Hepatocellular carcinoma (HCC), also known as liver cancer, is one of the leading causes of cancer death world wide. Molecular genetics underlying hepatocarcinogenesis are still poorly understood. One of the signaling pathways that have been implicated in HCC development is the Ras/MAPK pathway, as it has been shown that this pathway is activated in virtually all human HCC. However, Ras or B-Raf mutations are extremely rare in this malignancy. So how does Ras/MAPK signaling get activated in human HCC? In our previous genome-wide expression studies, we identified a large list of genes whose expression levels are de- regulated in human HCC samples. Using bioinformatics analysis, we identified Spry2 and EphA2, both feedback negative inhibitors of the Ras/MAPK signaling to be down-regulated in human HCC samples in a concomitant manner. To address the potential roles of Spry2 and EphA2 during HCC pathogenesis, we developed novel mouse models for these two genes. We show that inhibition of Spry activity by a dominant negative form of Spry2 (Spry2Y55F) cooperates with activated ?-catenin to induce liver cancer formation, and loss of EphA2 sensitizes DENA induced hepatic carcinogenesis in mice. These novel mouse models provide compelling evidence that Spry2 and EphA2 can indeed directly contribute to HCC pathogenesis in vivo and function as tumor suppressor genes. Based on these preliminary studies, we hypothesize that the loss of Spry2 and/or EphA2 leads to aberrant activation of the Ras/MAPK signaling pathway and cooperates with other genetic alterations to promote HCC pathogenesis. The hypotheses will be tested in three aims.
In Aim one, we will define the regulation and roles of Spry2 in HCC pathogenesis;
In Aim two, we will determine the effects of loss of EphA2 expression in HCC development;and in Aim three, we will investigate the functions of concomitant downregulation of Spry2 and EphA2 during hepatic carcinogenesis. Altogether, the goal of this application is to characterize the functional significance of Spry2 and EphA2 in HCC, and to elucidate novel mechanisms of activation of the Ras/MAPK pathway in the absence of Ras or B-Raf gene mutations during HCC pathogenesis. These mouse models can be used in drug screens to identify and test the efficacy of small molecules or antibodies that target Ras/MAPK pathway. These projects represent exciting and important functional genomic studies stemmed from a descriptive genomic analysis and will likely unveil novel molecular mechanisms for HCC pathogenesis.
PROPOSAL NARRATIVE Liver cancer is a deadly disease, lacking any effective treatment options. Liver cancer incidence is increasing in the US. Our lab focuses on studying the genetic alternations during liver cancer development. In this application we will characterize the functions of two genes, Spry2 and EphA2, whose expression levels are de- regulated in human liver cancers. These studies will likely provide us novel targets for the diagnosis and treatment of this malignancy.
|Zhang, Shanshan; Song, Xinhua; Cao, Dan et al. (2017) Pan-mTOR inhibitor MLN0128 is effective against intrahepatic cholangiocarcinoma in mice. J Hepatol 67:1194-1203|
|Cao, Dan; Song, Xinhua; Che, Li et al. (2017) Both de novo synthetized and exogenous fatty acids support the growth of hepatocellular carcinoma cells. Liver Int 37:80-89|
|Wu, Heng; Zhang, Tianpeng; Pan, Fei et al. (2017) MicroRNA-206 prevents hepatosteatosis and hyperglycemia by facilitating insulin signaling and impairing lipogenesis. J Hepatol 66:816-824|
|Méndez-Lucas, Andrés; Li, Xiaolei; Hu, Junjie et al. (2017) Glucose Catabolism in Liver Tumors Induced by c-MYC Can Be Sustained by Various PKM1/PKM2 Ratios and Pyruvate Kinase Activities. Cancer Res 77:4355-4364|
|Cigliano, Antonio; Pilo, Maria G; Li, Lei et al. (2017) Deregulated c-Myc requires a functional HSF1 for experimental and human hepatocarcinogenesis. Oncotarget 8:90638-90650|
|Liu, Pin; Calvisi, Diego F; Kiss, Andras et al. (2017) Central role of mTORC1 downstream of YAP/TAZ in hepatoblastoma development. Oncotarget 8:73433-73447|
|Cigliano, Antonio; Wang, Chunmei; Pilo, Maria G et al. (2017) Inhibition of HSF1 suppresses the growth of hepatocarcinoma cell lines in vitro and AKT-driven hepatocarcinogenesis in mice. Oncotarget 8:54149-54159|
|Che, Li; Pilo, Maria G; Cigliano, Antonio et al. (2017) Oncogene dependent requirement of fatty acid synthase in hepatocellular carcinoma. Cell Cycle 16:499-507|
|Wu, Heng; Tao, Junyan; Li, Xiaolei et al. (2017) MicroRNA-206 prevents the pathogenesis of hepatocellular carcinoma by modulating expression of met proto-oncogene and cyclin-dependent kinase 6 in mice. Hepatology 66:1952-1967|
|Liu, Pin; Ge, Mengmeng; Hu, Junjie et al. (2017) A functional mammalian target of rapamycin complex 1 signaling is indispensable for c-Myc-driven hepatocarcinogenesis. Hepatology 66:167-181|
Showing the most recent 10 out of 43 publications