Journal
GENES & DEVELOPMENT
Volume 31, Issue 11, Pages 1109-1121Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.296640.117
Keywords
PRKCI; YAP; ovarian cancer
Categories
Funding
- Ann and Sol Schreiber Mentored Investigator Award [POE/DF/02.2011]
- OCRF, Inc.
- Foundation for Women's Cancer, and Cancer Prevention [RP101502, RP101489, P50CA083639]
- Israeli Science Foundation
- European Commission
- Israeli Cancer Association
- Dr. Miriam and Sheldon Adelson Medical Research Foundation (AMRF)
- Honorable Tina Brozman Foundation
- Robert and Debra First Fund
- Department of Obstetrics and Gynecology at the University Of Pennsylvania Perelman School of Medicine
- National Institutes of Health [CA083639, UH3TR000943]
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A key feature of high-grade serous ovarian carcinoma (HGSOC) is frequent amplification of the 3q26 locus harboring PRKC-t (PRKCI). Here, we show that PRKCI is also expressed in early fallopian tube lesions, called serous tubal intraepithelial carcinoma. Transgenic mouse studies establish PRKCI as an ovarian cancer-specific oncogene. Mechanistically, we show that the oncogenic activity of PRKCI relates in part to the up-regulation of TNF alpha to promote an immune-suppressive tumor microenvironment characterized by an abundance of myeloid-derived suppressor cells and inhibition of cytotoxic T-cell infiltration. Furthermore, system-level and functional analyses identify YAP1 as a downstream effector in tumor progression. In human ovarian cancers, high PRKCI expression also correlates with high expression of TNF alpha and YAP1 and low infiltration of cytotoxic T cells. The PRKCI-YAP1 regulation of the tumor immunity provides a therapeutic strategy for highly lethal ovarian cancer.
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