Bcl-xL as a Critical Apoptosis Antagonist in Hepatocytes and Hepatocellular Carcinoma

Summary

Bcl-xL, an anti-apoptotic member of the Bcl-2 family, has been generally thought to be involved in the regulation of apoptosis in the liver, because this molecule tends to be upregulated during liver regeneration, as well as in certain types of liver injury. We employed a Cre/loxP conditional knockout model and found that deletion of the bcl-x gene resulted in accelerated apoptosis in hepaocytes in vivo, formally proving the critical role of this molecule in maintaining hepatocyte integrity. Furthermore, Bcl-xL may play an important role during hepatocarcinogenesis, because one-third of human hepatocellular carcinoma (HCC) tissues showed increased expression of Bcl-xL and its knockdown by antisense oligonueleotide stimulated apoptosis in hepatoma cells in response to cellular stresses, such as serum starvation, p53 activation, and staurosporine treatment. It was also found that Bcl-xL was post-translationally modified by deamidation in its loop domain in human liver tissues; deamidated Bcl-xL is a major form in normal liver tissues, whereas the level of deamidated Bcl-xL is lower than that of unmodified Bcl-xL in the majority of HCC tissues. As protein deamidation of Bcl-xL leads to a complete “loss of function” of this antiapoptotic molecule, HCCs may acquire resistance to apoptosis and a survival advantage by suppressing the deamidation, as well as by increasing the expression of Bcl-xL.