Expression of the multidrug resistance gene (MDR1) is frequently upregulated in human hepatocellular carcinomas (HCC). In rodents, MDR1 homologous mdr1a and mdr1b are consistently upregulated during heptocarcinogenesis in many different carcinogenic programs. These observations suggest that activation of mdr1 expression and hepatocarcinogenetic programs may share overlapping pathways. As a first step to test this hypothesis, we investigated the activation mechanisms of rat mdr1b in cultured cells induced by hepatocarcinogen 2-acetylaminofluorene (AAF). We found that the NF-KB signal is involved in the upregulation of mdr1b expression. Activation of NF-KB and elevated expression of MDR1 by the carcinogen also can be seen in human hepatoma cells. The goals of our research are to determine how NF-KB signaling is activated for the upregulation of mdr1b gene expression during hepatocarcinogenesis, and whetheractivation of this signal plays a role in the development of liver cancer.
Three specific aims are proposed.
The first aim i s to determine the upstream and downstream signals of NF-KB in AAF-induced mdr1b expression. The possible involvement of phosphoinosite 3 kinase (PI3K) and Akt as upstream signal and transcriptional coactivators as downstream signal in chromatin will be investigated.
The second aim i s to determine whether the same signal also involved in the upregulation of mdr1b regulation in vivo. Adenoviral vectors will be used to deliver inhibitors of the NF-KB signal to the liver to investigate whether modulation of this signal would alter the expression of mdr1b. The last aim is to investigate whether NF-KB plays a role in hepatocarcinogenesis. Nontoxic adenoviral vector will be used to target recombinant DNA constructs to the liver to determine whether intervention of NF-KB signal would affect the rate of AAF-induced liver cancer development. We hope from this research, which includes in vitro cell culture and in vivo animal and tumor models, to gain important molecular insights into the genetic resolution of drug resistance and hepatocarcinogenesis.
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