title: Cytoglobin has bimodal: tumour suppressor and oncogene functions in lung cancer cell lines.
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.
authors.affiliation: Department of Molecular and Clinical Cancer Medicine, Roy Castle Lung Cancer Research Programme, University of Liverpool, 200 London Rd, Liverpool L3 9TA,UK.
authors.forename: Urszula
authors.initials: U
authors.lastname: Oleksiewicz
authors.forename: Triantafillos
authors.initials: T
authors.lastname: Liloglou
authors.forename: Kalliopi-Maria
authors.initials: KM
authors.lastname: Tasopoulou
authors.forename: Nikoleta
authors.initials: N
authors.lastname: Daskoulidou
authors.forename: Julie
authors.initials: J
authors.lastname: Bryan
authors.forename: John R
authors.initials: JR
authors.lastname: Gosney
authors.forename: John K
authors.initials: JK
authors.lastname: Field
authors.forename: George
authors.initials: G
authors.lastname: Xinarianos
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology; D015687:Cell Hypoxia / Q000235:genetics; D045744:Cell Line, Tumor; D000078842:Cytoglobin; D019175:DNA Methylation; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D005914:Globins / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009857:Oncogenes; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
chemical_list: C000627265:CYGB protein, human; D000078842:Cytoglobin; C497442:HIF1A protein, human; D006877:Hydroxamic Acids; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C012589:trichostatin A; D005914:Globins