Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Due to the late diagnosis and the resistance to conventional chemotherapeutic drugs, the treatment options for unresectable HCC remain limited and the prognosis of the patients is dismal. Sorafenib is the only targeted therapy approved for HCC, however it prolongs life by an average of only three months! Thus, a better understanding of HCC molecular pathogenesis is mandatory for the identification of novel therapeutic targets and the development of effective treatments against this deadly disease. Recently, whole-wide sequencing studies reveal that mutations of genes of SWI/SNF chromosomal remodeling complex, including ARID1a and ARID2, are found in ~ 25% of all human HCC samples. Human genomic studies demonstrated the statistically significant enrichment of ARID1a and ARID2 mutation with activating ?-catenin mutants in human HCC. The central goal of our proposal is to determine the tumor suppressor activity of the SWI/SNF chromosomal remodeling complex using in vivo approaches. Specifically, we hypothesize that loss of SWI/SNF complex cooperates with in ?-catenin mutant to promote HCC development in mice. To test this hypothesis, we propose the two aims.
In Aim 1, we will determine whether activated ?-catenin mutant cooperates with loss of Brg1 to promote HCC development in mice.
In Aim 2, we determine whether activated ?-catenin mutant cooperates with loss of ARID1a or ARID2 to induce liver tumor development in mice. Altogether, the application fits well with the R03 grant mechanism for pilot experiments. The proposed studies will be of great help in illustrating the tumor suppressing activity of the SWI/SNF chromosomal remodeling complex and how its inactivation synergizes with other genetic events to promote hepatic carcinogenesis. The study will also provide novel insight into the molecular mechanisms about ARID1a and ARID2 mutants and their functional significance during HCC pathogenesis. The murine models generated from the proposed study will significantly benefit HCC research community and provide valuable models to study novel strategies for HCC prevention and treatment.
Liver Cancer is a deadly form of malignancy with limited treatment options. This application seeks to establish the functional role of SWI/SNF chromosomal remodeling complex in liver tumor development. The results will likely provide novel insight into the mechanisms of liver tumorigenesis; as well as new treatment strategy against this malignancy.
