Liver Cancer is a deadly disease, lacking any effective treatment options. Molecular genetics underlying this deadly malignancy remains poorly understood. The Hippo tumor suppressor cascade is an evolutionally conserved pathway that controls organ size, tissue regeneration, stem cell self-renewal, and tumor development. Recent genetic studies support the importance of Hippo pathway during liver cancer development. However, the precise functional role of Yap and TAZ, the two transcriptional co-activators downstream of Hippo kinases, and how they interact with other onocgenic pathways during hepatic carcinogenesis have not been characterized. In our recent studies, we found that Yap and TAZ are both highly expressed in a subset of human liver cancer samples. Importantly, we found that while Yap or TAZ alone is unable to induce liver tumor formation in vivo, overexpression of Yap or TAZ synergizes with activated AKT signaling to accelerate hepatic carcinogenesis in mice. The tumor cells show increased cell proliferation as well as activated Notch and Wnt/?-catenin pathways. Furthermore, we found that both Yap and TAZ are activated in multiple mouse liver tumor models, including HCC induced by AKT/Ras or c-Myc oncogenes. Overexpression of Lats2, which inhibits nuclear localization and promotes degradation of Yap or TAZ, strongly inhibited AKT/Ras and c-Myc induced hepatic carcinogenesis in mice, supporting a critical role of Hippo pathway in regulating oncogene induced liver tumor development. In this competing renewal application, we will systematically characterize the functional roles of Yap and TAZ during liver cancer development. We propose three aims.
In Aim One, we will elucidate the molecular mechanisms underlying accelerated liver tumor development induced by the co-expression of AKT/Yap or AKT/TAZ.
In Aim Two, we will define the role of Yap and TAZ in AKT/Ras induced liver tumor development. And in Aim Three, we will characterize the functional contribution of Yap and TAZ in c-Myc induced hepatic carcinogenesis. Altogether, in the proposed application, we will apply sophisticated mouse genetic approaches with the goal to uncover the functional significance of Yap and TAZ transcriptional co-activators during hepatic carcinogenesis. The study will also provide novel mechanistic insight into the genetic and biochemical crosstalk among the key oncogenic pathways, including Yap/TAZ, AKT/mTOR, Wnt/?-catenin, Notch and c-Myc cascades during liver cancer development. The study will likely provide strong evidence to support the development of small molecules or siRNA based therapeutics against Yap or TAZ as novel treatment strategies for liver cancer.

Public Health Relevance

Liver Cancer is a deadly disease, lacking any effective treatment options. The application seeks to understand the functional roles of Yap and TAZ, two candidate oncogenes, during liver cancer development. The study is likely to provide new insight into the molecular genetics of liver cancer and strong evidence to support the development of therapeutics against Yap or TAZ as novel treatment strategies for liver cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA136606-06A1
Application #
8630219
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Watson, Joanna M
Project Start
2014-09-01
Project End
2017-08-31
Budget Start
2014-09-08
Budget End
2015-08-31
Support Year
6
Fiscal Year
2014
Total Cost
$355,688
Indirect Cost
$130,688
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

Showing the most recent 10 out of 14 publications