COL1A1, PRPF40A, and UCP2 correlate with hypoxia markers in non-small cell lung cancer

John R Gosney,Triantafillos Liloglou,Urszula Oleksiewicz,Nikoleta Daskoulidou,John K Field,Kalliopi-Maria Tasopoulou,George Xinarianos

doi:10.1007/s00432-017-2381-y

Abstract

PurposeCollagen 1A1 (COL1A1), RNA-binding and pre-mRNA Processing Factor (PRPF40A), and Uncoupling Protein 2 (UCP2) were identified as downstream effectors of cytoglobin (CYGB), which was shown implicated in tumour biology. Although these three genes have been previously associated with cancer, little is known about their status in lung malignancies.MethodsHereby, we investigated the expression and promoter methylation of COL1A1, PRPF40A, and UCP2 in 156 non-small cell lung cancer (NSCLC) and adjacent normal tissues.ResultsWe demonstrate that COL1A1 and PRPF40A mRNAs are significantly overexpressed in NSCLC (p < 1 × 10−4), while UCP2 exhibits a trend of upregulation (p = 0.066). Only COL1A1 promoter revealed hypermethylation in NSCLCs (36%), which was particularly evident in squamous cell carcinomas (p = 0.024) and in the tumours with moderate-to-good differentiation (p = 0.01). Transcript level of COL1A1, as well as PRPF40A and UCP2, exhibited striking association (p ≤ 0.001) with the expression of hypoxia markers. In addition, we demonstrate in lung cancer cell lines exposed to hypoxia or oxidative stress that COL1A1 transcription significantly responds to oxygen depletion, while other genes showed the modest upregulation in stress conditions.ConclusionIn conclusion, our data revealed that COL1A1, UCP2, and PRPF40A are novel players implicated in the complex network of hypoxia response in NSCLC.

Highlights

Lung cancer is among the most prevalent neoplastic diseases accounting for the highest mortality in both genders worldwide (Boisvert et al 2010)
We demonstrate in lung cancer cell lines exposed to hypoxia or oxidative stress that collagen 1A1 (COL1A1) transcription significantly responds to oxygen depletion, while other genes showed the modest upregulation in stress conditions
In conclusion, our data revealed that COL1A1, Uncoupling Protein 2 (UCP2), and PRPF40A are novel players implicated in the complex network of hypoxia response in non-small cell lung cancer (NSCLC)

Summary

Introduction

Lung cancer is among the most prevalent neoplastic diseases accounting for the highest mortality in both genders worldwide (Boisvert et al 2010). CYGB was associated with hypoxia and cancer aggressiveness (Fang et al 2011; Oleksiewicz et al 2013). Shivapurkar and co-workers identified three downstream effector genes of CYGB, which were downregulated in CYGB-overexpressing lung and breast cancer cell lines (Shivapurkar et al 2008). These genes were: collagen 1A1 (COL1A1), RNA-binding and pre-mRNA Processing Factor (PRPF40A) and Uncoupling Protein 2 (UCP2). COL1A1, PRPF40A, and UCP2 expression was linked to the metabolic pathways implicated in hypoxia and oxidative stress (Baffy 2010; Falanga et al 2002; GarcíaTrevijano et al 1999; Papaiahgari et al 2007), events associated with more aggressive and therapy-resistant tumours (Harris 2002; Landriscina et al 2009)

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