IL-13 regulates cancer invasion and metastasis through IL-13Rα2 via ERK/AP-1 pathway in mouse model of human ovarian cancer

Previously, we have demonstrated that a variety of human cancers including the ovarian cancer express IL‐13Rα2, a high affinity receptor for IL‐13. Herein, we have examined if IL‐13 regulates invasion and metastasis of ovarian cancer through IL‐13Rα2 in vitro and in vivo in animal models of human ovarian cancer. We tested cell invasion and protease activity in IL‐13Rα2‐overexpressing and IL‐13Rα2‐negative ovarian tumor cell lines. IL‐13 treatment significantly augmented both cell invasion and enzyme activities in only IL‐13Rα2‐positive cells but not in IL‐13Rα2‐negative cells in vitro. Mechanistically, IL‐13 enhanced ERK1/2, AP‐1 and MMP activities only in IL‐13Rα2‐positive cells but not in IL‐13Rα2‐negative cells. In contrast, other signaling pathways such as IRS1/2, PI3K and AKT do not seem to be involved in IL‐13 induced signaling in ovarian cancer cell lines. Highly specific inhibitors for MMP and AP‐1 efficiently inhibited both invasion and protease activities without impacting the basal level invasion and protease activities in vitro. In orthotopic animal model of human ovarian cancer, IL‐13Rα2‐positive tumors metastasized to lymph nodes and peritoneum earlier than IL‐13Rα2‐negative tumors. Interestingly, the IL‐13Rα2‐positive tumor bearing mice died earlier than mice with IL‐13Rα2‐negative tumor. Intraperitoneal injection of IL‐13 further shortened survival of IL‐13Rα2‐positive tumor bearing mice compared to IL‐13Rα2‐negative tumor mice. IL‐13Rα2‐positive tumors and lymph node metastasis expressed higher levels of MMPs and higher ERK1/2 activation compared to IL‐13Rα2‐negative tumors. Taken together, IL‐13Rα2 is involved in cancer metastasis through activation of ERK/AP‐1 and that targeting IL‐13Rα2 might not only directly kill primary tumors but also prevent cancer metastasis.