Abstract
Abstract INTRODUCTION: Notch is an evolutionary conserved pathway essential for embryonic development and tissue renewal in metazoan. It plays a key role in liver development by regulating hepatic progenitor cell differentiation. Dysregulation of Notch pathway is found in several cancers, while there are few data regarding its role in hepatocarcinogenesis. AIMS: (1) To study Notch dysregulation in human hepatocellular carcinoma (HCC), and (2) to determine the oncogenic capacity of constitutive Notch activation in transgenic mice. METHODS: Eighteen key Notch pathway genes were evaluated in human samples covering the whole spectrum of human hepatocarcinogenesis (normal liver, cirrhosis, dysplasia and HCC) for DNA copy number changes (Affymetrix 238K, 132 samples) and mRNA levels (Affymetrix U133, 132 samples – Illumina DASL, 164 samples). Notch1 mutation analysis was performed in 50 human HCC samples using Sanger sequencing (GENEWIZ, Inc.). A knock in mouse line carrying the mouse Notch1 intracellular domain (NICD) inserted in the Rosa26 locus downstream of a floxed Neo/STOP codon was crossed with an AFP/albumin-Cre transgenic mouse line. To generate a Notch activation gene signature, we compared the transcriptome of control and transgenic liver samples. The presence of the Notch activation signature was evaluated in human HCC (225 samples) and intrahepatic cholangiocarcinoma (ICC) (149 samples) using the nearest template prediction method. CK19 staining and histopathological features were evaluated by a pathologist in paraffin embedded liver samples from control and transgenic mice. RESULTS: Several Notch genes were significantly up-regulated (corrected p-value<0.05) in human HCC when compared to normal liver, including ligands (JAG1, JAG2), putative targets/modifiers (DTX2, HEY1, SOX9, SPP1), and effectors (MAML1). Among them, HEY locus exhibited DNA gains that correlated with gene expression (p<0.009). Up-regulation of HEY1 (median 2.3 fold-increase), a Notch target, was significantly enriched in the “Proliferation” class of HCC molecular classification (Chiang et al. Cancer Res 2008). Notch1 was mutated in 4% of the human HCC samples (2/50) comprising exons 27 and 34. Notch activation signature significantly captured 15% of human HCCs and ICCs. In vivo activation of Notch in transgenic mice induced liver tumors with high frequency, reaching 100% at >10 months (11/11). Predominant tumor type was HCC, although 30% showed a mixed pattern with progenitor-like cells and CK19 positive staining (3/10). CONCLUSIONS: Notch pathway is significantly dysregulated in human HCC. Genetically engineered mice with constitutive activation of Notch1 undergo liver oncogenesis, suggesting that Notch behaves as an oncogene in liver cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2410. doi:10.1158/1538-7445.AM2011-2410
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