Jagged1 DNA Copy Number Variation Is Associated with Poor Outcome in Liver Cancer

• Published in: The American journal of pathology Vol. 186; no. 8; pp. 2055 - 2067
• Main Authors: Kawaguchi, Kazunori, Honda, Masao, Yamashita, Taro, Okada, Hikari, Shirasaki, Takayoshi, Nishikawa, Masashi, Nio, Kouki, Arai, Kuniaki, Sakai, Yoshio, Yamashita, Tatsuya, Mizukoshi, Eishiro, Kaneko, Shuichi
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2016
• Subjects: Adult; Aged; Aged, 80 and over; Animals; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - mortality; DNA Copy Number Variations - genetics; Female; Humans; Jagged-1 Protein - genetics; Kaplan-Meier Estimate; Liver Neoplasms - genetics; Liver Neoplasms - mortality; Male; Mice; Mice, Inbred NOD; Mice, SCID; Middle Aged; Oligonucleotide Array Sequence Analysis; Pathology; Real-Time Polymerase Chain Reaction
• ISSN: 0002-9440; 1525-2191
• DOI: 10.1016/j.ajpath.2016.04.011

Notch signaling abnormalities are reported to be involved in the acceleration of malignancy in solid tumors and stem cell formation or regeneration in various organs. We analyzed specific genes for DNA copy number variations in liver cancer cells and investigated whether these factors relate to clinical outcome. Chromosome 20p, which includes the ligand for Notch pathways, Jagged1, was found to be amplified in several types of hepatoma cells, and its mRNA was up-regulated according to α-fetoprotein gene expression levels. Notch inhibition using Jagged1 shRNA and γ-secretase inhibitors produced significant suppression of cell growth in α-fetoprotein–producing cells with suppression of downstream genes. Using in vivo hepatoma models, the administration of γ-secretase inhibitors resulted in reduced tumor sizes and effective Notch inhibition with widespread apoptosis and necrosis of viable tumor cells. The γ-secretase inhibitors suppressed cell growth of the epithelial cell adhesion molecule–positive fraction in hepatoma cells, indicating that Notch inhibitors could suppress the stem cell features of liver cancer cells. Even in clinical liver cancer samples, the expression of α-fetoprotein and Jagged1 showed significant correlation, and amplification of the copy number of Jagged1 was associated with Jagged1 mRNA expression and poor survival after liver cancer surgical resection. In conclusion, amplification of Jagged1 contributed to mRNA expression that activates the Jagged1-Notch signaling pathway in liver cancer and led to poor outcome.