Objective: To study obstruction of the TGF-beta(1) signal transduction by antisense RNA of Smad(4) and its effects on experimental hepatic carcinoma of mice.
Methods: We used the mouse model of primary hepatic carcinoma induced by CCl(4)/ethanol, and transferred antisense Smad(4)cDNA with retrovirus-mediated via portal vein infusion into liver. Southern Blot confirmed that the antisense Smad(4)cDNA had been integrated into the liver. The antisense Smad(4) gene could down-regulate the expression of Smad(4) in fibrotic liver observed by Northern and Western Blot.
Results: In the non-therapeutic cirrhotic liver, the expression of Smad(4) mRNA was significantly increased than normal liver. After antisense Smad(4) gene was transferred, the expression of Smad(4) mRNA in the therapeutic liver was significantly decreased compared with non-therapeutic cirrhotic liver. The fibrotic degree of therapeutic liver was alleviated compared with the non-therapeutic fibrotic liver. No significant difference was found between the rates of carcinogenesis of non-therapeutic cirrhotic liver and that of therapeutic cirrhotic liver. But the diameters and numbers of the liver cancers in the therapeutic cirrhotic group were less than that in the non-therapeutic cirrhotic group.
Conclusion: These results indicate that the antisense Smad(4) gene not only can obstruct the progression of liver fibrosis, but also can inhibit the progression of liver cancer, by obstructing the signal transduction of TGF-beta1.