The DOI matches its Crossref record; 52 of the 52 references it cites were found in a registry or an index.
Notch Signaling Is Activated in Human Hepatocellular Carcinoma and Induces Tumor Formation in Mice
Open accessAbstract
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, through Cre expression, under the control of an albumin and α-fetoprotein enhancer and promoter (AFP-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 (Igf2); 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 IGF 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 MAML 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.
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The roles of signaling pathways in bone repair and regeneration
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“Thus, YAP-dependent activation of the Jag-1/Notch pathway in these mice is probably relevant for the formation of HCC.5,8,32,35 YAP regulates target gene transcription in tumor and non-malignantly transformed cells through interaction with different transcription factors including TEAD family members.18 Our results de…”
Metadata
- Authors
- Villanueva, A., Alsinet, C., Yanger, K., Hoshida, Y., Zong, Y., Toffanin, S., Rodriguez–Carunchio, L., Solé, M., Thung, S., Stanger, B. Z., & Llovet, J. M.
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2012-12
- Volume
- 143
- Issue
- 6
- Pages
- 1660-1669.e7
- ISSN
- 0016-5085 (ISSN-L)
- OpenAlex
- W1966731849
- Cited by
- 318
- References
- 52
- FWCI
- 9.41
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Villanueva, A., Alsinet, C., Yanger, K., Hoshida, Y., Zong, Y., Toffanin, S., Rodriguez–Carunchio, L., Solé, M., Thung, S., Stanger, B. Z., & Llovet, J. M. (2012). Notch Signaling Is Activated in Human Hepatocellular Carcinoma and Induces Tumor Formation in Mice. Gastroenterology. https://doi.org/10.1053/j.gastro.2012.09.002
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