Autocrine production of IL-11 mediates tumorigenicity in hypoxic cancer cells
Barbara Onnis, … , Victor S. Perez, Giovanni Melillo
Barbara Onnis, … , Victor S. Perez, Giovanni Melillo
Published March 15, 2013
Citation Information: J Clin Invest. 2013;123(4):1615-1629. https://doi.org/10.1172/JCI59623.
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Research Article Oncology

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

Barbara Onnis, Nicole Fer, Annamaria Rapisarda, Victor S. Perez, Giovanni Melillo

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Figure 2

HIF-1α and HIF-2α are involved in the hypoxic induction of IL11.

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HIF-1α and HIF-2α are involved in the hypoxic induction of IL11. (A) P...
(A) PC3 cells were transfected with either NC siRNA or smartpool siRNA targeting HIF-1α and HIF-2α (25 nM). Twenty-four hours after transfection, cells were cultured under normoxia or hypoxia for an additional 24 hours. Results are presented as fold change of hypoxic induction of IL11 mRNA expression, relative to normoxic PC3 cells transfected with NC siRNA, which is arbitrarily considered equal to 1 (mean ± SEM of 3 independent experiments; t test). (B) PC3 cells were transfected as described above and incubated under hypoxic conditions for an additional 24 hours. HIF-1α and HIF-2α protein levels were measured by Western blot analysis. (C) PC3 cells were cultured and transfected, and results are expressed as described in A (t test). (D) PC3 cells were treated with either DFX (100 μM) or DMOG (1 mM ) for 24 hours under normoxic conditions, and IL11 mRNA expression was assessed using quantitative RT-PCR. Results are expresses as mean ± SEM of 3 independent experiments (t test). *P < 0.05, **P < 0.01, ***P < 0.001.