Notch signaling is activated in human hepatocellular carcinoma and induces tumor formation in mice
- PMID: 22974708
- PMCID: PMC3505826
- DOI: 10.1053/j.gastro.2012.09.002
Notch signaling is activated in human hepatocellular carcinoma and induces tumor formation in mice
Abstract
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 α-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 3 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 γ-secretase inhibitors or by expressing a dominant negative form of mastermind-like 1 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.
Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.
Figures
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Comment in
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Notch signaling in hepatocellular carcinoma: guilty in association!Gastroenterology. 2012 Dec;143(6):1430-4. doi: 10.1053/j.gastro.2012.10.025. Epub 2012 Oct 22. Gastroenterology. 2012. PMID: 23099244 Free PMC article. No abstract available.
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Notch-driven carcinogenesis: the merging of hepatocellular cancer and cholangiocarcinoma into a common molecular liver cancer subtype.J Hepatol. 2013 Jun;58(6):1244-5. doi: 10.1016/j.jhep.2013.01.017. Epub 2013 Jan 23. J Hepatol. 2013. PMID: 23352938 Free PMC article.
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