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Jagged-1 and Notch3 Juxtacrine Loop Regulates Ovarian Tumor Growth and Adhesion

Departments of ¹ Pathology, Oncology, Gynecology and Obstetrics, Johns Hopkins Medical Institutions; ² Laboratory of Cellular and Molecular Biology, National Institute on Aging, Baltimore, Maryland; ³ Department of Oriental Pharmacy, Kyung Hee University, Seoul, Korea; and ⁴ Department of Pathology, Radiumhospitalet-Rikshospitalet Medical Center, University of Oslo, Oslo, Norway

Requests for reprints: Tian-Li Wang, Departments of Gynecology and Obstetrics and Oncology, Johns Hopkins Medical Institutions, CRB-II, Room 306, 1550 Orleans Street, Baltimore, MD 21231. Phone: 410-502-0863; Fax: 410-502-7943; E-mail: tlw{at}jhmi.edu.

Key Words: Notch3 receptor • microenvironment • ovarian cancer • Notch receptor ligand • Jagged-1

Notch3 gene amplification and pathway activation have been reported in ovarian serous carcinoma. However, the primary Notch3 ligand that initiates signal transduction in ovarian cancer remains unclear. In this report, we identify Jagged-1 as the highest expressed Notch ligand in ovarian tumor cells as well as in peritoneal mesothelial cells that are in direct contact with disseminated ovarian cancer cells. Cell-cell adhesion and cellular proliferation were reduced in Notch3-expressing ovarian cancer cells that were cocultured with Jagged-1 knockdown mesothelial and tumor feeder cells. Interaction of Notch3-expressing ovarian cancer cells with Jagged-1–expressing feeder cells activated the promoter activity of candidate Notch3 target genes, and this activity was attenuated by Notch3 siRNA. Constitutive expression of the Notch3 intracellular domain significantly suppressed the Jagged-1 shRNA–mediated growth inhibitory effect. In Notch3-expressing ovarian cancer cells, Jagged-1–stimulating peptides enhanced cellular proliferation, which was suppressed by -secretase inhibitor and Notch3 siRNA. Taken together, our results show that Jagged-1 is the primary Notch3 ligand in ovarian carcinoma and Jagged-1/Notch3 interaction constitutes a juxtacrine loop promoting proliferation and dissemination of ovarian cancer cells within the intraperitoneal cavity. [Cancer Res 2008;68(14):5716–23]

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				J. T. Park, I.-M. Shih, and T.-L. Wang Identification of Pbx1, a Potential Oncogene, as a Notch3 Target Gene in Ovarian Cancer Cancer Res., November 1, 2008; 68(21): 8852 - 8860. [Abstract] [Full Text] [PDF]