NF-κB-Mediated CCL20 Reigns Dominantly in CXCR2-Driven Ovarian Cancer Progression.

Abstract

Ovarian cancer is an inflammation-associated malignancy with a high mortality rate. CXCR2 expressing ovarian cancers are aggressive with poorer outcomes. We previously demonstrated that CXCR2-driven ovarian cancer progression potentiated NF-κB activation through EGFR-transactivated Akt. Here, we identified the chemokine signature involved in CXCR2-driven ovarian cancer progression using a mouse peritoneal xenograft model for ovarian cancer spreading with CXCR2-negative (SKA) and positive (SKCXCR2) cells generated previously from parental SKOV-3 cells. Compared to SKA bearing mice, SKCXCR2 bearing mice had the following characteristics: 1) shorter survival time, 2) greater tumor spreading in the peritoneal cavity and 3) higher tumor weight in the omentum and pelvic site. Particularly, SKCXCR2-derived tumor tissues induced higher activation of the NF-κB signaling pathway, while having no change in EGFR-activated signaling such as Raf, MEK, Akt, mTOR and Erk compared to SKA-derived tumors. Chemokine PCR array revealed that CCL20 mRNA levels were significantly increased in SKCXCR2-derived tumor tissues. The CCL20 promoter activity was regulated by NF-κB dependent pathways. Interestingly, all three κB-like sites in the CCL20 promoter were involved in regulating CCL20 and the proximal region between -92 and -83 was the most critical κB-like site. In addition, SKCXCR2-derived tumor tissues maintained high CCL20 mRNA expression and induced greater CCL24 and CXCR4 compared to SKCXCR2 cells, indicating the shift of chemokine network during the peritoneal spreading of tumor cells via interaction with other cell types in tumor microenvironment. Furthermore, we compared expression profiling array between human ovarian cancer cell lines and tumor tissues based on GEO datasets. The expression profiles in comparison with cell lines revealed that dominant chemokines expressed in ovarian tumor tissues are likely shifted from CXCL1-3 and 8 to CCL20. Taken together, the progression of ovarian cancer in the peritoneal cavity involves NF-κB-mediated CCL20 as a main chemokine network, which is potentiated by CXCR2 expression.