BRE is an antiapoptotic protein in vivo and overexpressed in human hepatocellular carcinoma.
BRE binds to the cytoplasmic domains of tumor necrosis factor receptor-1 and Fas, and in cell lines can attenuate death receptor-initiated apoptosis by inhibiting t-BID-induced activation of the mitochondrial apoptotic pathway. Overexpression of BRE by transfection can also attenuate intrinsic apoptosis and promote growth of the transfected Lewis lung carcinoma line in mice. There is, however, a complete lack of in vivo data about the protein. Here, we report that by using our BRE-specific monoclonal antibody on the immunohistochemistry of 123 specimens of human hepatocellular carcinoma (HCC), significant differences in BRE expression levels between the paired tumoral and non-tumoral regions (P<2.2e-16) were found. Marked overexpression of BRE was detected in majority of the tumors, whereas most non-tumoral regions expressed the same low level of the protein as in normal livers. To investigate whether BRE overexpression could promote cell survival in vivo, liver-specific transgenic BRE mice were generated and found to be significantly resistant to Fas-mediated lethal hepatic apoptosis. The transgenic model also revealed post-transcriptional regulation of Bre level in the liver, which was not observed in HCC and non-HCC cell lines. Indeed, all cell lines analysed express high levels of BRE. In conclusion, BRE is antiapoptotic in vivo, and may promote tumorigenesis when overexpressed.
Chan
B C-L
BC
Clinical Immunology Unit and Sir YK Pao Centre for Cancer, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR, China.
Ching
A K-K
AK
To
K-F
KF
Leung
J C-K
JC
Chen
S
S
Li
Q
Q
Lai
P B-S
PB
Tang
N L-S
NL
Shaw
P-C
PC
Chan
J Y-H
JY
James
A E
AE
Lai
K-N
KN
Lim
P-L
PL
Lee
K K-H
KK
Chui
Y-L
YL
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000918:Antibody Specificity; D017209:Apoptosis / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology / Q000502:physiology*
D000911:Antibodies, Monoclonal; D051017:Apoptosis Regulatory Proteins; C091514:BABAM2 protein, human; D009419:Nerve Tissue Proteins