Explore the Efficacy of Jiawei Xiaoyao San in Preventing Hepatoma Progression Caused by Hepatic Fibrosis and Associated Microenvironment Regulation Mechanism

Hepatocellular carcinoma (HCC) is an emerging worldwide health impact that causes poor survival rate and high mortality, while hepatic fibrosis is a common etiology for HCC progression. However, the molecular cascades which predispose the fibrotic liver to cancer development are still unclear. Herein, we will particularly address the microenvironment of liver tumorigenesis that enhanced by liver fibrosis. The major predisposing features including activated hepatic stellate cells drive fibrogenesis, alterations of the extracellular matrix (ECM) composition, intracellular responses and signaling as well as the emerging events such as autophagy, exosomes and HCC progenitor cells. Meanwhile, the reduction in activity of natural killer and natural killer T cells that contribute the tumor surveillance will be investigated. Exploring the fibrosis-dependent tumorigenic mechanisms will rationalize antifibrotic therapies as a strategy to prevent and treat HCC. Most medicine for therapy of hepatic fibrosis or HCC could not fully meet the demand of patients due the development of pharmacoresistance as well as the side effects of drugs. The Chinese herbal formulae Jia-Wei-Xiao-Yao-San (JWXYS) has been utilized to perform therapeutic or protective functions against chronic liver diseases for centuries. JWXYS is wildly used to modulate liver qi, strengthen spleen and nourish blood. This formulae is also effective in clinical adjuvant therapy for cancer patients and improvement of the survival rate in patients with HCC. Taken together, we attempt to explore the efficacy, cellular microenvironment and molecular mechanisms linked to JWXYS-mediated therapy to liver fibrosis/HCC with systematic biology. This proposal will highlight the specific aims as follows: 1. Systematically and high-throughput screen the active components derived from JWXYS extract to attenuate hepatic fibrogenesis with cell model. 2. Establish the HCC murine model with TAA-induced liver fibrosis. Apply the effective extracts from JWXYS to evaluate the anti-fibrotic/anti-HCC function and collect the plasma and liver samples at specific time-points for further experiments. 3. Reveal samples obtained from cell co-culture systems and animal experiments for microenvironment study upon cytokine profiles, ECM constitution and secretion of exosomes. 4. Characterize the differential protein expression from liver tissues and plasma by proteomics combined with bioinformatics to identify the possible biomarkers as well as the signaling pathways for liver fibrosis/HCC diagnosis, prognosis and treatment. 5. Confirm the efficacy as well as the mechanisms of JWXYS by conducting histological and cellular biology experiments. 6. Functional experiments will be exploited to verify the feasibility of targeted therapy by delivery of the targeted proteins or molecules to relevant cells with genome-editing tool. 7. Integrate the experimental findings and clinical big data analysis for translational medicine. This project will present solid evidence in prevention of HCC deterioration via effective therapy of liver fibrosis with traditional Chinese herbal formulae, we also help to develop non-invasive biomarkers, which will contribute to the clinical applications in treatment of liver fibrosis/HCC. Meanwhile, the results can improve the public health and welfare of the citizen.

Project ID:PC10901-2017
External Project ID:MOST108-2320-B182-024-MY3