Farnesoid X Receptor (FXR, NR1H4) belongs to nuclear receptor superfamily and is a key metabolic regulator in liver metabolism, including bile acid (BA), lipid and glucose metabolism. We recently demonstrated that FXR-/- mice spontaneously developed liver tumors as they aged and the mice displayed prominent liver injury, inflammation and irregular regeneration. These results suggest a novel role of FXR in suppressing hepatocellular carcinoma (HCC). HCC remains a major cause of cancer death worldwide, and the incidence of HCC in developed countries, including the United States, is increasing. Although there are several animal models of HCC, FXR-/- mice provide a unique pathologically relevant model to study the mechanism of HCC development, especially the etiological connection between liver metabolism and hepatocarcinogenesis. The development of HCC in FXR-/- mice mimics the pathological progression of human HCC, therefore, better understanding the roles of FXR in HCC will help us to identify new targets and provide novel approaches for HCC prevention and therapy. Based on our previous work and more preliminary data accompanying this proposal, we hypothesize that FXR is a novel liver protector and HCC suppressor. Specifically, FXR regulates the expression of a superoxide dismutase (EC-SOD, SOD3) and other anti-oxidative stress genes that suppress the deleterious effect of reactive oxygen species (ROS) and prevents prolonged JNK1 activation in liver. FXR also directly modulates the expression of genes in anti-apoptosis pathways, and that dysfunction of FXR results in enhanced cell death and liver injury, thereby promoting the HCC development. We propose two Specific Aims in this proposal. In the first Aim, we will define the roles of FXR in ROS metabolism and JNK1 activation and their link to HCC development. In the second Aim, we will determine the roles of FXR in regulating the expression of anti-apoptotic genes. These experimental approaches will help us better understand the roles of FXR in HCC and provide insight into the human hepatocarcinogenesis. The proposed work is innovative as the proposed studies will define a novel link between liver metabolism and HCC. Successful completion of the proposed studies will lead to the development of novel approaches for the prevention and treatment of HCC.

Public Health Relevance

We propose to investigate the role of a key liver metabolic regulator, Farnesoid X Receptor (FXR), in HCC development. Results from these studies will not only provide insight into an etiological connection between liver metabolism and HCC but also help us develop novel approaches for the prevention and treatment of human HCC.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA139158-02
Application #
8215639
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Johnson, Ronald L
Project Start
2011-01-25
Project End
2015-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
2
Fiscal Year
2012
Total Cost
$344,450
Indirect Cost
$136,950
Name
City of Hope/Beckman Research Institute
Department
Type
DUNS #
027176833
City
Duarte
State
CA
Country
United States
Zip Code
91010
Ding, Lili; Sousa, Kyle M; Jin, Lihua et al. (2016) Vertical sleeve gastrectomy activates GPBAR-1/TGR5 to sustain weight loss, improve fatty liver, and remit insulin resistance in mice. Hepatology 64:760-73
Zhou, Hong; Zhang, Jiawei; Gu, Ying et al. (2016) Identification of a novel RNA giant nuclear body in cancer cells. Oncotarget 7:4724-34
Han, Weidong; Fu, Xianghui; Xie, Jiansheng et al. (2015) miR-26a enhances autophagy to protect against ethanol-induced acute liver injury. J Mol Med (Berl) 93:1045-55
Ding, Lili; Yang, Li; Wang, Zhengtao et al. (2015) Bile acid nuclear receptor FXR and digestive system diseases. Acta Pharm Sin B 5:135-44
Yu, Donna D; Sousa, Kyle M; Mattern, Daniell L et al. (2015) Stereoselective synthesis, biological evaluation, and modeling of novel bile acid-derived G-protein coupled bile acid receptor 1 (GP-BAR1, TGR5) agonists. Bioorg Med Chem 23:1613-28
Wang, Yan-Dong; Chen, Wei-Dong; Li, Cunbao et al. (2015) Farnesoid X receptor antagonizes JNK signaling pathway in liver carcinogenesis by activating SOD3. Mol Endocrinol 29:322-31
Huang, Xiong-fei; Zhao, Wei-yu; Huang, Wen-dong (2015) FXR and liver carcinogenesis. Acta Pharmacol Sin 36:37-43
Dong, Bingning; Lee, Ju-Seog; Park, Yun-Yong et al. (2015) Activating CAR and β-catenin induces uncontrolled liver growth and tumorigenesis. Nat Commun 6:5944
Gu, Ying; Zhou, Hong; Gan, Yichao et al. (2015) Small-molecule induction of phospho-eIF4E sumoylation and degradation via targeting its phosphorylated serine 209 residue. Oncotarget 6:15111-21
Fu, Xianghui; Dong, Bingning; Tian, Yan et al. (2015) MicroRNA-26a regulates insulin sensitivity and metabolism of glucose and lipids. J Clin Invest 125:2497-509

Showing the most recent 10 out of 34 publications