| Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal epithelial malignancies in human. In order to identify novel tumor suppressor genes (TSG) in HCC, we set out to make a tractable mouse model of liver cancer based on ex vivo manipulation of progenitor cells followed by retranplantation of genetically modified cells into livers of recipient mice. We used this model to identify new oncogenes in liver cancer and validated cIAP1 and YAP1 as cooperating novel oncogenes in HCC. We adapted in vivo RNAi to study the role of p53 tumor suppressor gene in tumor maintenance, where we identified a mechanism of tumor suppression involving senescence and a novel form of immune surveillance. We next set out to characterize new tumor suppressor genes using RNAi. We first characterized a candidate gene, Dlc1 (Deleted in liver cancer 1), and showed that its knockdown accelerates liver tumor formation by deregulating the RhoA signaling pathway. We then took advantage of oncogenomic information to screen for new tumor suppressor genes. In a broad screen we identified 13 new tumor suppressor genes in recurrent focal genomic deletions in HCC. One of the candidate genes, EXPORTIN 4 (XPO4), regulates nuclear export for EIF5A and SMAD3. In a focused screen of chromosome 8p22, we showed that multiple tumor suppressor genes can exist in the same chromosome band and can cooperate for the induction of tumors. Together, these data build a new platform for linking oncogenomics, mouse models, and RNAi to identify genes involved in the initiation and maintenance of liver cancer and other tumor types. |
