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Loss of liver E-cadherin induces sclerosing cholangitis and promotes carcinogenesis
- Source :
- Proceedings of the National Academy of Sciences. 111:1090-1095
- Publication Year :
- 2014
- Publisher :
- Proceedings of the National Academy of Sciences, 2014.
-
Abstract
- E-cadherin is an important adhesion molecule whose loss is associated with progression and poor prognosis of liver cancer. However, it is unclear whether the loss of E-cadherin is a real culprit or a bystander in liver cancer progression. In addition, the precise role of E-cadherin in maintaining liver homeostasis is also still unknown, especially in vivo. Here we demonstrate that liver-specific E-cadherin knockout mice develop spontaneous periportal inflammation via an impaired intrahepatic biliary network, as well as periductal fibrosis, which resembles primary sclerosing cholangitis. Inducible gene knockout studies identified E-cadherin loss in biliary epithelial cells as a causal factor of cholangitis induction. Furthermore, a few of the E-cadherin knockout mice developed spontaneous liver cancer. When knockout of E-cadherin is combined with Ras activation or chemical carcinogen administration, E-cadherin knockout mice display markedly accelerated carcinogenesis and an invasive phenotype associated with epithelial-mesenchymal transition, up-regulation of stem cell markers, and elevated ERK activation. Also in human hepatocellular carcinoma, E-cadherin loss correlates with increased expression of mesenchymal and stem cell markers, and silencing of E-cadherin in hepatocellular carcinoma cell lines causes epithelial-mesenchymal transition and increased invasiveness, suggesting that E-cadherin loss can be a causal factor of these phenotypes. Thus, E-cadherin plays critical roles in maintaining homeostasis and suppressing carcinogenesis in the liver.
- Subjects :
- Male
Pathology
medicine.medical_specialty
Epithelial-Mesenchymal Transition
Carcinogenesis
Cholangitis
Cholangitis, Sclerosing
Biology
medicine.disease_cause
Stem cell marker
Primary sclerosing cholangitis
Mice
Bacterial Proteins
medicine
Animals
Epithelial–mesenchymal transition
Neoplasm Metastasis
Extracellular Signal-Regulated MAP Kinases
Inflammation
Mice, Knockout
Multidisciplinary
Cadherin
Stem Cells
Liver Neoplasms
Cadherins
Prognosis
medicine.disease
Gene Expression Regulation, Neoplastic
Mice, Inbred C57BL
Luminescent Proteins
Phenotype
Liver
Mutation
Knockout mouse
Hepatocytes
Cancer research
Stem cell
Liver cancer
Subjects
Details
- ISSN :
- 10916490 and 00278424
- Volume :
- 111
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences
- Accession number :
- edsair.doi.dedup.....31f3425d20fb6b50a051af0682612a7e