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 7

STAT1 and p38 mediate IL-11–dependent responses under hypoxia.

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STAT1 and p38 mediate IL-11–dependent responses under hypoxia. (A) PC3-s...
(A) PC3-stable STAT1 knockdown cells were generated using lentiviral vectors expressing the corresponding shRNA. Total protein lysates were prepared and analyzed using Western blot analysis as described in the Methods. Actin was assessed as an internal control. (B) PC3 NC and STAT1KD#5 cells were cultured under normoxic conditions for 24 hours and then plated. Colonies were stained after 10 days (mean ± SEM of 3 independent experiments). (C) PC3 NC and STAT1KD#5 cells were cultured under normoxic or hypoxic conditions for 24 hours and then plated in soft agar. Results shown are the average of 2 independent experiments (t test; ***P < 0.0001). (D) PC3 cells were serum starved for 24 hours and treated with SB203580 (10 μM), a known p38 inhibitor, for an additional 48 hours under normoxia or hypoxia. Protein lysates were prepared and analyzed using Western blot analysis as described in the Methods. Actin was assessed as an internal control. Results shown are a representative experiment of 3 independent experiments.