Department of Molecular and Clinical Cancer Medicine, Roy Castle Lung Cancer Research Programme, University of Liverpool, 200 London Rd, Liverpool L3 9TA,UK.
Hum Mol Genet. 2013 Aug 15;22(16):3207-17. doi: 10.1093/hmg/ddt174. Epub 2013 Apr 15.
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.
细胞球蛋白 (CYGB) 在许多人类恶性肿瘤中经常下调，其外源性过表达可减少癌细胞的增殖。尽管它具有潜在的肿瘤抑制 (TSG) 功能，但由于 CYGB 的上调也与肿瘤缺氧和侵袭性相关，其在致癌作用中的确切作用仍不清楚。在这项研究中，我们探讨了 CYGB 的 TSG 作用、它在应激条件下对癌细胞表型的影响以及非小细胞肺癌 (NSCLC) 中 CYGB 表达和启动子甲基化的临床意义。在临床样本和细胞系中均证明了 CYGB 的 DNA 甲基化依赖性表达沉默。CYGB 启动子在肺腺癌中更频繁地甲基化（P = 1.4×10(-4)）。5'-氮杂脱氧胞苷的去甲基化部分恢复了细胞系中的 CYGB 表达。有趣的是，曲古抑菌素 A 触发了癌细胞系中 CYGB 的上调和非肿瘤细胞系中的下调。NSCLC 手术标本中的 CYGB mRNA 表达与 HIF1α 和 VEGFa 的表达相关（P < 1×10(-4)）。在癌细胞系中过表达 CYGB 可降低细胞迁移、侵袭和非锚定依赖性生长。此外，CYGB 可抑制细胞增殖，但仅在肺腺癌细胞系 (H358) 中。过氧化氢处理后，CYGB 通过减轻氧化损伤来保护细胞活力、迁移潜能和非锚定独立性。在低氧条件下，CYGB 过表达以细胞类型特异性方式降低细胞活力、增加迁移和非锚定独立性。总之，CYGB 在常氧条件下表现出 TSG 特性，但在应激暴露的细胞中促进了肿瘤发生潜能，这表明其在肺肿瘤发生中具有双模态功能，取决于细胞类型和微环境条件。
