High expression of the proliferation and apoptosis associated CSE1L/CAS gene in hepatitis and liver neoplasms: Correlation with tumor progression

The CSE1L/CAS protein (CAS) is a Ran-binding protein with a function as nuc lear transport (export) factor. Like recently observed for ran and other la n-binding proteins, CSE1L/CAS simultaneously plays a role in the mitotic sp indle checkpoint, which assures genomic stability during cell division. Thi s checkpoint is frequently disturbed in neoplasias of various origin, inclu ding hepatic tumors. We have evaluated by immunohistology the expression of CAS in adult and embryonic liver, hepatitis, and in liver hyperplasias. No rmal hepatocytes revealed no CAS expression while embryonic liver showed st rong expression in all parenchymal cells. Bile ducts stained positive with anti-CAS antibodies, and strong CAS expression was also detected at the int el face between bile ducts and hepatocytes under conditions associated with regenerative proliferation. The localization of these CAS expressing cells correlated with the distribution of 'oval' putative liver stem-cells. In a ctive viral (but not in inactive) hepatitis, strong hepatocytal CAS express ion correlates in site and intensity with degree of inflammation. Neoplasti c liver demonstrated different degrees of CAS expression: no remarkable exp ression in adenomas, moderate expression in a narrow rim of hepatocytes and in periseptal cholangiolar proliferations in focal nodular hyperplasia, an d strong CAS expression in hepatocellular carcinoma. Less differentiated tu mors stain stronger than well differentiated. Cholangio-cellular carcinomas show even stronger CAS expression than hepatocellular carcinomas. Our obse rvation of strong expression of CAS in liver cells that are committed for p roliferation among them possibly liver stem cells, and in liver neoplasms, is consistant with the fact that CAS functions not solely as a nuclear tran sport factor but that it is also essential for cell proliferation, particul arly for the mitotic spindle checkpoint. Interestingly, genomic instability is frequently observed in hepatic tumors which we have shown here to expre ss large amounts of GAS. Since the degree of GAS-expression correlates with the grade of tumor dedifferentiation, we suggest that CAS should also be f urther investigated as prognostic marker for hepatic neoplasms.