Autocrine production of IL-11 mediates tumorigenicity in hypoxic cancer cells.
IL-11 and its receptor, IL-11Ra, are expressed in human cancers; however, the functional role of IL-11 in tumor progression is not known. We found that IL11 is a hypoxia-inducible, VHL-regulated gene in human cancer cells and that expression of IL11 mRNA was dependent, at least in part, on HIF-1. A ... cooperative interaction between HIF-1 and AP-1 mediated transcriptional activation of the IL11 promoter. Additionally, we found that human cancer cells expressed a functional IL-11Ra subunit, which triggered signal transduction either by exogenous recombinant human IL-11 or by autocrine production of IL-11 in cells cultured under hypoxic conditions. Silencing of IL11 dramatically abrogated the ability of hypoxia to increase anchorage-independent growth and significantly reduced tumor growth in xenograft models. Notably, these results were phenocopied by partial knockdown of STAT1 in a human prostate cancer cell line (PC3), suggesting that this pathway may play an important role in mediating the effects of IL-11 under hypoxic conditions. In conclusion, these results identify IL11 as an oxygen- and VHL-regulated gene and provide evidence of a pathway "hijacked" by hypoxic cancer cells that may contribute to tumor progression.
Mesh Terms:
Animals, Antigens, Neoplasm, Autocrine Communication, Basic Helix-Loop-Helix Transcription Factors, Binding Sites, Carbonic Anhydrase IX, Carbonic Anhydrases, Cell Hypoxia, Cell Proliferation, Cell Transformation, Neoplastic, Female, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, HCT116 Cells, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Interleukin-11, Interleukin-11 Receptor alpha Subunit, MAP Kinase Signaling System, Mice, Mice, Nude, Neoplasm Transplantation, Phosphorylation, Protein Processing, Post-Translational, RNA Interference, Response Elements, STAT1 Transcription Factor, Transcription Factor AP-1, Transcriptional Activation, Vascular Endothelial Growth Factor A, Von Hippel-Lindau Tumor Suppressor Protein
Animals, Antigens, Neoplasm, Autocrine Communication, Basic Helix-Loop-Helix Transcription Factors, Binding Sites, Carbonic Anhydrase IX, Carbonic Anhydrases, Cell Hypoxia, Cell Proliferation, Cell Transformation, Neoplastic, Female, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, HCT116 Cells, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Interleukin-11, Interleukin-11 Receptor alpha Subunit, MAP Kinase Signaling System, Mice, Mice, Nude, Neoplasm Transplantation, Phosphorylation, Protein Processing, Post-Translational, RNA Interference, Response Elements, STAT1 Transcription Factor, Transcription Factor AP-1, Transcriptional Activation, Vascular Endothelial Growth Factor A, Von Hippel-Lindau Tumor Suppressor Protein
J. Clin. Invest.
Date: Apr. 01, 2013
PubMed ID: 23549086
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