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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Watson, Joanna M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Francisco
Schools of Pharmacy
San Francisco
United States
Zip Code
Xu, Zhong; Hu, Junjie; Cao, Hui et al. (2018) Loss of Pten synergizes with c-Met to promote hepatocellular carcinoma development via mTORC2 pathway. Exp Mol Med 50:e417
Wang, Jingxiao; Dong, Mingjie; Xu, Zhong et al. (2018) Notch2 controls hepatocyte-derived cholangiocarcinoma formation in mice. Oncogene 37:3229-3242
Qiao, Yu; Xu, Meng; Tao, Junyan et al. (2018) Oncogenic potential of N-terminal deletion and S45Y mutant ?-catenin in promoting hepatocellular carcinoma development in mice. BMC Cancer 18:1093
Dong, Mingjie; Liu, Xianqiong; Evert, Katja et al. (2018) Efficacy of MEK inhibition in a K-Ras-driven cholangiocarcinoma preclinical model. Cell Death Dis 9:31
Zhang, Shanshan; Wang, Jingxiao; Wang, Haichuan et al. (2018) Hippo Cascade Controls Lineage Commitment of Liver Tumors in Mice and Humans. Am J Pathol 188:995-1006
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
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
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
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

Showing the most recent 10 out of 47 publications