Abstract
We screened 124 genes that are amplified in human hepatocellular carcinoma (HCC) using a mouse hepatoblast model and identified 18 tumor-promoting genes, including CCND1 and its neighbor on 11q13.3, FGF19. Although it is widely assumed that CCND1 is the main driving oncogene of this common amplicon (15% frequency in HCC), both forward-transformation assays and RNAi-mediated inhibition in human HCC cells established that FGF19 is an equally important driver gene in HCC. Furthermore, clonal growth and tumorigenicity of HCC cells harboring the 11q13.3 amplicon were selectively inhibited by RNAi-mediated knockdown of CCND1 or FGF19, as well as by an anti-FGF19 antibody. These results show that 11q13.3 amplification could be an effective biomarker for patients most likely to respond to anti-FGF19 therapy.
Copyright © 2011 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Monoclonal / immunology
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Antibodies, Monoclonal / pharmacology
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Carcinoma, Hepatocellular / drug therapy
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Carcinoma, Hepatocellular / genetics*
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Carcinoma, Hepatocellular / pathology
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Chromosomes, Human, Pair 11 / genetics
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Cyclin D1 / genetics
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Cyclin D1 / metabolism
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Female
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Fibroblast Growth Factors / genetics*
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Fibroblast Growth Factors / immunology
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Fibroblast Growth Factors / metabolism
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Gene Amplification
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Gene Expression Regulation, Neoplastic
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Genetic Predisposition to Disease
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Genomics / methods
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Humans
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Immunoblotting
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Liver Neoplasms / drug therapy
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Liver Neoplasms / genetics*
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Liver Neoplasms / pathology
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Mice
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Mice, Nude
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Oncogene Proteins / genetics*
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Oncogene Proteins / metabolism
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RNA Interference
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Tumor Burden / drug effects
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Xenograft Model Antitumor Assays
Substances
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Antibodies, Monoclonal
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FGF19 protein, human
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Oncogene Proteins
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Cyclin D1
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Fibroblast Growth Factors