Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Antigens, Neoplasm / genetics
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Antigens, Neoplasm / metabolism
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Autocrine Communication
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Basic Helix-Loop-Helix Transcription Factors / physiology
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Binding Sites
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Carbonic Anhydrase IX
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Carbonic Anhydrases / genetics
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Carbonic Anhydrases / metabolism
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Cell Hypoxia
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Cell Proliferation
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Cell Transformation, Neoplastic / metabolism*
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Female
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Gene Expression Regulation, Neoplastic*
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Gene Knockdown Techniques
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HCT116 Cells
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / physiology
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Interleukin-11 / genetics
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Interleukin-11 / metabolism*
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Interleukin-11 / physiology
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Interleukin-11 Receptor alpha Subunit / genetics
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Interleukin-11 Receptor alpha Subunit / metabolism*
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Interleukin-11 Receptor alpha Subunit / physiology
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MAP Kinase Signaling System
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Mice
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Mice, Nude
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Neoplasm Transplantation
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Phosphorylation
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Protein Processing, Post-Translational
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RNA Interference
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Response Elements
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STAT1 Transcription Factor / metabolism
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Transcription Factor AP-1 / physiology
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Transcriptional Activation
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Vascular Endothelial Growth Factor A / genetics
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Vascular Endothelial Growth Factor A / metabolism
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Von Hippel-Lindau Tumor Suppressor Protein / physiology
Substances
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Antigens, Neoplasm
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Basic Helix-Loop-Helix Transcription Factors
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HIF1A protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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IL11 protein, human
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IL11RA protein, human
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Interleukin-11
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Interleukin-11 Receptor alpha Subunit
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STAT1 Transcription Factor
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STAT1 protein, human
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Transcription Factor AP-1
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VEGFA protein, human
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Vascular Endothelial Growth Factor A
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endothelial PAS domain-containing protein 1
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Von Hippel-Lindau Tumor Suppressor Protein
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CA9 protein, human
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Carbonic Anhydrase IX
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Carbonic Anhydrases
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VHL protein, human