Abstract 343: The homeobox gene DLX4 promotes inflammatory signaling and peritoneal metastasis of ovarian cancer

Abstract

Abstract The lethality of ovarian cancer stems from the propensity of the disease to involve the peritoneal cavity. However, the mechanisms that drive peritoneal metastasis of ovarian cancer are poorly understood. We previously identified that high expression of the homeobox gene DLX4 in ovarian cancer is strongly associated with advanced disease stage and reduced survival. In this study, we identified that DLX4 stimulates the attachment of ovarian cancer cells to mesothelial cells that line the peritoneal cavity. DLX4 induced expression of the cell adhesion molecule CD44 which interacts with hyaluronic acid, a glycosaminoglycan that is produced by peritoneal mesothelial cells. Neutralization of CD44 abrogated the ability of DLX4 to stimulate tumor-mesothelial cell interactions. The induction of CD44 expression by DLX4 was found to be largely due to the ability of DLX4 to transcriptionally activate the gene encoding the pro-inflammatory cytokine interleukin-1beta (IL-1beta) which in turn stimulated the nuclear factor kappa B (NF-kB) signaling pathway. Furthermore, inhibition of IL-1beta or of NF-kB activity abrogated the stimulatory effect of DLX4 on tumor-mesothelial cell interactions. This study provides insights into the mechanisms of inflammatory signaling and peritoneal metastasis of ovarian cancer, and raises the possibility that targeting inflammatory signaling might be a strategy for treatment of advanced-stage ovarian cancer. Citation Format: Dhwani Haria, Bon Q. Trinh, Song Yi Ko, Nicolas Barengo, Honami Naora. The homeobox gene DLX4 promotes inflammatory signaling and peritoneal metastasis of ovarian cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 343. doi:10.1158/1538-7445.AM2015-343