17P - Examination of EXOSC4 as a new prognostic marker and a novel therapeutic avenue in lung adenocarcinoma

Date 15 April 2016
Event European Lung Cancer Conference 2016 (ELCC) 2016
Session Poster lunch
Topics Thoracic malignancies
Translational Research
Basic Principles in the Management and Treatment (of cancer)
Presenter Kenneth O'Byrne
Citation Journal of Thoracic Oncology (2016) 11 (supplement 4): S57-S166. S1556-0864(16)X0004-4
Authors K. O'Byrne1, N. Paquet1, J.K. Box1, M. Adams2, D. Richard1
  • 1Institute Of Health And Biomedical Innovation, Cancer And Ageing Research Program, Queensland University of Technology, 4102 - Brisbane/AU
  • 2Institute Of Health And Biomedical Innovation, Cancer And Ageing Research Program, Queensland University of Technology, Brisbane/AU

Abstract

Background

Although prevention and early detection of the disease greatly improved over the past few years, lung cancer remains the leading cause of cancer deaths. In order to be able to treat a larger population, we are in urgent need for novel treatments. While it is known that DNA repair genes play a major role in the oncogenic transformation, they also represent a weakness of cancers that constitute a therapeutic opportunity. To identify novel DNA repair genes implicated in Lung cancers, we conducted an in silico investigation to identify genes co-regulated with two DNA repair factors, BRCA2 and hSSB1. This approach allowed for the identification of EXOSC4, a component of the RNA Exosome machinery, as a potential factor involved in the maintenance of genome stability and that is deregulated in lung cancer.

Methods

We performed a detailed genomic analysis of EXOSC4 in lung cancers from The Cancer Genome Atlas project, including DNA copy number alteration (CNA), RNA expression analyses. Association between EXOSC4 expression and patient survival was determined with the Kaplan–Meier log-rank. Multiple cell lines were investigated for EXOSC4 levels by RT-PCR and western blots. Deregulation of EXOSC4 by knockdown was used to delineate the function of EXOSC4 in cancer progression. Ex vivo functional studies including cell proliferation and viability assays were performed on cell lines.

Results

Significant copy number alteration was found in lung cancer, and was shown to correlate with EXOSC4 transcripts accumulation when compared with normal tissues. Over-expression of EXOSC4 is significantly associated with poor cancer survival in adenocarcinoma (HR = 1.9, logrank P = 8e-8) but not in SCLC. Preliminary results obtain from qRT-PCR and Western blot analysis confirmed that EXOSC4 accumulates in cancer cells when compared to immortalized lung epithelial cells. First results indicate that EXOSC4 knock down in these cells is associated with a significant reduction in cells proliferation. Our preliminary results indicated that cell survival is not significantly impacted by EXOSC4 depletion.

Conclusions

These results provide an insight into EXOSC4 deregulation in lung cancer and suggest that EXOSC4 expression is necessary for cancer progression.

Clinical trial identification

Legal entity responsible for the study

Queensland University of Technology

Funding

Queensland Health

Disclosure

All authors have declared no conflicts of interest.