Malignant tumors secrete high levels of transforming growth factor-beta1 (TGF-beta1). Increased secretion of TGF-beta1 by cells that have lost responsiveness to their growth inhibitory activities is thought to facilitate tumor progression by indirect means such as suppression of immune surveillance and stimulation of tumor stroma. The level of TGF-beta1 mRNA is significantly increased in livers from the hepatitis B virus X (Hbx) transgenic mice and that expression of TGF-beta1 correlates well with that of the Hbx protein. Recently, we have demonstrated that viral transactivators, including cytomegalovirus regulatory protein, IE2, and hepatitis B virus X protein activate transcription of TGF-beta1 gene through the Egr-1 binding site. In addition to transcriptional control, numerous reports suggest that expression of TGF-betas may also be regulated post-transcriptionally. We have found that lovastatin, a competitive inhibitor of HMG-CoA reductase specifically destabilizes the TGF-beta2 mRNA, whereas zargozic acid, an inhibitor of squalene synthase, does not affect the stability of the TGF-beta2 mRNA. Recently, we have shown a high frequency of genetic alterations of the TGF-beta type II receptor gene in human gastric cancer cells. Southern blot analysis showed deletion of the type II receptor gene in 2 of 8 cell lines and amplification in another 2 lines. These results suggest that these changes are associated with the progression or metastasis of gastric carcinoma and loss of negative growth control can result from a lesion in the receptor for a negative growth factor.
