PWE-041 Reduced Expression of TJP-2 Is Associated with Chronic Liver Disease and Hepatic Malignancy

Abstract

IntroductionTight Junction Protein–2 (TJP-2) belongs to a family of proteins that are predominantly expressed at the junctions between epithelial cells. TJP-2 has been implicated in the progression of breast and pancreatic cancer through regulation of downstream signalling pathways responsible for invasion and metastasis. Recently, gene alterations in TJP-2 have been discovered in patients with progressive familial intrahepatic cholestasis leading us to hypothesise that TJP-2 might be differentially regulated in chronic liver disease and liver cancer. Our aim was to characterise the expression of TJP-2 in liver disease with a particular focus on malignancy.MethodsThe cellular localization and expression of TJP-2 in human liver tissue sections was studied using immunohistochemistry, multi-colour confocal immunofluorescence and immunocytochemistry. TJP-2 mRNA expression was quantified by qRT-PCR and protein expression was determined by western blotting of tissue lysates prepared from pathological control and diseased liver samples. Image J analysis was used to quantify expression of TJP-2 in chronic liver disease and liver cancers.ResultsTJP-2 expression in human tissue sections was significantly downregulated in chronic liver disease and liver cancer, specifically hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), when compared to pathological control tissue. The majority of TJP-2 protein was restricted to cellular junctions of biliary epithelial cells and hepatocytes in both pathological control and chronically diseased livers. In HCC and CCA tissue sections the protein was also found to adopt a characteristic perinuclear distribution, consistent with previous studies on pancreatic cancer cell lines. Western blotting and qRT-PCR studies revealed a significant decrease in TJP-2 expression in both chronic liver disease and primary liver cancer when compared to pathological control livers. Preliminary analysis of tissue samples taken from patients who had undergone hemihepatectomy for intrahepatic cholangiocarcinoma, and who were matched for anatomical location and tumour histology, suggested a correlation between TJP-2 expression and overall survival.ConclusionThis is the first report on TJP-2 expression in liver disease. TJP-2 was expressed on epithelial cells, with reduced mRNA and protein levels detected in chronic liver disease and liver cancer, suggesting that progressive loss of this molecule may contribute to altered epithelial function in hepatic injury and malignancy. Our data suggest that measurement of TJP-2 expression might have utility in the staging of liver cancer.Disclosure of InterestNone Declared

Rare Inherited Cholestatic Disorders and Molecular Links to Hepatocarcinogenesis

“…It has been suggested that TJP2 may, in fact, have a role as a tumour suppressor gene. One group found that TJP2 expression was downregulated in chronic liver disease, HCC and CCA compared with pathological control tissue [ 73 ]. Moreover, in their study, most ZO-2 protein was found at the cellular junctions of biliary epithelial cells and hepatocytes in pathological control and chronically diseased hepatic tissue, while most ZO-2 protein was found in the perinuclear region in HCC and CCA tissue.…”

“…Moreover, in their study, most ZO-2 protein was found at the cellular junctions of biliary epithelial cells and hepatocytes in pathological control and chronically diseased hepatic tissue, while most ZO-2 protein was found in the perinuclear region in HCC and CCA tissue. These findings suggest important differences in TJP2 expression and protein localisation in HCC compared with noncancerous liver tissue [ 73 ]. Aberrant expression of TJP2 has also been noted in nonliver cancers.…”