Transforming Growth Factor β1 Promotes Migration and Invasion of Human Hepatocellular Carcinoma Cells Via Up-Regulation of Connective Tissue Growth Factor

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors with a poor patient survival. Expression of TGF-beta 1 is up-regulated in HCC and is thought to play a crucial role in the occurrence and development of HCC. However, the mechanism of TGF-beta 1-mediated facilitation of malignant growth and invasion remains unclear, although some previous studies highlighted a potential involvement of the connective tissue growth factor (CTGF). Here we demonstrate that the in vitro migration of the HCC cell line SMMC-7721 is increased in the presence of recombinant TGF-beta 1, and that this effect is reversed by the specific inhibitor SB431542. Furthermore, TGF-beta 1 treatment up-regulated the expression of its own mRNA as well as the expression of CTGF mRNA. The TGF-beta 1-stimulated migration of SMMC-7721 cells was diminished by siRNA silencing of CTGF. These in vitro observations were validated in a murine xenograft model. In particular, silencing of CTFG diminished the TGF-beta 1-induced tumorigenesis in experimental animals. In conclusion, TGF-beta 1 plays a critical role in HCC migration and invasion, and this effect is dependent on CTGF.