been implicated in Ras signaling, however, a role for PKCι in oncogenic Ras-mediated transformation has not been established. Here, we show that PKCι is a critical downstream effector of oncogenic Ras in the colonic epithelium. Transgenic mice expressing constitutively active PKCι in the colon are highly susceptible to carcinogen-induced colon carcinogenesis, whereas mice expressing kinase-deficient PKCι (kdPKCι) are resistant to both carcinogen- and oncogenic Ras-mediated carcinogenesis. Expression of kdPKCι in Ras-transformed rat intestinal epithelial cells blocks oncogenic Ras-mediated activation of Rac1, cellular invasion, and anchorage-independent growth. Constitutively active Rac1 (RacV12) restores invasiveness and anchorage-independent growth in Ras-transformed rat intestinal epithelial cells expressing kdPKCι. Our data demonstrate that PKCι is required for oncogenic Ras- and carcinogen-mediated colon carcinogenesis in vivo and define a procarcinogenic signaling axis consisting of Ras, PKCι, and Rac1.

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Impact of Laminitis on the Canonical Wnt Signaling Pathway in Basal Epithelial Cells of the Equine Digital Laminae

PLoS ONE ◽

10.1371/journal.pone.0056025 ◽

2013 ◽

Vol 8 (2) ◽

pp. e56025 ◽

Cited By ~ 16

Author(s):

Le Wang ◽

Erica A. Pawlak ◽

Philip J. Johnson ◽

James K. Belknap ◽

Susan Eades ◽

...

Keyword(s):

Epithelial Cells ◽

Wnt Signaling ◽

Signaling Pathway ◽

Wnt Signaling Pathway ◽

Canonical Wnt Signaling ◽

Canonical Wnt ◽

Basal Epithelial Cells

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867 The Intestinal Epithelial Insulin-Like Growth Factor-1 Receptor Is Required for Acute Intestinal Adaptive Growth Effects But Not Activation of Canonical Wnt Signaling By Glucagon-Like Peptide-2

Gastroenterology ◽

10.1016/s0016-5085(09)60596-5 ◽

2009 ◽

Vol 136 (5) ◽

pp. A-133 ◽

Cited By ~ 1

Author(s):

Katherine J. Rowland ◽

Shivangi Trivedi ◽

Patricia L. Brubaker

Keyword(s):

Growth Factor ◽

Wnt Signaling ◽

Insulin Like Growth Factor ◽

Intestinal Epithelial ◽

Canonical Wnt Signaling ◽

Adaptive Growth ◽

Growth Effects ◽

Glucagon Like Peptide ◽

Canonical Wnt

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M1862 Activation of Wnt Signaling Protects Intestinal Epithelial Cells from Apoptosis By Increasing Cytoplasmic Levels of RNA-Binding Protein HuR

Gastroenterology ◽

10.1016/s0016-5085(08)64116-5 ◽

2008 ◽

Vol 134 (4) ◽

pp. A-877

Author(s):

Emily C. Bellavance ◽

Lan Liu ◽

Rao N. Jaladanki ◽

Tongtong Zou ◽

Douglas J. Turner ◽

...

Keyword(s):

Epithelial Cells ◽

Wnt Signaling ◽

Rna Binding ◽

Intestinal Epithelial Cells ◽

Binding Protein ◽

Rna Binding Protein ◽

Intestinal Epithelial

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Heparan sulfate on intestinal epithelial cells plays a critical role in intestinal crypt homeostasis via Wnt/β-catenin signaling

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00480.2012 ◽

2013 ◽

Vol 305 (3) ◽

pp. G241-G249 ◽

Cited By ~ 18

Author(s):

Shuji Yamamoto ◽

Hiroshi Nakase ◽

Minoru Matsuura ◽

Yusuke Honzawa ◽

Kayoko Matsumura ◽

...

Keyword(s):

Heparan Sulfate ◽

Wnt Signaling ◽

Binding Affinity ◽

Target Genes ◽

Glycogen Synthase ◽

Critical Role ◽

Intestinal Epithelial ◽

Canonical Wnt Signaling ◽

Small Intestinal ◽

Canonical Wnt

Heparan sulfate (HS), a constituent of HS proteoglycans (HSPGs), is a linear polysaccharide present on the cell surface. HSPGs modulate functions of several growth factors and signaling molecules. We examined whether small intestinal epithelial HS plays some roles in crypt homeostasis using intestinal epithelium cell (IEC)-specific HS-deficient C57Bl/6 mice. Survival rate after total body irradiation was significantly reduced in HS-deficient mice due to profound intestinal injury. HS-deficient IECs exhibited Wnt/β-catenin pathway disruption, decreased levels of β-catenin nuclear localization, and reduced expression of Wnt target genes, including Lgr5 during crypt regeneration. Moreover, epithelial HS increased Wnt binding affinity of IECs, promoted phosphorylation of Wnt coreceptor LRP6, and enhanced Wnt/β-catenin signaling following ex vivo stimulation with Wnt3a, whereas activation of canonical Wnt signaling following direct inhibition of glycogen synthase kinase-3β by lithium chloride was similar between HS-deficient and wild-type mice. Thus HS influences the binding affinity of IECs to Wnt, thereby promoting activation of canonical Wnt signaling and facilitating regeneration of small intestinal crypts after epithelial injury.

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