We are using a global gene expression profiling approach based on state-of-the-art microarray technology to profile clinical specimens that are associated with different stages of liver diseases. For example, by comparing liver samples from chronic liver disease patients with varying degrees of risk for developing hepatocellular carcinoma, we have identified a unique signature that may be useful in diagnosing patients with early onset of liver cancer. Several serum proteins have been identified as potential diagnostic markers for hepatocellular carcinoma that are present at an early stage or in those negative for alpha-fetoprotein. We have also developed a unique molecular signature based on the mRNA gene expression of metastatic primary hepatocellular carcinoma specimens to predict prognosis and metastasis of hepatocellular carcinoma patients. We have recently validated the predictive capacity of this signature in two independent cohorts of differing etiology. Importantly, we found that this molecular signature could identify those patients who were most at risk for recurrence even in patients with early stage disease. Since hepatocellular carcinoma is usually present in inflamed liver, due to fibrosis, cirrhosis and/or chronic hepatitis, we also developed a unique molecular prognostic signature based on mRNA gene expression of the liver microenvironment of hepatocellular carcinoma patients. We found that a predominant humoral cytokine profile occurs in the metastatic liver microenvironment and that a shift toward anti-inflammatory/immune-suppressive responses may promote hepatocellular carcinoma metastases. These studies therefore suggest an important role of the local tissue microenvironment in hepatocellular carcinoma metastasis. Interestingly, the tumor signature is principally different from that of liver microenvironment. In addition, we have used molecular profiling to identify five genes that may serve as biomarkers for early onset of hepatocellular carcinoma, especially for those that are negative for alpha-fetoprotein. We have also explored the role of small non-coding RNAs, termed microRNAs, in hepatocellular carcinoma metastasis and survival. We found that certain microRNA expression changes are associated with metastasis and could significantly predict patient survival and relapse even in early stage disease. These microRNAs may provide a simple profiling method to assist in identifying HCC patients who are likely to develop metastases. In addition, functional analysis of these microRNAs may enhance our biological understanding of hepatocellular carcinoma metastasis. To further assess the role of microRNAs in the liver, we examined the microRNA expression patterns, survival and response to interferon in men and women with hepatocellular carcinoma. We found that the expression of microRNA-26 differed among men and women and was higher in tumor versus nontumor tissue. Tumors with reduced microRNA-26 expression had a distinct transcriptomic pattern with activation of the NFkB/IL6 signalling pathways. Patients with low microRNA-26 had poor survival and were better responders to interferon therapy than those with normal expression. Our findings have been extremely fruitful and offer useful tools for personalized patient management and also challenge the current paradigm of tumor evolution. Clearly, gene expression profiling has expanded our knowledge of the global changes that occur in liver cancer, and has provided numerous insights into the molecular mechanisms of this disease. In addition, these studies will undoubtedly contribute to the establishment of novel markers with potential diagnostic and prognostic value, as well as potential therapeutic targets for direct clinical intervention.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
Application #
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
National Cancer Institute Division of Basic Sciences
Zip Code
Chaisaingmongkol, Jittiporn; Budhu, Anuradha; Dang, Hien et al. (2017) Common Molecular Subtypes Among Asian Hepatocellular Carcinoma and Cholangiocarcinoma. Cancer Cell 32:57-70.e3
Dang, Hien; Takai, Atsushi; Forgues, Marshonna et al. (2017) Oncogenic Activation of the RNA Binding Protein NELFE and MYC Signaling in Hepatocellular Carcinoma. Cancer Cell 32:101-114.e8
Scarzello, Anthony J; Jiang, Qun; Back, Timothy et al. (2016) LT?R signalling preferentially accelerates oncogenic AKT-initiated liver tumours. Gut 65:1765-75
Ploeger, Carolin; Waldburger, Nina; Fraas, Angelika et al. (2016) Chromosome 8p tumor suppressor genes SH2D4A and SORBS3 cooperate to inhibit interleukin-6 signaling in hepatocellular carcinoma. Hepatology 64:828-42
Auslander, Noam; Yizhak, Keren; Weinstock, Adam et al. (2016) A joint analysis of transcriptomic and metabolomic data uncovers enhanced enzyme-metabolite coupling in breast cancer. Sci Rep 6:29662
Wang, Rui-Hong; Zhao, Tingrui; Cui, Kairong et al. (2016) Negative reciprocal regulation between Sirt1 and Per2 modulates the circadian clock and aging. Sci Rep 6:28633
Fako, Valerie; Yu, Zhipeng; Henrich, Curtis J et al. (2016) Inhibition of wnt/?-catenin Signaling in Hepatocellular Carcinoma by an Antipsychotic Drug Pimozide. Int J Biol Sci 12:768-75
Zhao, Xuelian; Parpart-Li, Sonya; Wang, Xin Wei (2016) The importance of integrated genomics to uncover clinically relevant cancer driver genes. Mol Cell Oncol 3:e1019975
Greten, Tim F; Wang, Xin W; Korangy, Firouzeh (2015) Current concepts of immune based treatments for patients with HCC: from basic science to novel treatment approaches. Gut 64:842-8
Ji, Junfang; Zheng, Xin; Forgues, Marshonna et al. (2015) Identification of microRNAs specific for epithelial cell adhesion molecule-positive tumor cells in hepatocellular carcinoma. Hepatology 62:829-40

Showing the most recent 10 out of 40 publications