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.

Genome-Wide DNA Methylation as an Epigenetic Consequence of Epstein-Barr Virus Infection of Immortalized Keratinocytes

“…CYGB is ubiquitously expressed and is thought to protect against oxidative stress. Downregulation of CYGB has been observed in many human malignancies (59). qRT-PCR analysis confirmed an approximate 2-fold reduction in mRNA levels in cells exposed to EBV compared to uninfected controls (Fig.…”

Redox and Peroxidase Activities of the Hemoglobin Superfamily: Relevance to Health and Disease

“…Furthermore, in human lung cancer data sets, the interaction of ∆Np63 with Cygb gene significantly predicts reduction of patient survival (59). From the studies of Cygb and cancer prevention and promotion it is clear that Cygb has a bimodal tumor suppressors and oncogene functions (73).…”

Prostaglandin E-Major Urinary Metabolite as a Biomarker for Inflammation in Ulcerative Colitis: Prostaglandins Revisited

“…In hepatic fibrosis, inflammation stimulates carcinogenesis. The stellate cell is characterized by the expression of α-smooth muscle actin and cytoglobin (which turned out to be a suppressor gene) [26,27] . In UC, significant alterations in cytoglobin and α-smooth muscle actin expression are observed in subepithelial MFB, corresponding to colonic stellate cells similar to those observed in cirrhosis [28] .…”