150P - IL-23 is epigenetically regulated and induced by chemotherapy in NSCLC

Date 30 September 2012
Event ESMO Congress 2012
Session Poster presentation II
Topics Basic Science
Lung and other Thoracic Tumours
Presenter Anne-Marie Baird
Authors A. Baird, J. Leonard, L. Kilmartin, E. Dockry, K.J. O'Byrne, S.G. Gray
  • Clinical Medicine, Trinity College Dublin/St. James's Hospital, Dublin/IE

Abstract

Introduction

Inflammation plays a role in many malignant states including lung carcinogenesis. IL-23A is one such inflammatory mediator which may have a role in lung cancer. 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 signalling pathway and NF-?B. This study sought to determine the expression and regulation of IL-23A in NSCLC.

Methods

IL-23A expression levels were determined in a series of 34 tumour specimens with matched normal tissue taken from patients presenting with 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 (adenocarcinoma and squamous cell carcinoma). 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.

Results

In a cohort of NSCLC patients, IL-23A expression levels were significantly elevated in tumour tissue compared with normal (p < 0.05). This elevation was also evident within the NSCLC sub types. Treatment with TSA (p < 0.05) and SAHA (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 NSCLC cell lines that express functional IL-23R receptors.

Conclusion

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 cell line proliferation. These results may have important implications for treating NSCLC patients with epigenetic targeted therapies or Gemcitabine.

Disclosure

All authors have declared no conflicts of interest.