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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

Treatment with sulindac upregulates HIF2α and downregulates MIF in Hif1αΔIEC mice compared with Hif1αF/F mice. Q-PCR analysis for gene expression of Hif1α (A), ITF (B), Glut1 (C), Pgk1 (D), Vegfa (E), Hif2α (F), MIF (G) and the macrophage marker F4/80 (H). RNA was extracted from the mucosal scrapings, and lesions were harvested from the proximal colon of Hif1αΔIEC and Hif1αF/F mice that had been treated with sulindac (Sul) or the control (Con) diet. The q-PCR primers for Hif1α span exons 2 and 3. Gene expression was normalised to that of Rpl19. Error bars indicate s.e.m. Star (*) indicates P<0.05.
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DMM019000F3: Treatment with sulindac upregulates HIF2α and downregulates MIF in Hif1αΔIEC mice compared with Hif1αF/F mice. Q-PCR analysis for gene expression of Hif1α (A), ITF (B), Glut1 (C), Pgk1 (D), Vegfa (E), Hif2α (F), MIF (G) and the macrophage marker F4/80 (H). RNA was extracted from the mucosal scrapings, and lesions were harvested from the proximal colon of Hif1αΔIEC and Hif1αF/F mice that had been treated with sulindac (Sul) or the control (Con) diet. The q-PCR primers for Hif1α span exons 2 and 3. Gene expression was normalised to that of Rpl19. Error bars indicate s.e.m. Star (*) indicates P<0.05.

Mentions: We observed a 19-fold reduction of Hif1α mRNA expression in Hif1αΔIEC mice compared with that of the control genotype (Fig. 3A). The generation of Hif1αΔIEC involves deletion of exon 2, which contains sequences encoding the basic helix-loop-helix (bHLH) domain that is essential for DNA binding and dimerisation of HIF1α and HIF1β (Jiang et al., 1996), and that results in downregulation of HIF1α-target genes (Iyer et al., 1998; Ryan et al., 1998). As we have previously shown in wild-type mice, the sulindac diet increased HIF1α expression in Hif1αF/F mice, and this effect was most pronounced in the inflammatory colon lesions (Fig. 3A). HIF1α expression remained low in the colon of the Hif1αΔIEC mice that had been treated with sulindac.Fig. 3.


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)

Treatment with sulindac upregulates HIF2α and downregulates MIF in Hif1αΔIEC mice compared with Hif1αF/F mice. Q-PCR analysis for gene expression of Hif1α (A), ITF (B), Glut1 (C), Pgk1 (D), Vegfa (E), Hif2α (F), MIF (G) and the macrophage marker F4/80 (H). RNA was extracted from the mucosal scrapings, and lesions were harvested from the proximal colon of Hif1αΔIEC and Hif1αF/F mice that had been treated with sulindac (Sul) or the control (Con) diet. The q-PCR primers for Hif1α span exons 2 and 3. Gene expression was normalised to that of Rpl19. Error bars indicate s.e.m. Star (*) indicates P<0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

DMM019000F3: Treatment with sulindac upregulates HIF2α and downregulates MIF in Hif1αΔIEC mice compared with Hif1αF/F mice. Q-PCR analysis for gene expression of Hif1α (A), ITF (B), Glut1 (C), Pgk1 (D), Vegfa (E), Hif2α (F), MIF (G) and the macrophage marker F4/80 (H). RNA was extracted from the mucosal scrapings, and lesions were harvested from the proximal colon of Hif1αΔIEC and Hif1αF/F mice that had been treated with sulindac (Sul) or the control (Con) diet. The q-PCR primers for Hif1α span exons 2 and 3. Gene expression was normalised to that of Rpl19. Error bars indicate s.e.m. Star (*) indicates P<0.05.
Mentions: We observed a 19-fold reduction of Hif1α mRNA expression in Hif1αΔIEC mice compared with that of the control genotype (Fig. 3A). The generation of Hif1αΔIEC involves deletion of exon 2, which contains sequences encoding the basic helix-loop-helix (bHLH) domain that is essential for DNA binding and dimerisation of HIF1α and HIF1β (Jiang et al., 1996), and that results in downregulation of HIF1α-target genes (Iyer et al., 1998; Ryan et al., 1998). As we have previously shown in wild-type mice, the sulindac diet increased HIF1α expression in Hif1αF/F mice, and this effect was most pronounced in the inflammatory colon lesions (Fig. 3A). HIF1α expression remained low in the colon of the Hif1αΔIEC mice that had been treated with sulindac.Fig. 3.

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