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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
    Keywords: CANCER ; EXPRESSION ; MODEL ; NEOPLASIA ; PROGRESSION ; MUTATIONS ; APC GENE ; LYMPHOCYTE DEVELOPMENT ; TRANSCRIPTION FACTOR E2-2 ; COLORECTAL TUMORIGENESIS
    Abstract: Deregulation of Wnt/beta-catenin signaling following inactivation of the adenomatous polyposis coli (APC) tumor suppressor gene is frequently found in colorectal cancer. We have previously shown that levels of ITF-2B, encoded by the beta-catenin target gene ITF2 that is located on the tumor suppressor gene locus 18q21, are increased in colonic adenomas with deregulated beta-catenin activity. However, during tumor progression ITF-2B levels are reduced, suggesting that ITF-2B interferes with tumor development. To investigate the role of ITF2 in intestinal tumorigenesis, we specifically inactivated Itf2 in the intestinal epithelium of Apc(Min/+) mice. We found that genetic disruption of Itf2 on the Apc(Min/+) background results in earlier death and a significant increase in tumor number and size in the small intestine. Based on these data Itf2 acts as a tumor suppressor gene of the intestinal tract that inhibits tumor initiation and growth.
    Type of Publication: Journal article published
    PubMed ID: 25869068
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  • 3
    Keywords: EXPRESSION ; PROGRESSION ; COLON-CANCER ; METAANALYSIS ; TARGET GENES ; APC ; MICROSATELLITE-INSTABILITY
    Abstract: The majority of sporadic forms of colorectal carcinomas is characterized by deregulation of Wnt/beta-catenin signaling early in colorectal carcinogenesis. As a consequence, ITF-2B protein levels are increased in adenomas of these patients. However, ITF-2B protein levels are strongly reduced with increasing carcinoma stages, suggesting that reduction of ITF-2B protein is required for progression of adenomas to colorectal carcinomas. To find out if ITF-2B protein levels are correlated with the survival of patients with colorectal carcinomas, a tissue microarray containing samples from 213 colorectal carcinomas (T-categories T2 and T3) with corresponding survival information was stained with an ITF-2B antibody. In addition, we analyzed if detection of ITF-2B in microsatellite instable and microsatellite stable carcinomas as well as in colorectal carcinomas with KRAS mutations is correlated with survival. Detection of cytoplasmic ITF-2B protein was associated with better overall and progression free survival of patients with colorectal carcinomas (P=0.033 and 0.024, respectively). Multivariate Cox regression analysis revealed an increased risk to suffer from poor overall survival and recurrent disease if no cytoplasmic ITF-2B was detectable (HR=1.91; P=0.033 and HR=1.75; P=0.033, respectively). Similarly, patients with MSS carcinomas had a better overall survival, if they showed cytoplasmic positivity for ITF-2B (P=0.013). Remarkably, patients with colorectal carcinomas carrying KRAS mutations had a better overall and progression free survival rate if the carcinomas were positive for cytoplasmic ITF-2B (HR=4.71; P=0.002 and HR=2.57; P=0.024, respectively). These data suggest that cytoplasmic protein levels of ITF-2B could be used as a prognostic marker for patients with colorectal carcinomas.
    Type of Publication: Journal article published
    PubMed ID: 26328254
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