Journal
JOURNAL OF HEPATOLOGY
Volume 58, Issue 6, Pages 1244-1245Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jhep.2013.01.017
Keywords
Phenotype; Genotype; Oncogenic pathway; NICD; SOX19; CK19; HPC
Categories
Funding
- NIDDK NIH HHS [P30 DK084567, DK59427, R01 DK059427, T32 DK007198] Funding Source: Medline
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Background & Aims: The Notch signaling pathway is activated in leukemia and solid tumors (such as lung cancer), but little is known about its role in liver cancer. Methods: The intracellular domain of Notch was conditionally expressed in hepatoblasts and their progeny (hepatocytes and cholangiocytes) in mice. This was achieved through Cre expression under the control of an albumin and alpha-fetoprotein (AFP) enhancer and promoter (AFP-Notch intracellular domain [NICD]). We used comparative functional genomics to integrate transcriptome data from AFP-NICD mice and human hepatocellular carcinoma (HCC) samples (n = 683). A Notch gene signature was generated using the nearest template prediction method. Results: AFP-NICD mice developed HCC with 100% penetrance when they were 12 months old. Activation of Notch signaling correlated with activation of three promoters of insulin-like growth factor 2; these processes appeared to contribute to hepatocarcinogenesis. Comparative functional genomic analysis identified a signature of Notch activation in 30% of HCC samples from patients. These samples had altered expression in Notch pathway genes and activation of insulin-like growth factor signaling, despite a low frequency of mutations in regions of NOTCH1 associated with cancer. Blocking Notch signaling in liver cancer cells with the Notch activation signature using gamma-secretase inhibitors or by expressing a dominant negative form of mastermind-like I reduced their proliferation in vitro. Conclusions: Notch signaling is activated in human HCC samples and promotes formation of liver tumors in mice. The Notch signature is a biomarker of response to Notch inhibition in vitro. (C) 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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