FUNCTIONS OF THE HOMEOBOX GENE DLX4 IN CONTROLLING INFLAMMATORY SIGNALING AND METASTASIS OF EPITHELIAL OVARIAN CANCER

Epithelial ovarian cancer (EOC) accounts for the most number of deaths among women with gynecological malignancies in the United States. Approximately 80% of EOC patients are diagnosed with disease that has disseminated beyond the confines of the ovaries. The five year survival rate for patients with advanced stage EOC is less than 30% and the recurrence of chemoresistant disease is high. Identifying the mechanisms that control peritoneal metastasis of EOC is therefore critical for improving treatment of advanced stage disease. The homeobox gene DLX4 encodes a transcription factor that is absent from most normal adult tissues. Previous studies from our laboratory have identified that DLX4 is highly expressed in advanced stage EOC and is strongly associated with reduced survival. The underlying hypothesis of my study is that DLX4 promotes peritoneal dissemination of EOC. The overall goal of my study is to determine the role and mechanisms of DLX4 in controlling peritoneal metastasis of EOC. My specific aims are: 1) to determine whether DLX4 promotes peritoneal dissemination of EOC, and 2) to identify the mechanisms by which DLX4 controls tumor–peritoneum interactions. Firstly, my studies have identified that DLX4 promotes EOC dissemination by inducing expression of the cell adhesion molecule CD44 which is a major receptor for hyaluronan, a glycosaminoglycan that is expressed on mesothelial cells lining the peritoneal cavity and abdominal organs. Secondly, my studies have identified that DLX4 induces CD44 expression by activating the pro-inflammatory cytokine interleukin 1-beta (IL-1β) which in turn stimulates the nuclear factor kappa B (NF-κB) signaling pathway. This study provides insights into the mechanisms of peritoneal metastasis of EOC and raises the possibility that targeting inflammatory signaling could be a strategy for treatment of advanced stage EOC