We uncovered a novel finding in which HCV promotes genomic DNA damage and mutations (mutator phenotype) that enable viral transformation. Overall, these results define a unique strategy by which host tumor suppressor genes are effectively abolished by viral proteins. This research led to five first-author publications (PNAS 2004 101:4262-4267; J. Virol. 2004 78:8835-8843; J. Virol. 2005 79:8079-8089; J. Virol. 2006 80:866-874; J. Virol. 2006 80:7199-7207).

Our research addressed new mechanistic hypotheses based on the novel discovery that the HCV NS5A protein induces Toll-like receptor 4 (TLR4) an innate immune sensor molecule for Gram (-) bacteria. We also collaborate with Professor Hidekazu Tsukamoto, Department of Pathology, studying the synergy between HCV and alcoholism and delineating oncogenic signaling pathways. We developed a novel mouse HCC model induced by HCV and alcoholism by feeding animals an alcohol-containing diet for 12 months. In contrast, alcohol-fed TLR4-deficient HCV Tg mice did not develop HCC, indicating that TLR4 signaling is critical for HCC development. Global mRNA profiling analysis identified NANOG (the stem/progenitor cell marker) as one of major downstream targets of TLR4 for oncogenesis. This study allowed me to merge my background in HCV research with knowledge of alcoholic liver disease and TICs using Tg mice (PNAS 2009 106:1548-1553).

We investigated further the roles of TIC signaling in human malignancies associated with virus and alcoholism and/or obesity. We found that the hormone produced by adipose tissue, that controls appetite, stimulates self-renewal and expansion of TICs through the activation of tumor-generating genes (PNAS. 2012 109: 829-834). Furthermore, our study demonstrates that TLR4 is induced, activated, and responsible for liver oncogenesis in other HCC mouse models and that TICs isolated from these models are all TLR4-dependent (J. Clin. Invest. 2013 123:2832-2849).

Current Research and Future Plans: Based on insights from the genetic mouse model of HCC, we have initiated several IRB-approved clinical studies to further expand research to isolate, characterize and treat TICs derived from human HCC patients at USC. Using knowledge gained from the oncogenic signaling of TICs, we are addressing new mechanistic hypotheses based on the novel discovery that the pluripotent transcription factor, NANOG, can reprogram the metabolism of HCC-derived TICs. These studies will motivate novel strategies for targeting and removing TICs and suggest new avenues to treat malignancies associated with human HCV and alcoholism and/or obesity. This newly discovered mechanistic framework for TIC proliferation represents a key innovation and holds significant potential as a therapeutic target.