A Novel Role of Interleukin-13 Receptor α2 in Pancreatic Cancer Invasion and Metastasis

Whereas interleukin-13 receptor alpha 2 chain (IL-13R alpha 2) is over-expressed in a variety of human solid cancers including pancreatic cancer, we investigated its significance in cancer invasion and metastasis. We used two pancreatic cancer cell lines, IL-13R alpha 2-negative HPAF-H and IL-13R alpha 2-positive HS766T, and generated IL-13Ra2 stably transfected HPAF-II as well as IL-13Ra2 RNA interference knocked-down HS766T cells. Ability of invasion and signal transduction was compared between IL-13R alpha 2-negative and IL-13R alpha 2-positive cells and tumor metastasis was assessed in murine model for human pancreatic cancer with orthotopic implantation of tumors. IL-13 treatment enhanced cell invasion in IL13R alpha 2-positive cancer cell lines but not in IL-13R alpha 2-negative cell lines. Furthermore, gene transfer of IL-13R alpha 2 in negative cell lines enhanced invasion, whereas its silencing downmodulated invasion of pancreatic cell lines in a Matrigel invasion assay. In vivo study revealed that II-13R alpha 2-positive cancer metastasized to lymph nodes, liver, and peritoneum at. a significantly higher rate compared with IL-13R alpha 2-negative tumors. The expression of IL-13R alpha 2 in metastatic lesions was found to be increased compared with primary tumors, and mice with IL-13R alpha 2-positive cancer displayed cachexia and poor prognosis. Invasion and metastasis also correlated with increased matrix metalloproteinase protease activity in these cells. Mechanistically, IL-13 activated extracellular signal-regulated kinase 1/2 and activator protein-1 nuclear factors in IL-13R alpha 2-positive pancreatic cancer cell lines but not in IL-13R alpha 2-negative cell lines. Taken together, our results show for the first time that IL-13 can signal through IL-13R alpha 2 in pancreatic cancer cells and IL-13Ra2 may serve as a prognostic biomarker of invasion and metastasis in pancreatic cancer. [Cancer Res 2009;69(22):8678-85]