Hepatitis B virus X protein and c-Myc cooperate in the upregulation of ribosome biogenesis and in cellular transformation.

Viral and cellular oncogenes are well known to enhance rRNA synthesis, leading to increased ribosome biogenesis and cell proliferation. Our study on the molecular underpinnings of the interaction between viral HBx and c-Myc, which is implicated in the development of hepatocellular carcinoma, showed a marked increase in the biosynthesis of rRNA, ribosomes and protein in hepatoma cells. A profound alteration in the nucleolar morphology and biochemical content of these cells was also observed. Increased biosynthetic activity was associated with increased cell proliferation and transformation of immortalized human hepatocytes. Furthermore, inhibition of RNA polymerase III activity impaired the proliferative advantage of hepatoma cells and transformation of immortalized hepatocytes as effectively as cisplatin treatment. These findings were corroborated in a transgenic HBx-myc microenvironment, in which an elevated hepatic level of rRNA was associated with conspicuous morphological and biochemical changes in the hepatocytic nucleoli. Thus, HBx and c-Myc seem to work cooperatively to support ribosome biogenesis and cellular transformation.