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HIF1α deficiency reduces inflammation in a mouse model of proximal colon cancer.

Mladenova DN, Dahlstrom JE, Tran PN, Benthani F, Bean EG, Ng I, Pangon L, Currey N, Kohonen-Corish MR - Dis Model Mech (2015)

Bottom Line: Microscopically, Hif1α(ΔIEC) mice had significantly less severe colon inflammation than Hif1α(F/F) mice.Molecular analysis showed reduced MIF expression and increased E-cadherin mRNA expression in the colon of sulindac-treated Hif1α(ΔIEC) mice.Taken together, HIF1α expression augments inflammation in the proximal colon of sulindac-treated mice, and AHR activation by sulindac might lead to the reduction of E-cadherin protein levels through the mitogen-activated protein kinase (MAPK) pathway.

View Article: PubMed Central - PubMed

Affiliation: Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales, 2010, Australia.

No MeSH data available.


Related in: MedlinePlus

HIF1α deficiency predisposes the colon mucosa to a defect in E-cadherin protein expression in sulindac-treated mice. (A) Representative photomicrographs of E-cadherin staining in the P2 region of Hif1αΔIEC and Hif1αF/F mice treated with sulindac (Sul) or the control (Con) diet. (B) Quantification of the staining intensity of E-cadherin in the cytoplasm and membrane of colon epithelial cells using the H-score. Error bars indicate s.e.m. Star (*) indicates P<0.05. ΔIEC=Hif1αΔIEC; F/F=Hif1αF/F.
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DMM019000F5: HIF1α deficiency predisposes the colon mucosa to a defect in E-cadherin protein expression in sulindac-treated mice. (A) Representative photomicrographs of E-cadherin staining in the P2 region of Hif1αΔIEC and Hif1αF/F mice treated with sulindac (Sul) or the control (Con) diet. (B) Quantification of the staining intensity of E-cadherin in the cytoplasm and membrane of colon epithelial cells using the H-score. Error bars indicate s.e.m. Star (*) indicates P<0.05. ΔIEC=Hif1αΔIEC; F/F=Hif1αF/F.

Mentions: E-cadherin is detected in both the cytoplasm and the membrane of colon epithelial cells. Membrane-bound E-cadherin is crucial in maintaining the integrity of the intercellular junctions. We next determined whether sulindac changed E-cadherin protein expression in the mucosa of the proximal colon, which is most affected by sulindac-induced epithelial damage (Fig. 5). Consistent with the results of mRNA analyses, E-cadherin protein levels were higher in Hif1αΔIEC mice compared with those in Hif1αF/F mice, but this was only seen in the mice that received the control feed. Remarkably, with sulindac exposure, there was a clear decrease in E-cadherin protein level in Hif1αΔIEC mice despite an increase in E-cadherin mRNA level (Fig. 4A). This was due to reduced expression of both cytoplasmic and membrane-bound E-cadherin. Thus, although the Hif1αΔIEC mice showed less inflammatory damage in the colon following treatment with sulindac, these mice displayed a defect in E-cadherin protein expression. This suggests that E-cadherin protein expression in the proximal colon is reduced by sulindac and that this is more pronounced in the absence of HIF1α.Fig. 5.


HIF1α deficiency reduces inflammation in a mouse model of proximal colon cancer.

Mladenova DN, Dahlstrom JE, Tran PN, Benthani F, Bean EG, Ng I, Pangon L, Currey N, Kohonen-Corish MR - Dis Model Mech (2015)

HIF1α deficiency predisposes the colon mucosa to a defect in E-cadherin protein expression in sulindac-treated mice. (A) Representative photomicrographs of E-cadherin staining in the P2 region of Hif1αΔIEC and Hif1αF/F mice treated with sulindac (Sul) or the control (Con) diet. (B) Quantification of the staining intensity of E-cadherin in the cytoplasm and membrane of colon epithelial cells using the H-score. Error bars indicate s.e.m. Star (*) indicates P<0.05. ΔIEC=Hif1αΔIEC; F/F=Hif1αF/F.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4582097&req=5

DMM019000F5: HIF1α deficiency predisposes the colon mucosa to a defect in E-cadherin protein expression in sulindac-treated mice. (A) Representative photomicrographs of E-cadherin staining in the P2 region of Hif1αΔIEC and Hif1αF/F mice treated with sulindac (Sul) or the control (Con) diet. (B) Quantification of the staining intensity of E-cadherin in the cytoplasm and membrane of colon epithelial cells using the H-score. Error bars indicate s.e.m. Star (*) indicates P<0.05. ΔIEC=Hif1αΔIEC; F/F=Hif1αF/F.
Mentions: E-cadherin is detected in both the cytoplasm and the membrane of colon epithelial cells. Membrane-bound E-cadherin is crucial in maintaining the integrity of the intercellular junctions. We next determined whether sulindac changed E-cadherin protein expression in the mucosa of the proximal colon, which is most affected by sulindac-induced epithelial damage (Fig. 5). Consistent with the results of mRNA analyses, E-cadherin protein levels were higher in Hif1αΔIEC mice compared with those in Hif1αF/F mice, but this was only seen in the mice that received the control feed. Remarkably, with sulindac exposure, there was a clear decrease in E-cadherin protein level in Hif1αΔIEC mice despite an increase in E-cadherin mRNA level (Fig. 4A). This was due to reduced expression of both cytoplasmic and membrane-bound E-cadherin. Thus, although the Hif1αΔIEC mice showed less inflammatory damage in the colon following treatment with sulindac, these mice displayed a defect in E-cadherin protein expression. This suggests that E-cadherin protein expression in the proximal colon is reduced by sulindac and that this is more pronounced in the absence of HIF1α.Fig. 5.

Bottom Line: Microscopically, Hif1α(ΔIEC) mice had significantly less severe colon inflammation than Hif1α(F/F) mice.Molecular analysis showed reduced MIF expression and increased E-cadherin mRNA expression in the colon of sulindac-treated Hif1α(ΔIEC) mice.Taken together, HIF1α expression augments inflammation in the proximal colon of sulindac-treated mice, and AHR activation by sulindac might lead to the reduction of E-cadherin protein levels through the mitogen-activated protein kinase (MAPK) pathway.

View Article: PubMed Central - PubMed

Affiliation: Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales, 2010, Australia.

No MeSH data available.


Related in: MedlinePlus