Livers overexpressing BRE transgene are under heightened state of stress-response, as revealed by comparative proteomics

BRE (TNFRSF1A modulator/BRCC45) is a stress-responsive gene that is normally expressed at low levels in human and mouse livers. It binds to TNF-R1 and Fas, and modulates the actions of these cytokines [Chan, B.C.L., Ching, A.K.K., To, K.F., Leung, J.C.K. et al., Oncogene 2008, 27, 1208-1217]. We demonstrated that BRE expression was rapidly induced when the liver was insulted with carbon tetrachloride. In addition, it is highly expressed in human hepatocellular carcinoma. Transgenic mice were produced that specifically overexpressed BRE in the liver to determine the effects of high levels of BRE on the liver. We found these transgenic livers were histologically normal when compared with their wild-type counterpart. Hence, comparative proteomics were used to elucidate the molecular alterations in these tissues. It was established that several stress-responsive proteins were upregulated in BRE-transgenic hepatocytes. These include heat shock-related 70 kDa protein 2, putative heat shock 70 kDa protein 7 and mitogen-activated protein kinase 12. Furthermore, we demonstrated that silencing BRE expression in non-tumoral Chang cells could directly inhibit the expression of these stress-responsive genes. In conclusion, we propose that the liver in our BRE transgenic mice is under constant heightened stress-response and this may be a major contributing factor to the hepatocellular carcinoma phenotype.