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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

Sulindac-treated Hif1αΔIEC mice develop smaller lesions and less mucosal inflammation in the colon compared with control Hif1αF/F mice. (A) Average size of individual lesions±s.e.m. (B) Total inflammation score in different regions of the colon (outside lesions). Hif1αF/F n=26, Hif1αΔIEC n=12. (C) Severity and depth of inflammation and crypt damage in the proximal P2 region (outside lesions) of the colon. Hif1αF/F n=26, Hif1αΔIEC n=12. (D) Severity and depth of inflammation, crypt damage and the total inflammation score in the pathologically most severe lesion for each mouse. Hif1αF/F n=19, Hif1αΔIEC n=8. (E) The total inflammation score of all dissected lesions from Hif1αΔIEC and Hif1αF/F mice plotted against the pathology assessment for neoplasia (dysplasia or cancer). Hif1αΔIEC and Hif1αF/F mice were given 320 ppm sulindac in the diet for 20 weeks, after which biopsies were taken from the flat mucosa and lesions along the entire length of the colon and assessed by a pathologist as described in Materials and Methods. The bars represent the average histological score±s.e.m. The total histological score is a sum of the three individual scores for severity of inflammation, depth of inflammation and crypt damage. Star (*) indicates P<0.05. ΔIEC, Hif1αΔIEC; F/F, Hif1αF/F; Mid, middle colon; Dist, distal colon.
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DMM019000F1: Sulindac-treated Hif1αΔIEC mice develop smaller lesions and less mucosal inflammation in the colon compared with control Hif1αF/F mice. (A) Average size of individual lesions±s.e.m. (B) Total inflammation score in different regions of the colon (outside lesions). Hif1αF/F n=26, Hif1αΔIEC n=12. (C) Severity and depth of inflammation and crypt damage in the proximal P2 region (outside lesions) of the colon. Hif1αF/F n=26, Hif1αΔIEC n=12. (D) Severity and depth of inflammation, crypt damage and the total inflammation score in the pathologically most severe lesion for each mouse. Hif1αF/F n=19, Hif1αΔIEC n=8. (E) The total inflammation score of all dissected lesions from Hif1αΔIEC and Hif1αF/F mice plotted against the pathology assessment for neoplasia (dysplasia or cancer). Hif1αΔIEC and Hif1αF/F mice were given 320 ppm sulindac in the diet for 20 weeks, after which biopsies were taken from the flat mucosa and lesions along the entire length of the colon and assessed by a pathologist as described in Materials and Methods. The bars represent the average histological score±s.e.m. The total histological score is a sum of the three individual scores for severity of inflammation, depth of inflammation and crypt damage. Star (*) indicates P<0.05. ΔIEC, Hif1αΔIEC; F/F, Hif1αF/F; Mid, middle colon; Dist, distal colon.

Mentions: We first determined whether Hif1α deficiency in the colon affected the severity of sulindac-induced mucosal inflammation. After 20 weeks of sulindac treatment, the colons were harvested and analysed at the macroscopic level. Visible inflammatory lesions were carefully measured with a fitted eyepiece grid, and their size and location in the colon recorded. Hif1αΔIEC mice still developed visible lesions in the P2 region of the proximal colon (Mladenova et al., 2011), but the individual lesions were significantly smaller in Hif1αΔIEC mice compared with those in Hif1α-floxed mice (Hif1αF/F) mice (P=0.037) (Fig. 1A). The Hif1αΔIEC mice also developed fewer large lesions (>10 mm2) (3.6% vs 17%, P=not significant). Three out of 26 Hif1αF/F mice (12%) had macroscopic colon inflammation outside the lesions, involving large areas of the colon, with the affected area in these three cases estimated to cover 10, 15 and 5% of the whole colon, respectively. No Hif1αΔIEC mice showed macroscopic damage outside of the lesions.Fig. 1.


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)

Sulindac-treated Hif1αΔIEC mice develop smaller lesions and less mucosal inflammation in the colon compared with control Hif1αF/F mice. (A) Average size of individual lesions±s.e.m. (B) Total inflammation score in different regions of the colon (outside lesions). Hif1αF/F n=26, Hif1αΔIEC n=12. (C) Severity and depth of inflammation and crypt damage in the proximal P2 region (outside lesions) of the colon. Hif1αF/F n=26, Hif1αΔIEC n=12. (D) Severity and depth of inflammation, crypt damage and the total inflammation score in the pathologically most severe lesion for each mouse. Hif1αF/F n=19, Hif1αΔIEC n=8. (E) The total inflammation score of all dissected lesions from Hif1αΔIEC and Hif1αF/F mice plotted against the pathology assessment for neoplasia (dysplasia or cancer). Hif1αΔIEC and Hif1αF/F mice were given 320 ppm sulindac in the diet for 20 weeks, after which biopsies were taken from the flat mucosa and lesions along the entire length of the colon and assessed by a pathologist as described in Materials and Methods. The bars represent the average histological score±s.e.m. The total histological score is a sum of the three individual scores for severity of inflammation, depth of inflammation and crypt damage. Star (*) indicates P<0.05. ΔIEC, Hif1αΔIEC; F/F, Hif1αF/F; Mid, middle colon; Dist, distal colon.
© Copyright Policy - open-access
Related In: Results  -  Collection

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DMM019000F1: Sulindac-treated Hif1αΔIEC mice develop smaller lesions and less mucosal inflammation in the colon compared with control Hif1αF/F mice. (A) Average size of individual lesions±s.e.m. (B) Total inflammation score in different regions of the colon (outside lesions). Hif1αF/F n=26, Hif1αΔIEC n=12. (C) Severity and depth of inflammation and crypt damage in the proximal P2 region (outside lesions) of the colon. Hif1αF/F n=26, Hif1αΔIEC n=12. (D) Severity and depth of inflammation, crypt damage and the total inflammation score in the pathologically most severe lesion for each mouse. Hif1αF/F n=19, Hif1αΔIEC n=8. (E) The total inflammation score of all dissected lesions from Hif1αΔIEC and Hif1αF/F mice plotted against the pathology assessment for neoplasia (dysplasia or cancer). Hif1αΔIEC and Hif1αF/F mice were given 320 ppm sulindac in the diet for 20 weeks, after which biopsies were taken from the flat mucosa and lesions along the entire length of the colon and assessed by a pathologist as described in Materials and Methods. The bars represent the average histological score±s.e.m. The total histological score is a sum of the three individual scores for severity of inflammation, depth of inflammation and crypt damage. Star (*) indicates P<0.05. ΔIEC, Hif1αΔIEC; F/F, Hif1αF/F; Mid, middle colon; Dist, distal colon.
Mentions: We first determined whether Hif1α deficiency in the colon affected the severity of sulindac-induced mucosal inflammation. After 20 weeks of sulindac treatment, the colons were harvested and analysed at the macroscopic level. Visible inflammatory lesions were carefully measured with a fitted eyepiece grid, and their size and location in the colon recorded. Hif1αΔIEC mice still developed visible lesions in the P2 region of the proximal colon (Mladenova et al., 2011), but the individual lesions were significantly smaller in Hif1αΔIEC mice compared with those in Hif1α-floxed mice (Hif1αF/F) mice (P=0.037) (Fig. 1A). The Hif1αΔIEC mice also developed fewer large lesions (>10 mm2) (3.6% vs 17%, P=not significant). Three out of 26 Hif1αF/F mice (12%) had macroscopic colon inflammation outside the lesions, involving large areas of the colon, with the affected area in these three cases estimated to cover 10, 15 and 5% of the whole colon, respectively. No Hif1αΔIEC mice showed macroscopic damage outside of the lesions.Fig. 1.

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