Expression and role of Bcl-xL in human hepatocellular carcinomas

Transformed hepatocytes survive various apoptotic insults during their grow th in vivo. However, molecular mechanisms that inhibit apoptosis and suppor t their survival are not well understood. In this study, we investigated th e expression and role of Bcl-xL, an antiapoptotic member of the Bcl-2 famil y, in human hepatocellular carcinoma (HCC). The Bcl-xL protein was expresse d in HepG2, Hep3B, and Huh7 human hepatoma cell lines at high levels, but n one of these cells expressed Bcl-2. Down-modulation of Bcl-xL by antisense oligonucleotide activated apoptosis in HepG2 cells in response to cellular stresses induced by staurosporine treatment or by serum starvation. Ectopic expression of transcriptionally active p53 alone was not sufficient for th e activation of apoptosis in p53-null Hep3B cells, but apoptosis was induce d when endogenous Bcl-xL was simultaneously inhibited by antisense oligonuc leotide in these cells. Bcl-xL was expressed in all 20 surgically resected human HCC tissues when examined by Western blot analysis and immunohistoche mistry, and levels of its expression were higher in a subset of HCC tissues than those of adjacent nontumor liver tissues or normal livers. We conclud e that Bcl-xL expressed in human HCC cells inhibits apoptosis produced by v arious cellular stresses, such as staurosporine treatment, serum starvation , and p53 activation, and may play an important role in their survival.