BRE over-expression promotes growth of hepatocellular carcinoma.
BRE, also known as TNFRSF1A modulator and BRCC45, is an evolutionarily highly conserved protein. It is a death receptor-associated protein in cytoplasm and a component of BRCA1/2-containing DNA repair complex in nucleus. BRE was found to have anti-apoptotic activity. Over-expression of BRE by transfection promoted survival of cell lines against apoptotic induction; whereas depletion of the protein by siRNA resulted in the opposite. In vivo anti-apoptotic activity of BRE was demonstrated by significant attenuation of Fas-induced acute fulminant hepatitis in transgenic mice expressing the human protein specifically in the liver. BRE was also implicated in tumor promotion by the accelerated tumor growth of Lewis Lung carcinoma transfected with human BRE; and by high expression of BRE specifically in the tumoral regions of human hepatocellular carcinoma (HCC). The present study was to test directly if transgenic expression of BRE in livers could promote HCC development in neonatal diethylnitrosamine model. By 8months after tumor induction, the maximal sizes of tumor nodules of transgenic mice were significantly larger than those of the non-transgenic controls, although the numbers of tumor nodules between the two groups did not significantly differ. Importantly, as in human HCC, the mouse endogenous BRE level was up-regulated in mouse HCC nodules. These results show that BRE over-expression can indeed promote growth, though not initiation, of liver tumors. Furthermore, the common occurrence of BRE over-expression in human and mouse HCC suggests that up-regulation of BRE is functionally important in liver tumor development.
Chui
Yiu-Loon
YL
Department of Chemical Pathology and Sir Y.K. Pao Centre for Cancer, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China. yiuloonchui@cuhk.edu.hk
Ching
Arthur Ka-Keung
AK
Chen
Shuyan
S
Yip
Fung-Ping
FP
Rowlands
Dewi Kenneth
DK
James
Anthony Edward
AE
Lee
Kenneth Ka-Ho
KK
Chan
John Yuek-Hon
JY
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D004052:Diethylnitrosamine / Q000633:toxicity; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008113:Liver Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D014162:Transfection; D015854:Up-Regulation
C091514:BABAM2 protein, human; D009419:Nerve Tissue Proteins; D004052:Diethylnitrosamine