Maid is a specific guardian gene to regulate DNA damage in liver fibrosis and hepatocarcinogenesis

Generation of hepatocellular carcinoma (HCC) is related with the progression of liver fibrosis. The interaction is key factor to prevent HCC. Maid (Maternal inhibitor of differentiation) gene, which is HLH transcriptional regulator, binds to Cyclin D1, Rad51, E12, Jab1 and oligo1 and regulates cell cycle and differentiation. From the aspect of TGF-beta signaling and Maid's structure, Maid might be stress response regulator and regulated cell inhibition and ECM. We have also reported that HHM (Human homologue of Maid) was a specific marker of human dysplastic nodule and well-differentiated HCC. We therefore analyzed how maid regulate liver fibrosis and hepatocarcinogenesis in persistent liver damage condition. In 16 weeks-CCl4-treated Maid KO livers, tumor incidence was 50 % (n=3/6), but CCl4-treated wild type mice did not have liver tumor (n=0/6). Moreover, CCl4-treated-Maid KO mice accelerated to induce liver fibrosis compared with wild type mice (P<0.05, n=20). To understand how Maid regulated liver fibrosis and hepatocarcinogenesis, we did DNA-chip analysis and confirmed that DNA-repair and chromatin related genes were important to regulate them, consistent with the up-regulated phopho-H2AX protein in Maid KO livers (P<0.01). We also found that phosphor-ATM protein was over-expressed in wild type mice but not in Maid KO mice after X-ray irradiation. These results suggested that Maid might be a regulator of DNA-damage and regulate liver fibrosis and hepatocarcinogenesis.