Identification and Functional Analysis of Novel Biomarkers for Liver Cancer

Wendy Shuwen Chen
Appointment Period: 2017-2018, Grant Year: [32]

The goal of my PhD thesis project is to identify novel biomarker molecules for liver cancer that can be used for early diagnosis of this deadly disease and also for dissection of the biochemical pathways underlying liver cancer initiation and progression. Primary liver cancer, mainly hepatocellular carcinoma (HCC), is now the 2nd most fatal cancer worldwide. Due to the extremely poor prognosis of patients with late-stage HCC, early diagnosis is crucial for more effective therapy and improvement of patient survival. Unfortunately, since the establishment of a-fetoprotein (AFP) as an HCC biomarker in 1963, no new better biomarker has been identified. We seek to tackle this problem by using multi-disciplinary approaches to identify a set of molecules highly expressed in liver tumor cells in mice. By integrating the results from animal models with TCGA and other human patient data, we shall generate a clinically-viable HCC score to function as a diagnostic panel, and to determine score significance in relation to patient survival. We shall also use this new panel of molecules as probes to interrogate the pathogenesis of HCC and to explore their potential value as therapeutic targets.

Consistent with frequent detection of over-expression or mutations in the HGF/c-MET and Wnt/β- catenin pathways in HCC patients, co-transfection of c-MET and an active β-catenin mutant (MET/CAT) robustly induced HCC development in mice in 8-10 weeks, as reported by us and several groups. For this project, I have established a successful experimental system. RNA-sequencing (RNA-seq) analysis showed high levels of similarity in transcriptomes between the mouse and human HCC tumors driven by aberrantly activated c-MET and β-catenin signaling, indicating the value of this animal model to study liver cancer. It was reported that CD133+ and EpCAM+ tumor cells represent a group of highly invasive cancer stem cells (CSC) or tumor-initiating cells (TICs) in the liver. However, these molecules are normally expressed on hepatobiliary cells or hepatic progenitor cells in healthy liver. Our strategy is to isolate CD133+ and EpCAM+ cells from both tumor tissues and normal livers, and use RNA-seq and other assays to identify a set of molecules that are robustly enriched in stem-like tumor tissues, relative to healthy liver tissues. Then, the list of candidate molecules will be used in conjunction with TCGA and other databases for human HCCs, to narrow down, validate, and eventually establish new biomarkers for liver cancer.

In sum, I have obtained promising results to support the feasibility and significance of this project. I am working closely with other lab members on RNA-seq data analysis in a highly supportive and insightful group that focuses on liver cancer research.

PUBLICATIONS (resulting from this training)

Liu JJ, Li Y, Chen WS, Liang Y, Wang G, Zong M, Kaneko K, Xu R, Karin M, Feng GS. Shp2 deletion in hepatocytes suppresses hepatocarcinogenesis driven by oncogenic β- Catenin, PIK3CA and MET. (2018) J Hepatol. S0168-8278(18)30131-4. doi: 10.1016/j.jhep.2018.02.014. PMID: 29505847

Treating leukemia at the risk of inducing severe anemia. Chen WS, Zhu HH, Feng GS. (2016) Exp Hematol. 44(5):329-31. doi: 10.1016/j.exphem.2016.01.004. PMID: 26826310