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American Liver Foundation
39 Broadway, Suite 2700
New York, New York 10006
Charles Trey, MD Memorial Postdoctoral Research Fellowship
University of California, San Diego
Project Title: Elucidating the functional role of CD44 in hepatocellular carcinoma
Background: Very little is known about HCC initiation and progression particularly the role of cancer stem cells (CSC). Although, CD44 is a well-known cancer stem cell marker and is over expressed in human HCC, its role in HCC initiation and/or progression is not known. Preneoplastic lesions and HCC progenitor cells (HPC) isolated from carcinogen-exposed mouse liver over-express CD44 and only CD44+ HPCs can progress to HCC in transplanted mice. Moreover, Dr. Dhar found that CD44 knockout mice are resistant to DEN induced HCC. Unlike wild-type mice CD44-/- mice contained very small premalignant lesions with very few HPC. This strongly implicates the functional importance of CD44 in an early step of HCC pathogenesis with critical signaling and other functional abilities that are crucial for malignant conversion.
Aims: In the proposed study Dr. Dhar will, (1) define the mechanistic role of CD44 in HCC development, (2) Identify the CD44 isoform that is required for HCC development. (3) Investigate the mechanisms that control CD44 expression.
Dr. Dhar’s current study is based on their ability to identify and isolate an earlier type of progenitor cell that can give rise to HCC and his unique ability to separate the process of tumor initiation from tumor progression using a transplantation system to MUP-uPA mice. Both wild-type and CD44-/- mice will be used to understand the role of CD44 in vivo. Lentivirus shRNA mediated knockdown of specific genes, use of pharmacological inhibitors for specific pathways and over-expression using Lentivirus will be used to dissect the molecular pathways. CD44 mediated signaling will be assessed by Immunoblotting, Immunoprecipitation, Immunohistochemistry and Immunofluorescence.
Dr. Dhar anticipates that CD44 expression in hepatocytes is induced soon after DEN induced inflammatory damage that provides the CD44 expressing cells with growth advantage by modulating key transcription factors such as STAT3 and b-catenin and also by signaling through c-Met and EGFR. Absence of CD44 might predispose the cells to apoptosis. Production of inflammatory cytokines and growth factors by Kupffer cells in response to DEN may also depend on CD44. This study will generate insight into molecular pathways affected by the presence/absence of CD44 and will provide novel targets for HCC treatment and prevention.