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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA136606-05S1
Application #
8837734
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Johnson, Ronald L
Project Start
2009-05-01
Project End
2015-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
5
Fiscal Year
2014
Total Cost
$13,000
Indirect Cost
$4,755
Name
University of California San Francisco
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Wang, Chunmei; Cigliano, Antonio; Jiang, Lijie et al. (2015) 4EBP1/eIF4E and p70S6K/RPS6 axes play critical and distinct roles in hepatocarcinogenesis driven by AKT and N-Ras proto-oncogenes in mice. Hepatology 61:200-13
Pellegrino, Rossella; Calvisi, Diego F; Neumann, Olaf et al. (2014) EEF1A2 inactivates p53 by way of PI3K/AKT/mTOR-dependent stabilization of MDM4 in hepatocellular carcinoma. Hepatology 59:1886-99
Chen, Xin; Calvisi, Diego F (2014) Hydrodynamic transfection for generation of novel mouse models for liver cancer research. Am J Pathol 184:912-23
Tao, Junyan; Calvisi, Diego F; Ranganathan, Sarangarajan et al. (2014) Activation of ?-catenin and Yap1 in human hepatoblastoma and induction of hepatocarcinogenesis in mice. Gastroenterology 147:690-701
Tschaharganeh, Darjus Felix; Chen, Xin; Latzko, Philipp et al. (2013) Yes-associated protein up-regulates Jagged-1 and activates the Notch pathway in human hepatocellular carcinoma. Gastroenterology 144:1530-1542.e12
Li, Lei; Wang, Chunmei; Calvisi, Diego F et al. (2013) SCD1 Expression is dispensable for hepatocarcinogenesis induced by AKT and Ras oncogenes in mice. PLoS One 8:e75104
Wang, Chunmei; Cigliano, Antonio; Delogu, Salvatore et al. (2013) Functional crosstalk between AKT/mTOR and Ras/MAPK pathways in hepatocarcinogenesis: implications for the treatment of human liver cancer. Cell Cycle 12:1999-2010
Chow, Edward Kai-Hua; Fan, Ling-ling; Chen, Xin et al. (2012) Oncogene-specific formation of chemoresistant murine hepatic cancer stem cells. Hepatology 56:1331-41
Ho, Coral; Wang, Chunmei; Mattu, Sandra et al. (2012) AKT (v-akt murine thymoma viral oncogene homolog 1) and N-Ras (neuroblastoma ras viral oncogene homolog) coactivation in the mouse liver promotes rapid carcinogenesis by way of mTOR (mammalian target of rapamycin complex 1), FOXM1 (forkhead box M1)/SKP2, Hepatology 55:833-45
Calvisi, Diego F; Wang, Chunmei; Ho, Coral et al. (2011) Increased lipogenesis, induced by AKT-mTORC1-RPS6 signaling, promotes development of human hepatocellular carcinoma. Gastroenterology 140:1071-83

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