MECHANISM OF PAP-I GENE INDUCTION DURING HEPATOCARCINOGENESIS - CLINICAL IMPLICATIONS

Pancreatitis-associated protein I (PAP I) is a secretory protein first described as an acute phase reactant during acute pancreatitis. Recen tly, induction of the PAP I gene was also described in liver during he patocarcinogenesis. To investigate the molecular mechanisms of this in duction, we used constructs carrying progressive deletions of the PAP I promoter fused to the CAT gene. We showed that the silencer conferri ng tissue specificity on the PAP I gene was inactive in hepatoma cells . Then, in an in vitro transcription system, we compared the transcrip tion capacity of nuclear extracts from normal liver and HepG2 cells on constructs containing the silencer. The results confirmed that a tran sacting factor interacting with the PAP I silencer was present in live r cells and absent from hepatoma cells. On the other hand, immunohisto chemistry showed that PAP I was expressed in a limited number of trans formed hepatocytes. It was concluded that expression of PAP I in hepat ocarcinoma occurred through inactivation of its silencer element and w as not concomitant in all malignant cells. On that basis, we assayed P AP I in serum from patients with chronic hepatitis, liver cirrhosis or hepatocarcinoma. PAP I levels were normal in chronic active or persis tent hepatitis, significantly higher in cirrhosis and strongly elevate d in hepatocarcinoma. Because those clinical entities often develop in that sequence, serum PAP I appeared as a potential marker of hepatoca rcinoma development.