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Winter Meeting 2011 - The Pathological Society of Great Britain ...

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P69<br />

Investigation <strong>of</strong> the Fate <strong>of</strong> Cholangiocytes in Cholestatic Liver<br />

Disease<br />

P J Brain 1 ; AD Burt 2 ; JA Kirby 1 ; H Robertson 1<br />

1 Institute <strong>of</strong> Cellular Medicine, Newcastle upon Tyne, United Kingdom;<br />

2 Institute <strong>of</strong> Cellular Medicine, Newcastle University, Newcastle upon Tyne,<br />

United Kingdom<br />

During cholestatic liver disease, cholangiocytes are exposed to oxidative stress and may<br />

become senescent. Senescent renal epithelial cells can secrete cytokines, such as TGF-β,<br />

which promote fibrosis in kidneys by activation <strong>of</strong> epithelial to mesenchymal transition<br />

(EMT). <strong>The</strong> current study was designed to examine the relationship between the<br />

induction <strong>of</strong> senescence and EMT in human liver after transplantation.<br />

Human cholangiocytes (H69 cell line) were subjected to oxidative stress by treatment<br />

with 600µM H2O2 for 1h. After 24, 48, 72 and 120 hours the treated cells were immunostained<br />

to allow quantification <strong>of</strong> the EMT markers S100A4, αSMA and ZO-1 and the<br />

senescence marker p21. Analysis by immun<strong>of</strong>luorescence confocal microscopy showed<br />

an increase in S100A4 and αSMA (p=0.034) expression after 48h, with decreasing<br />

expression <strong>of</strong> ZO-1 to background after 120h (p20% <strong>of</strong> cases <strong>of</strong> follicular lymphoma, and between 5-15% <strong>of</strong> cases <strong>of</strong> chronic lymphocytic<br />

leukaemia, MALT-lymphoma and hairy cell leukaemia. We conclude that miR-182 is a<br />

strong candidate novel tumour suppressor miRNA in lymphoma.<br />

<strong>The</strong> overall gene expression signature <strong>of</strong> SMZL was found to be strongly distinct from<br />

those <strong>of</strong> other lymphomas. Functional analysis <strong>of</strong> gene expression data revealed SMZL<br />

to be characterised by abnormalities in B-cell receptor signalling (especially through the<br />

CD19/21-PI3K/AKT pathway) and apoptotic pathways. In addition, genes involved in the<br />

response to viral infection appeared upregulated. SMZL shows a unique epigenetic pr<strong>of</strong>ile,<br />

but analysis <strong>of</strong> differentially methylated genes showed few with methylation related<br />

transcriptional deregulation, suggesting that DNA methylation abnormalities are not a<br />

critical component <strong>of</strong> the SMZL malignant phenotype.<br />

Scientific Programme | <strong>Winter</strong> <strong>Meeting</strong> (199 th ) 6 – 7 January <strong>2011</strong> | Visit our website: www.pathsoc.org<br />

39

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