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- Title
Autocrine production of IL-11 mediates tumorigenicity in hypoxic cancer cells.
- Authors
Onnis, Barbara; Fer, Nicole; Rapisarda, Annamaria; Perez, Victor S.; Melillo, Giovanni
- Abstract
IL-11 and its receptor, IL-11Rα, 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-11Rα 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.
- Subjects
INTERLEUKIN-11; CANCER genetics; CANCER cells; MESSENGER RNA; GENETIC transcription; PROMOTERS (Genetics); AUTOCRINE mechanisms; TUMOR growth
- Publication
Journal of Clinical Investigation, 2013, Vol 123, Issue 4, p1615
- ISSN
0021-9738
- Publication type
Article
- DOI
10.1172/JCI59623