title: Autocrine production of IL-11 mediates tumorigenicity in hypoxic cancer cells.
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.
authors.affiliation: Developmental Therapeutics Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Onnis
authors.forename: Nicole
authors.initials: N
authors.lastname: Fer
authors.forename: Annamaria
authors.initials: A
authors.lastname: Rapisarda
authors.forename: Victor S
authors.initials: VS
authors.lastname: Perez
authors.forename: Giovanni
authors.initials: G
authors.lastname: Melillo
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism; D019898:Autocrine Communication; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology; D001665:Binding Sites; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000235:genetics / Q000378:metabolism; D015687:Cell Hypoxia; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D045325:HCT116 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology; D017370:Interleukin-11 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D053703:Interleukin-11 Receptor alpha Subunit / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D020935:MAP Kinase Signaling System; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D034622:RNA Interference; D020218:Response Elements; D050794:STAT1 Transcription Factor / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000502:physiology; D015533:Transcriptional Activation; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000502:physiology; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D000951:Antigens, Neoplasm; D051792:Basic Helix-Loop-Helix Proteins; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017370:Interleukin-11; D053703:Interleukin-11 Receptor alpha Subunit; D050794:STAT1 Transcription Factor; D018808:Transcription Factor AP-1; D042461:Vascular Endothelial Growth Factor A; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human; C508611:IL11 protein, human; C508428:IL11RA protein, human; C494079:STAT1 protein, human; C467484:VEGFA protein, human; C089226:CA9 protein, human; C497446:VHL protein, human
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