Nuclear proteins in primary biliary cirrhosis as guardians against HCC development

Abstract

Background: Primary biliary cirrhosis (PBC) is an autoimmune disorder of the liver which is characterised by an aseptic inflammation, accompanied by destruction of cholangiocytes of the small bile ducts. The subgroup M2 of antimitochondrial antibodies (AMA-M2) is considered as specific for the disease. In addition, there is evidence in about 30% of patients to express antibodies against certain nuclear-dot proteins (Anti-ND), SP100- and promyelocytic leucemia (PML) – protein. However, implications of the respective antigenes, PML- and SP100-protein, for pathogenesis and course of PBC have not yet been further investigated. Methods: We analysed liver biopsies of 93 PBC patients with respect to expression of PML and SP100. To this end, an immunohistological staining for PML und SP100 had to be established. Expression of both proteins was qualitatively and quantitatively analysed and statistically linked with the course of disease, stage, activity, tumor development and antibody-levels of the patients. As control, we used biopsies from cirrhotic livers with hepatitis B or C or NASH/ASH as underlying disease. Results: PML-expression level correlate significantly with PBC stage and activity. Nuclear dots which express PML increase in size and number with progress of disease. Expression of SP100, in contrast to PML, does not go in line with disease activity or inflammation. Expression of both antigenes does not significantly correlate with a serologic prove of the respective antibody. However, there is a significant correlation between PML expression and HCC (hepatocellular carcinoma) development. While HCC develops predominantly in the context of cirrhosis caused by virus hepatitis (30%) and NASH/ASH (50%), only 1% of HCCs develop in the context of PBC in our population. PBC at the stage of cirrhosis displays a high density of PML expression, whereas PML expression in cirrhosis of other origins is only scarce. Conclusions: Our results suggest a considerable importance of the nuclear proteins PML and SP100 for development and progress of PBC. The role of both proteins for gene expression implies an influence on factors regulating tissue destruction and fibrogenesis. Moreover, the fact that PML is highly expressed in advanced stages of PBC but not in cirrhosis of other origin, this tumor suppressor may contribute a protective effect against HCC development in PBC.