Cytoglobin has bimodal: tumour suppressor and oncogene functions in lung cancer cell lines

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

Research output: Contribution to journalArticle (journal)peer-review

38 Citations (Scopus)

Abstract

Cytoglobin (CYGB) is frequently downregulated in many types of human malignancies, and its exogenous overexpression reduces proliferation of cancer cells. Despite its implied tumour suppressor (TSG) functions, its exact role in carcinogenesis remains unclear as CYGB upregulation is also associated with tumour hypoxia and aggressiveness. In this study, we explore the TSG role of CYGB, its influence on the phenotype of cancerous cells under stress conditions and the clinical significance of CYGB expression and promoter methylation in non-small cell lung cancer (NSCLC). DNA methylation-dependent expression silencing of CYGB is demonstrated in both clinical samples and cell lines. CYGB promoter was more frequently methylated in lung adenocarcinomas (P = 1.4 × 10(-4)). Demethylation by 5'-azadeoxycytidine partially restored CYGB expression in cell lines. Interestingly, trichostatin A triggered upregulation of CYGB expression in cancer cell lines and downregulation in non-tumourigenic ones. CYGB mRNA expression in NSCLC surgical specimens correlated with that of HIF1α and VEGFa (P < 1 × 10(-4)). Overexpression of CYGB in cancer cell lines reduced cell migration, invasion and anchorage-independent growth. Moreover, CYGB impaired cell proliferation, but only in the lung adenocarcinoma cell line (H358). Upon hydrogen peroxide treatment, CYGB protected cell viability, migratory potential and anchorage independence by attenuating oxidative injury. In hypoxia, CYGB overexpression decreased cell viability, augmented migration and anchorage independence in a cell-type-specific manner. In conclusion, CYGB revealed TSG properties in normoxia but promoted tumourigenic potential of the cells exposed to stress, suggesting a bimodal function in lung tumourigenesis, depending on cell type and microenvironmental conditions.

Original languageEnglish
Pages (from-to)3207-17
Number of pages11
JournalHuman Molecular Genetics
Volume22
Issue number16
DOIs
Publication statusPublished - 15 Aug 2013

Keywords

  • Adenocarcinoma/genetics
  • Adenocarcinoma of Lung
  • Carcinoma, Non-Small-Cell Lung/genetics
  • Cell Hypoxia/genetics
  • Cell Line, Tumor
  • Cytoglobin
  • DNA Methylation
  • Gene Expression Regulation, Neoplastic
  • Gene Silencing
  • Genes, Tumor Suppressor
  • Globins/genetics
  • Humans
  • Hydroxamic Acids/pharmacology
  • Hypoxia-Inducible Factor 1, alpha Subunit/genetics
  • Lung Neoplasms/genetics
  • Oncogenes
  • Vascular Endothelial Growth Factor A/genetics

Fingerprint

Dive into the research topics of 'Cytoglobin has bimodal: tumour suppressor and oncogene functions in lung cancer cell lines'. Together they form a unique fingerprint.

Cite this