Decrease of Deleted in Malignant Brain Tumour-1 (DMBT-1) expression is a crucial late event in intrahepatic cholangiocarcinoma

Aims: To investigate the participation of DMBT-1, a candidate tumour suppressor gene, in the development of intrahepatic cholangiocarcinoma via intraductal papillary neoplasm of the liver (IPN-L) arising in hepatolithiasis. DMBT-1 plays a role in mucosal immune defence. Methods and results: The expression of DMBT-1 was examined immunohistochemically in biliary epithelial cells in hepatolithiasis (n = 25), invasive and non-invasive cholangiocarcinoma associated with hepatolithiasis (n = 52), IPN-L with hepatolithiasis (n = 49), cholangiocarcinoma without hepatolithiasis (n = 32). and 10 normal control livers. DMBT-1 was expressed more frequently in the biliary epithelia of hepatolithiasis when compared with normal livers (P < 0.05). DMBT-1 expression was also frequent in IPN-L (57%) and non-invasive cholangiocarcinoma (79%). By contrast, DMBT-1 was decreased in invasive cholangiocarcinoma with and without hepatolithiasis (50% and 30%, respectively) (P < 0.05). The homozygous deletion of the DMBT-1 gene was recognized in four (20%) of 20 cholangiocarcinoma tissues and two (50%) of four cholangiocarcinoma cell lines, corresponding to the reduction of DMBT-1 expression. No deletion was detected in hepatolithiasis tissues. Conclusion: DMBT-1 expression is increased in IPN-L and non-invasive cholangiocarcinoma as well as in biliary epithelia in hepatolithiasis. Decreased expression of DMBT-1 and homozygous deletion of the DMBT-1 gene in invasive cholangiocarcinoma suggest that they occur in the late stage of cholangiocarcinogenesis.