Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 210029, Jiangsu, PR China.
Toxicol Lett. 2013 Apr 12;218(2):105-17. doi: 10.1016/j.toxlet.2013.01.004. Epub 2013 Jan 17.
Both arsenite and benzo(a)pyrene (BaP) are known human carcinogens. Studies on the mode-of-action of arsenite indicate that it can also act as co-carcinogen or as a cancer promoter, and that it can facilitate progression of cancers. Some studies on development of lung cancers have suggested a synergism between arsenite exposure and cigarette smoking. The mechanism of action for such an effect, however, remains obscure. In the present study, we investigated the effects of HIF-2α on arsenite- and BaP-induced cell malignant transformation as well as on signal transduction pathways in human bronchial epithelial (HBE) cells. The results show that arsenite accelerates the neoplastic transformation and migration of cells and enhances chromosomal aberrations induced by BaP. HIF-2α is involved in blocking the effects of arsenite in activating the ATM/Chk-2 pathway and in repair of DNA damage induced by BaP. Moreover, blocking of HIF-2α prevents the effects of arsenite on the neoplastic transformation, cell migration, and chromosomal aberrations caused by BaP. These results indicate that the repressive effect of HIF-2α on the ATM/Chk-2 pathway leads to genomic instability, which is involved in arsenite-accelerated, BaP-induced malignant transformation of HBE cells.
砷和苯并(a)芘都是已知的人类致癌物。对砷作用机制的研究表明，它也可以作为协同致癌物或癌症促进剂，并且可以促进癌症的发展。一些关于肺癌发展的研究表明，砷暴露与吸烟之间存在协同作用。然而，这种效应的作用机制仍然不清楚。在本研究中，我们研究了 HIF-2α 在砷和 BaP 诱导的细胞恶性转化以及人支气管上皮细胞（HBE）信号转导通路中的作用。结果表明，砷加速了细胞的癌变和迁移，并增强了 BaP 诱导的染色体畸变。HIF-2α 参与阻断砷激活 ATM/Chk-2 途径和修复 BaP 诱导的 DNA 损伤的作用。此外，阻断 HIF-2α 可防止砷对 BaP 引起的细胞癌变、迁移和染色体畸变的影响。这些结果表明，HIF-2α 对 ATM/Chk-2 途径的抑制作用导致基因组不稳定，这参与了砷加速的 BaP 诱导的 HBE 细胞恶性转化。
