EXPRESSION, LOCALIZATION AND ALTERNATIVE SPLICING PATTERN OF FIBRONECTIN MESSENGER-RNA IN FIBROTIC HUMAN LIVER AND HEPATOCELLULAR-CARCINOMA

Background/Aims: Fibronectin is a multifunctional glycoprotein and pla ys important roles in cell-to-cell or cell-to-matrix interaction, The molecular and functional diversity of fibronectin arises from alternat ive splicing of pre-mRNA at three variable regions, termed ED-A, ED-B and IIICS, Cellular fibronectin with ED-A and ED-B regions has differe nt biological activities from plasma fibronectin lacking these regions , This study was aimed at investigating the type-specific expression o f fibronectin in human liver diseases. Methods: Immunohistochemistry w ith anti-total and anti-cellular fibronectin monoclonal antibodies, in sial hybridization with cDNA probes detecting common and ED-A regions and RT-PCR to amplify each variable region were performed in 35 speci mens, including 4 control, 16 chronic hepatitis, 7 liver cirrhosis and 8 hepatocellular carcinoma. Results: In control liver, there were sli ght deposits of cellular fibronectin [ED-A(+)fibronectin] in portal ar eas, In chronic hepatitis, it was strongly deposited at the margin of the fibrously enlarged portal areas where new collagen fibers were for med, Cellular fibronectin was evenly and abundantly accumulated in fib rotic septa in liver cirrhosis, and in fibrotic septa and capsules of tumor nodules in hepatocellular carcinoma, In control liver, cellular fibronectin mRNA was localized in a few hepatocytes and non-parenchyma l cells around central veins, and was increased in the same cell popul ations near fibrously enlarged portal areas as hepatic fibrosis progre ssed, In hepatocellular carcinoma, it was expressed in most hepatoma c ells, Fibronectin mRNA with three variable regions was detectable by R T-PCR in control liver as well as in each disease group. Conclusions: The expression of cellular fibronectin was increased in fibrotic human liver and hepatocellular carcinoma, In human liver, both non-parenchy mal cells and hepatocytes participated together in cellular fibronecti n production, In hepatocellular carcinoma, hepatoma cells were the mai n producer, Our results indicate that, in human liver, cellular fibron ectin may participate in the hepatic fibrogenesis and in the malignant phenotypes of hepatocellular carcinoma.