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 6

Phenotype and signaling effects in IL-11 knockdown HCT116 cells.

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Phenotype and signaling effects in IL-11 knockdown HCT116 cells. (A) HCT...
(A) HCT116 NC, IL-11KD#1, and IL-11KD#2 cells were generated using lentiviral vectors expressing the corresponding shRNA. Levels of IL11 mRNA expression were tested using quantitative RT-PCR in cells cultured under normoxic or hypoxic conditions for 24 hours. Results are expressed as fold increase relative to normoxic HCT116 NC cells. (B) HCT116 NC, IL-11KD#1, and IL-11KD#2 cells were cultured under normoxic or hypoxic conditions for 24 hours and then plated in soft agar. The graph reports the number of colonies detected after 13 days of growth in soft agar. Results shown are the average of 2 independent experiments (t test; *P < 0.05, **P < 0.001). (C) HCT116 NC, IL-11KD#1, and IL-11KD#2 cells were cultured under normoxic or hypoxic conditions for 24 hours and then plated. Colonies were stained after 10 days (mean ± SEM of 2 independent experiments). (D) Left: HCT116 NC, IL-11KD#1, and IL-11KD#2 cells were serum starved for 24 hours and cultured for an additional 48 hours under normoxic or hypoxic conditions. Levels of phosphorylated STAT1 (Ser727) and STAT3 (Ser 727 and Tyr705) were assessed using Western blot. Actin was assessed as an internal control. Right: HCT116 cells were serum starved for 24 hours and then incubated in normoxia for the indicated times in the presence of 100 ng/ml of rhIL-11. Levels of pSTAT1 (Ser727) and pSTAT3 (Ser 727 and Tyr705) were assessed using Western blot. Results shown are representative of 2 independent experiments.