A novel role of interleukin-13 receptor alpha2 in pancreatic cancer invasion and metastasis.
Whereas interleukin-13 receptor alpha2 chain (IL-13Ralpha2) 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-13Ralpha2-negative HPAF-II and IL-13Ralpha2-positive HS766T, and generated IL-13Ralpha2 stably transfected HPAF-II as well as IL-13Ralpha2 RNA interference knocked-down HS766T cells. Ability of invasion and signal transduction was compared between IL-13Ralpha2-negative and IL-13Ralpha2-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-13Ralpha2-positive cancer cell lines but not in IL-13Ralpha2-negative cell lines. Furthermore, gene transfer of IL-13Ralpha2 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-13Ralpha2-positive cancer metastasized to lymph nodes, liver, and peritoneum at a significantly higher rate compared with IL-13Ralpha2-negative tumors. The expression of IL-13Ralpha2 in metastatic lesions was found to be increased compared with primary tumors, and mice with IL-13Ralpha2-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-13Ralpha2-positive pancreatic cancer cell lines but not in IL-13Ralpha2-negative cell lines. Taken together, our results show for the first time that IL-13 can signal through IL-13Ralpha2 in pancreatic cancer cells and IL-13Ralpha2 may serve as a prognostic biomarker of invasion and metastasis in pancreatic cancer.
Fujisawa
Toshio
T
Tumor Vaccines and Biotechnology Branch, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892, USA.
Joshi
Bharat
B
Nakajima
Atsushi
A
Puri
Raj K
RK
D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis; D015153:Blotting, Western; D045744:Cell Line, Tumor; D005260:Female; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D006801:Humans; D053663:Interleukin-13 Receptor alpha2 Subunit / Q000235:genetics / Q000378:metabolism*; D020782:Matrix Metalloproteinases / Q000096:biosynthesis; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011379:Prognosis; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000096:biosynthesis; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
D014408:Biomarkers, Tumor; D053663:Interleukin-13 Receptor alpha2 Subunit; D018808:Transcription Factor AP-1; D020782:Matrix Metalloproteinases