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  • 1
    Keywords: CANCER ; EXPRESSION ; SURVIVAL ; HEPATOCELLULAR-CARCINOMA ; GENES ; GROWTH-FACTOR RECEPTOR ; TUMOR PROGRESSION ; snail ; hepatitis
    Abstract: 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 diethylnitrosamin, 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 (CI), 51-391) compared to 131 weeks in patients with cytosolic expression (95% CI, 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.
    Type of Publication: Journal article published
    PubMed ID: 24840851
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  • 2
    Abstract: 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.
    Type of Publication: Journal article published
    PubMed ID: 27645901
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  • 3
    Abstract: 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 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 down-regulated 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 ApcMin/+ 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 ApcMin/+ 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 ApcMin/+ 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.
    Type of Publication: Journal article published
    PubMed ID: 25053805
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