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

Schneider, Marlon R.; Hiltwein, Felix; Grill, Jessica I.; Blum, Helmut; Krebs, Stefan; Klanner, Andrea; Bauersachs, Stefan; Bruns, Christiane; Longerich, Thomas; Horst, David; Brandl, Lydia; Toni, Enrico N. De; Herbst, Andreas; Kolligs, Frank T.

doi:10.1093/carcin/bgu109

Cited by 30 publications

(27 citation statements)

References 26 publications

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“…Adherens junction protein E‐cadherin is important for polarization formation of hepatocytes, and inactivation of human E‐cadherin is strongly associated with tumorigenesis and increased cancer invasiveness . It was reported that E‐cadherin decreased immunohistochemically in patients with ARC syndrome .…”

Section: Resultsmentioning

confidence: 99%

Vacuolar Protein Sorting 33B Is a Tumor Suppressor in Hepatocarcinogenesis

et al. 2018

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Polarity defects are frequently involved in liver diseases, such as chronic hepatitis and hepatocellular carcinoma (HCC). It was reported that vacuolar protein sorting 33B (Vps33b) plays critical roles in the maintenance of hepatocyte polarity; however, the functional roles and mechanisms of Vps33b in HCC occurrence and progression remain unknown. First of all, we showed that Vps33b is down-regulated in human and mouse liver cancer samples, and the low expression levels of Vps33b correlate with the poor prognosis of many HCC patients. Liver-specific Vps33b deficiency induces liver damage, progressive hepatitis, fibrosis, and HCC in male mice, indicating that Vps33b is a crucial contributory factor to hepatocarcinogenesis. Vps33b deficiency-caused liver damage was primarily due to the disorders of structural and functional hepatocyte polarity, which were reflected by the decreased protein levels of E-cadherin because of inaccurate location to lysosomes and polarity defects at both apical and lateral plasma membrane proteins. The results of a mechanism study revealed that Vps33b interacts with VPS33B-interacting protein, which is involved in polarity and apical protein restriction; vesicle-trafficking protein Sec22b; and Flotillin-1 in hepatocytes and is in charge of the normal distribution of polarity-determined proteins. Expression levels of Vps33b negatively correlated with the degree of inflammatory cell infiltration in livers from diethylnitrosamine-induced or transgenic HCC mouse models, and the inflammatory stimuli suppressed the expression of Vps33b in vitro. Conclusion: Down-regulation of Vps33b expression is a critical step for inflammation-driven HCC, and Vps33b serves as an important tumor suppressor in hepatocarcinogenesis.

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Section: Resultsmentioning

confidence: 99%

Vacuolar Protein Sorting 33B Is a Tumor Suppressor in Hepatocarcinogenesis

et al. 2018

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“…A hallmark of EMT is the aberrant expression of E-cadherin (encoded by CDH1 ), which is always linked to the tumorigenesis of many epithelial cancers [29]. E-cadherin is a key factor of cell-cell adhesion junctions in the maintenance of cell polarity and structure.…”

Section: Discussionmentioning

confidence: 99%

Analysis of epithelial-mesenchymal transition markers in the histogenesis of hepatic progenitor cell in HBV-related liver diseases

Wang

et al. 2016

Diagn Pathol

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BackgroundThe origin and heterogeneity of hepatic progenitor cells (HPCs) remain unclear. This study aimed to investigate the involvement of epithelial-mesenchymal transition (EMT) in the histogenesis of HPCs.MethodsSurgical liver specimens from patients with HBV-related hepatitis and cirrhosis were investigated with double immunofluorescence labeling to detect antigens associated with HPCs and EMT. Ductular reactions were subjected to quantitative reverse transcription PCR following isolation by laser capture microdissection. Electron microscopic examination was performed to find an ultrastructural evidence of EMT.ResultsThe number of EpCAM-positive HPCs was proportional to the disease severity. The S100A4 expression of HPCs was firstly observed in mild hepatitis and increased significantly in moderate hepatitis, but decreased in severe hepatitis and cirrhosis. The levels of MMP-2, Twist, and Snail increased in direct proportion to the number of HPCs. Some hepatocytes adjacent to portal tracts in cirrhosis showed positivity for MMP-2. Although CK7 and E-cadherin levels decreased in mild and moderate hepatitis, HPCs re-expressed both of them in severe hepatitis and cirrhosis. However, HPCs expressed neither vimentin nor αSMA. The relative mRNA expression levels of EpCAM and EMT-associated markers supported immunohistochemical results. Electron microscopic examination demonstrated the existence of intercellular junctions among HPCs, cholangiocytes, and intermediate hepatocyte-like cells.ConclusionWe provided preliminary evidence for the involvement of EMT in the histogenesis of HPCs from cholangiocytes in HBV-related liver diseases. HPCs may re-transdifferentiate into hepatocytes, and the differentiation direction depends, at least in part, on interactions between HPCs and the surrounding microenvironment, especially the non-resolving inflammation caused by HBV infection.

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“…In contrast, specific invalidation of E-cadherin in biliary epithelial cells was associated with portal inflammation and ductular reaction. Consistently, mice invalidated for hepatic E-cadherin that maintain E-cadherin expression in non-hepatocyte cells do not show ductular proliferation and portal fibrosis [12]. Thus, accumulation of bile acids in the portal space may be the first trigger inducing inflammation and proliferation of biliary epithelial cells.…”

mentioning

confidence: 84%

“…The fact that, the number of tumor rises when carcinogenesis is primed in mice deficient for liver E-cadherin, indicates that E-cadherin is mainly involved in the progression of the primary tumors. Consistently, diethylnitrosamine (DEN)-induced HCC tumor growth is accelerated in liver of E-cadherin deficient mice [3,12].…”

mentioning

confidence: 91%

E-cadherin, guardian of liver physiology

Gonzalez-Sanchez

Vaquero

Fouassier

et al. 2015

Clinics and Research in Hepatology and Gastroenterology

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E-cadherin is a cell-to-cell adhesion molecule involved in epithelial cell behavior, tissue formation and cancer suppression. In the liver, E-cadherin is expressed by hepatocytes and biliary epithelial cells. However, the exact role of E-cadherin in hepatic pathophysiology remains largely unknown. Recently, specific loss of E-cadherin in liver epithelial cells has been shown to favor periportal fibrosis, periportal inflammation and liver cancer progression, suggesting that E-cadherin is a central liver protector.

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

Cited by 30 publications

References 26 publications

Vacuolar Protein Sorting 33B Is a Tumor Suppressor in Hepatocarcinogenesis

Vacuolar Protein Sorting 33B Is a Tumor Suppressor in Hepatocarcinogenesis

Analysis of epithelial-mesenchymal transition markers in the histogenesis of hepatic progenitor cell in HBV-related liver diseases

E-cadherin, guardian of liver physiology

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