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A Novel Role of Interleukin-13 Receptor 2 in Pancreatic Cancer Invasion and Metastasis

¹ Tumor Vaccines and Biotechnology Branch, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland and ² Gastroenterology Division, Yokohama City University Graduate School of Medicine, Yokohama, Japan

Requests for reprints: Raj K. Puri, Tumor Vaccines and Biotechnology Branch, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, NIH Building 29B, Room 2NN20 HFM-735, 29 Lincoln Drive, Bethesda, MD 20892. Phone: 301-827-0471; Fax: 301-827-0449; E-mail: raj.puri{at}fda.hhs.gov.

Whereas interleukin-13 receptor 2 chain (IL-13R2) is overexpressed 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-13R2–negative HPAF-II and IL-13R2–positive HS766T, and generated IL-13R2 stably transfected HPAF-II as well as IL-13R2 RNA interference knocked-down HS766T cells. Ability of invasion and signal transduction was compared between IL-13R2–negative and IL-13R2–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 IL-13R2–positive cancer cell lines but not in IL-13R2–negative cell lines. Furthermore, gene transfer of IL-13R2 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 IL-13R2–positive cancer metastasized to lymph nodes, liver, and peritoneum at a significantly higher rate compared with IL-13R2–negative tumors. The expression of IL-13R2 in metastatic lesions was found to be increased compared with primary tumors, and mice with IL-13R2–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-13R2–positive pancreatic cancer cell lines but not in IL-13R2–negative cell lines. Taken together, our results show for the first time that IL-13 can signal through IL-13R2 in pancreatic cancer cells and IL-13R2 may serve as a prognostic biomarker of invasion and metastasis in pancreatic cancer. [Cancer Res 2009;69(22):8678–85]

Key Words: IL-13R2 • Metastasis • Pancreatic cancer • MMPs • ERK1/2