Intestinal E-cadherin Deficiency Aggravates Dextran Sodium Sulfate-Induced Colitis.

BACKGROUND: E-cadherin is a cell adhesion protein with crucial roles in development, tissue homeostasis, and disease. Loss of E-cadherin in the adult intestinal epithelium disrupts tissue architecture and is associated with impaired localization and function of goblet and Paneth cells, reduced expression of antibacterial factors, and deficiency in clearing enteropathogenic bacteria. Several studies have suggested a role of E-cadherin in human inflammatory bowel disease. AIM: To investigate the role of E-cadherin deficiency in the pathogenesis of inflammatory bowel disease in a mouse model of experimentally induced colitis. METHODS: To induce E-cadherin deficiency, Villin-Cre-ER (T2) ;Cdh1 (fl/fl) mice received intraperitoneal injections of tamoxifen at days 1, 2, 5, and 8. Experimental colitis was induced by oral administration of dextran sodium sulfate (DSS, 3.5 % in the drinking water) for 3 days, starting at the third day after the first tamoxifen injection. RESULTS: E-cadherin deficiency in the adult mouse intestinal epithelium aggravates the clinical and histological features of DSS-induced colitis. Upon DSS treatment, mice deficient in E-cadherin lost more weight, were more severely dehydrated, and showed more frequently blood in the feces. Histologically, intestinal E-cadherin deficiency was associated with exacerbated acute and chronic inflammation and increased regenerative epithelial changes. Finally, the changes in the epithelium were distributed more diffusely in E-cadherin-deficient mice, while the mucosal damage was more focally localized in control animals. CONCLUSIONS: Our findings suggest that E-cadherin may play an important role in the pathogenesis of ulcerative colitis, one of the major clinical forms of inflammatory bowel disease.

Evidence for a role of E-cadherin in suppressing liver carcinogenesis in mice and men.

The cell adhesion molecule E-cadherin has critical functions in development and carcinogenesis. Impaired expression of E-cadherin has been associated with disrupted tissue homeostasis, progression of cancer and a worse patient prognosis. So far, the role of E-cadherin in homeostasis and carcinogenesis of the liver is not well understood. By use of a mouse model with liver-specific deletion of E-cadherin and administration of the carcinogen diethylnitrosamine, we demonstrate that loss of E-cadherin expression in hepatocytes results in acceleration of the growth of hepatocellular carcinoma (HCC). In contrast, liver regeneration is not disturbed in mice lacking E-cadherin expression in hepatocytes. In human HCC, we observed four different expression patterns of E-cadherin. Notably, atypical cytosolic expression of E-cadherin was positively correlated with a poorer patient prognosis. The median overall survival of patients with HCC expressing E-cadherin on the membrane only was 221 weeks (95% confidence interval: 51-391) compared with 131 weeks in patients with cytosolic expression (95% confidence interval: 71-191 weeks; P < 0.05). In conclusion, we demonstrate that impaired expression of E-cadherin promotes hepatocellular carcinogenesis and is associated with a worse prognosis in humans.

Does environmental stress affect cortisol biodistribution in freshwater mussels?

As of today, regulation and physiological purpose of steroid hormones in invertebrates such as mussels are not completely understood. Many studies were able to show their presence, but their origin and genesis are not clear. Nevertheless, knowledge about changes in steroid hormone biodistribution in reaction to treatments could improve our understanding of their physiological functions in these species. Cortisol is a corticosteroid, which is frequently used as a stress biomarker in vertebrates, like fish or higher organisms. The aim of the study was to optimize cortisol extraction from various tissues of mussels, to develop a quantitative ELISA test system, and to study changes in biodistribution of cortisol in reaction to negative and positive stimulation treatments. As model organism, we used Anodonta anatina, a widespread freshwater mussel species native to Europe. We quantified cortisol concentrations in hepatopancreas, mantle, gills, gonads and the foot muscle. Tissue-specific reactions to environmental influences, simulated with the chemical stressors copper (II) chloride and sodium chloride, were assessed. During the 24-hours treatment, we additionally observed changes in cortisol regulation in response to feeding activity of the mussels. Besides, we found highly significant variations in the biodistribution of cortisol in different tissues, with a peak in the hepatopancreas. Whole body cortisol did not increase in the treated groups. However, balancing of all measured tissues showed redistribution of more than 10% of total body cortisol from the hepatopancreas to all other tissues during copper (II) chloride stressor treatment, but also when mussels ingested feed, compared to the non-fed control group. No redistribution was observed during sodium chloride treatment. We conclude that there can be a redistribution of cortisol in mussels, depending on external influences.

Loss of DRO1/CCDC80 results in obesity and promotes adipocyte differentiation.

To investigate the role of DRO1 in obesity and adipogenesis in vivo, we generated a constitutive Dro1 knockout mouse model and analyzed the effect of DRO1 loss on body growth under standard and high fat diet feeding conditions. Loss of DRO1 resulted in a significant increase in body weight which was accompanied by a substantial expansion of white adipose tissue depots. The obese phenotype could be further enhanced by a high fat dietary challenge which also resulted in impaired glucose metabolism and the development of hepatosteatosis in Dro1 knockout mice. To study the role of DRO1 in adipocyte differentiation, primary stromal-vascular (SV) cells were isolated from inguinal white fat pads of knockout and control mice. In primary SV cells, depletion of DRO1 significantly promoted adipogenesis with upregulation of markers for adipogenesis (Cebpa, Pparg, Adipoq) and lipid metabolism (Dgat1, Dgat2). Our results demonstrate that DRO1 is a crucial regulator of energy homeostasis in vivo and functions as an inhibitor of adipogenesis in primary cells.

DRO1 inactivation drives colorectal carcinogenesis in ApcMin/+ mice.

UNLABELLED: Colorectal cancer develops from adenomatous precursor lesions by a multistep process that involves several independent mutational events in oncogenes and tumor suppressor genes. Inactivation of the adenomatous polyposis coli (APC) tumor suppressor gene is an early event and a prerequisite for the development of human colorectal adenoma. Previous in vitro studies identified DRO1 (CCDC80) to be a putative tumor suppressor gene that is negatively regulated in colorectal cancers and downregulated upon neoplastic transformation of epithelial cells. To investigate the in vivo role of DRO1 in colorectal carcinogenesis, a constitutive DRO1 knockout mouse model was generated. Disruption of DRO1 did not result in spontaneous intestinal tumor formation, consistent with the notion that DRO1 might have a role in suppressing the development of colon tumors in Apc(Min) (/+) mice, a widely used model for studying the role of APC in intestinal tumorigenesis that is hampered by the fact that mice predominantly develop adenomas in the small intestine and not in the colon. Here, deletion of DRO1 in Apc(Min) (/+) mice results in earlier death, a dramatically increased colonic tumor burden, and frequent development of colorectal carcinoma. Furthermore, enhanced phosphorylation of ERK1/2 is observed in colon epithelium and tumors from DRO1 knockout mice. Thus, this study reveals that inactivation of DRO1 is required for colorectal carcinogenesis in the Apc(Min) (/+) mouse and establishes a new mouse model for the study of colorectal cancer. IMPLICATIONS: This report characterizes a new mouse model for the study of colorectal cancer and establishes DRO1 (CCDC80) as a tumor suppressor via a mechanism involving ERK phosphorylation.