Expression and role of Bcl-xL in human hepatocellular carcinomas.
Transformed hepatocytes survive various apoptotic insults during their growth in vivo. However, molecular mechanisms that inhibit apoptosis and support their survival are not well understood. In this study, we investigated the expression and role of Bcl-xL, an antiapoptotic member of the Bcl-2 family, in human hepatocellular carcinoma (HCC). The Bcl-xL protein was expressed in HepG2, Hep3B, and Huh7 human hepatoma cell lines at high levels, but none 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 the activation of apoptosis in p53-null Hep3B cells, but apoptosis was induced when endogenous Bcl-xL was simultaneously inhibited by antisense oligonucleotide in these cells. Bcl-xL was expressed in all 20 surgically resected human HCC tissues when examined by Western blot analysis and immunohistochemistry, and levels of its expression were higher in a subset of HCC tissues than those of adjacent nontumor liver tissues or normal livers. We conclude that Bcl-xL expressed in human HCC cells inhibits apoptosis produced by various cellular stresses, such as staurosporine treatment, serum starvation, and p53 activation, and may play an important role in their survival.
Takehara
T
T
Gastrointestinal Unit and Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Liu
X
X
Fujimoto
J
J
Friedman
S L
SL
Takahashi
H
H
D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D015870:Gene Expression; D016158:Genes, p53 / Q000235:genetics; D006801:Humans; D020287:In Situ Nick-End Labeling; D008113:Liver Neoplasms / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis / Q000235:genetics* / Q000502:physiology*; D012326:RNA Splicing; D019311:Staurosporine / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; D016376:Oligonucleotides, Antisense; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D019311:Staurosporine