Jagged-1 and Notch3 juxtacrine loop regulates ovarian tumor growth and adhesion.
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 gamma-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.
Choi
Jung-Hye
JH
Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.
Park
Joon T
JT
Davidson
Ben
B
Morin
Patrice J
PJ
Shih
Ie-Ming
IeM
Wang
Tian-Li
TL
D002135:Calcium-Binding Proteins / Q000502:physiology*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D000072100:Jagged-1 Protein; D008024:Ligands; D008565:Membrane Proteins / Q000502:physiology*; D008954:Models, Biological; D010051:Ovarian Neoplasms / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000378:metabolism / Q000502:physiology*; D000072099:Serrate-Jagged Proteins
D002135:Calcium-Binding Proteins; D004791:Enzyme Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; D000072100:Jagged-1 Protein; D008024:Ligands; D008565:Membrane Proteins; C499374:NOTCH3 protein, human; D000071656:Receptor, Notch3; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins