生物谷报道:肺癌(Lung.Carcinoma)是常见的恶性肿瘤之一,近数十年肺癌的发病率和死亡率都有明显增高的趋势。吸烟、被动吸烟、环境污染尤其是大气污染是促成这一严峻现实的罪魁祸首,却又都是一个长期得不到解决的老大难问题。很多研究显示,抽烟与肺癌之间有着紧密的联系,但是具体机制一直没有弄清。近日,科学家发现一种特殊蛋白含量的降低会导致DNA损伤,从而触发肺癌。这一发现可能有助于科学家在将来改善对肺癌的治疗。
领导此次研究的是美国俄勒冈健康与科学大学癌症研究所的Laura Hays。这种特殊的蛋白名为FANCD2,它所在的蛋白质家族与遗传性范可尼贫血症(Fanconi anemia)有关,患有此贫血症的人该家族蛋白含量低,更易在年轻的时候患癌症。
研究人员在实验室中制造了一个人造气管以模拟抽烟者的肺部环境,以此研究了香烟对细胞中不同蛋白的影响。结果发现,当肺细胞暴露于香烟中时,FANCD2的制造速度就会变缓,导致其含量降低。而FANCD2的作用在于通过修补DNA损伤或促进有缺陷细胞自杀来预防癌症,所以低水平的FANCD2会导致DNA损伤,从而触发癌症。
Hays表示,“这一发现显示了FANCD2在保护肺细胞抵御香烟侵袭中扮演着重要角色,也可能解释了为什么香烟对肺细胞如此有害。”
论文作者、美国波特兰老兵事务医学中心的Grover Bagby说:“这一研究显示了FANCD2是个重要的抵御癌症蛋白,而香烟会破坏它的制造过程。虽然这里面还可能包含有其它蛋白,但我们知道FANCD2是关键的一个,因为含有非常高水平FANCD2的细胞能够抵御香烟的毒害作用。”
英国癌症研究院的Lesley Walker说:“这一研究增加了我们对抽烟致命性原因的理解。抽烟目前是导致癌症的最大单一可预防原因,10例肺癌中有9例都是抽烟所致。不过好消息是,戒烟是有作用的——戒烟5年后,心脏病发作的风险将会降到抽烟者的一半,10年后,患肺癌的风险同样也会减半。”(生物谷www.bioon.com)
生物谷推荐原始出处:
British Journal of Cancer,doi:10.1038/sj.bjc.6604362,L E Hays,G C Bagby
Cigarette smoke induces genetic instability in airway epithelial cells by suppressing FANCD2 expression
L E Hays1,2,3, D M Zodrow1,3, J E Yates1,3, M E Deffebach2,3, D B Jacoby2, S B Olson4, J F Pankow5 and G C Bagby1,2,3,4
1OHSU Cancer Institute, Oregon Health & Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, USA
2Department of Medicine, Oregon Health & Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, USA
3Veterans Administration Medical Center, 3710 Southwest United States Veteran's Hospital Road, Portland, OR 97239, USA
4Department of Molecular and Medical Genetics, Oregon Health & Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, USA
5Department of Environmental and Biomolecular Systems, Oregon Graduate Institute, Oregon Health & Science University, 20000 Northwest Walker Road, Beaverton, OR 97006, USA
Chromosomal abnormalities are commonly found in bronchogenic carcinoma cells, but the molecular causes of chromosomal instability (CIN) and their relationship to cigarette smoke has not been defined. Because the Fanconi anaemia (FA)/BRCA pathway is essential for maintenance of chromosomal stability, we tested the hypothesis that cigarette smoke suppresses that activity of this pathway. Here, we show that cigarette smoke condensate (CSC) inhibited translation of FANCD2 mRNA (but not FANCC or FANCG) in normal airway epithelial cells and that this suppression of FANCD2 expression was sufficient to induce both genetic instability and programmed cell death in the exposed cell population. Cigarette smoke condensate also suppressed FANCD2 function and induced CIN in bronchogenic carcinoma cells, but these cells were resistant to CSC-induced apoptosis relative to normal airway epithelial cells. We, therefore, suggest that CSC exerts pressure on airway epithelial cells that results in selection and emergence of genetically unstable somatic mutant clones that may have lost the capacity to effectively execute an apoptotic programme. Carcinogen-mediated suppression of FANCD2 gene expression provides a plausible molecular mechanism for CIN in bronchogenic carcinogenesis.