Reactive Oxygen Species-Induced CXCL8 in Ovarian Cancer

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Recent studies have shown that increased levels of reactive oxygen species (ROS) play an important role in the biology of high grade serous ovarian carcinoma (HGSOC), but the precise mechanisms for the involvement of ROS have not yet been elucidated. Our preliminary findings revealed that higher levels of ROS induced expression of CXCL8 and inactivation of GSK-3b in ovarian cancer cell lines and primary human tumor tissues. Increased expression of CXCL8, as well as elevated levels of the cognate receptors, CXCR1/2, in HGSOC tissues have been associated with an unfavorable clinical course. We hypothesize that ROS regulate CXCL8 expression to mediate tumor growth and angiogenesis in which CXCL8 plays a significant role as a paracrine factor for promoting angiogenesis, and, potentially as an autocrine growth factor for increasing proliferation. To test this hypothesis, we propose to perform the following three aims. In Aim 1, we will use a mouse orthotopic xenograft model to determine the role and mechanism by which ROS induce CXCL8 expression in tumor cells via phosphorylation of GSK-3b, resulting in inactivation of its negative regulation of tumor growth. Modulation of expression levels of ROS, CXCL8 and active GSK- 3b in tumor cells will obtained by expression of catalase, CXCL8 knockdown or over-expression, and expression of constitutively active or dominant negative GSK-3b. In Aim 2, we will determine the paracrine and autocrine effects of CXCL8 in ROS-induced tumor growth and angiogenesis using a humanized chimeric tumor model in which human endothelial cells (EC) and human cancer cells are co-implanted via porous PLGA sponges in vivo. The effect on tumor growth and angiogenesis of the knockdown of CXCR1 and CXCR2 in EC and tumor cells (separately or simultaneously) will be investigated. In Aim 3, we will determine levels and correlations of ROS, CXCL8, and GSK-3b phosphorylation/inactivation or/and activities with tumor stages and survival in patients with HGSOC in a panel of primary human tumor tissues (with clinical annotation). This study will provide important insights into a new molecular mechanism for the regulation of ovarian tumor biology via CXCL8, and may reveal the future potential for the ROS/GSK-3b/CXCL8 signaling pathway to serve as novel therapeutic target for HGSOC.
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