Home » Key Scientific Articles » IL-23 is pro-proliferative, epigenetically regulated and modulated by chemotherapy in non-small cell lung cancer.

IL-23 is pro-proliferative, epigenetically regulated and modulated by chemotherapy in non-small cell lung cancer.

Baird AM, Leonard J, Naicker KM, Kilmartin L, O’Byrne KJ, Gray SG.

Lung Cancer. 2013 Jan;79(1):83-90.

 

Thoracic Oncology Research Group, Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland. [email protected].

 

Abstract

BACKGROUND:

IL-23 is a member of the IL-6 super-family and plays key roles in cancer. Very little is currently known about the role of IL-23 in non-small cell lung cancer (NSCLC).

METHODS:

RT-PCR and chromatin immunopreciptiation (ChIP) were used to examine the levels, epigenetic regulation and effects of various drugs (DNA methyltransferase inhibitors, Histone Deacetylase inhibitors and Gemcitabine) on IL-23 expression in NSCLC cells and macrophages. The effects of recombinant IL-23 protein on cellular proliferation were examined by MTT assay. Statistical analysis consisted of Student’s t-test or one way analysis of variance (ANOVA) where groups in the experiment were three or more.

RESULTS:

In a cohort of primary non-small cell lung cancer (NSCLC) tumours, IL-23A expression was significantly elevated in patient tumour samples (p < 0.05). IL-23A expression is epigenetically regulated through histone post-translational modifications and DNA CpG methylation. Gemcitabine, a chemotherapy drug indicated for first-line treatment of NSCLC also induced IL-23A expression. Recombinant IL-23 significantly increased cellular proliferation in NSCLC cell lines.

CONCLUSIONS:

These results may therefore have important implications for treating NSCLC patients with either epigenetic targeted therapies or Gemcitabine.

Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

 

Go To PubMed

 

Additional Information

Due to the massive global burden of lung cancer in both smoking and non-smoking individuals, and in particular the dramatic rise in the disease in never smokers, there is an urgent need to identify new biomarkers and novel druggable targets to improve therapeutic options and increase survival rates. Smoking results in inflammation of the lung and individuals who smoke, or have a previous history of benign inflammatory lung disease, are more likely to develop lung cancer even in the absence of tobacco use. To this end inflammatory mediators may provide a significant innovative therapeutic avenue in this disease.

Interleukin (IL)-23A is one such inflammatory mediator, which may play a role in lung cancer development. It is a hetero-dimeric cytokine composed of two covalently linked subunits consisting of p19 and p40. IL-23A plays a key role in chronic inflammation and angiogenesis through the promotion of IL-17 production by T helper 17 cells via the STAT pathway and NF-κB. This study sought to determine the expression and regulation of IL-23A in non small cell lung cancer (NSCLC).

IL-23A expression levels were determined in a series of 34 tumour specimens with matched normal tissue taken from patients presenting with early stage NSCLC. Basal expression levels were also examined in a panel of normal and NSCLC cell lines at the mRNA level. Using histone deacetylase (HDi), DNA methyltransferase (DNMTi) inhibitors and a ChIP assay it was determined if IL-23A was subject to epigenetic regulation in NSCLC cell lines. The effect of Gemcitabine on IL-23A expression was also studied. In addition, the effect of recombinant IL-23 treatment on NSCLC cell line proliferation was examined.

In a cohort of NSCLC patients, IL-23A levels were significantly elevated in tumour tissue compared with normal (p<0.05). Treatment with TSA (p<0.05) and SAHA (Vorinostat) (p<0.05) induced the expression of IL-23A in the A549 and SK-MES-1 cell lines. A ChIP assay confirmed dynamic remodelling of the IL-23A promoter region. Significant induction of IL-23A was also evident post treatment with a DNMTi (5-Aza-2’-Deoxycytidine) and Gemcitabine. Furthermore, treatment with recombinant IL-23 increased cellular proliferation in the NSCLC cell lines.              

IL-23A was significantly elevated in a cohort of NSCLC patient tissues and is epigenetically regulated through histone post-translational modifications and DNA CpG residue methylation. The chemotherapy agent, Gemcitabine, also induced IL-23A expression. Additionally, IL-23 promoted NSCLC cellular proliferation. These results may have important implications for treating NSCLC patients with epigenetic targeted therapies or Gemcitabine.