[Obstruction of TGF-beta1 signal transduction can decrease the process of hepatocellular carcinoma in mice induced by CCl4/ethanol].
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.


CONCLUSIONS
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.
Hepatobiliary Surgery Department, People's Hospital, Beijing University, Beijing 100044, China.
Xin-Bao
XB
Xu
Xi-Sheng
XS
Leng
Xiao
X
Yang
Zhen-Ping
ZP
He
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D016375:Antisense Elements (Genetics) / Q000627:therapeutic use*; D002251:Carbon Tetrachloride; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors; D000431:Ethanol; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000628:therapy; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000628:therapy*; D008297:Male; D051379:Mice; D011897:Random Allocation; D015398:Signal Transduction; D051901:Smad4 Protein; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000502:physiology; D053773:Transforming Growth Factor beta1
D016375:Antisense Elements (Genetics); D004268:DNA-Binding Proteins; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; C508961:Tgfb1 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D000431:Ethanol; D002251:Carbon Tetrachloride