Enhanced colon tumor induction in uncoupling protein-2 deficient mice is associated with NF-κB activation and oxidative stress
Enhanced colon tumor induction in uncoupling protein-2 deficient mice is associated with NF-κB activation and oxidative stress
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DOI：
10.1093/carcin/bgi335
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发表时间：
2006-05-01
期刊：
影响因子：
4.7
通讯作者：
Baffy, G
中科院分区：
文献类型：
--
作者：
Derdák, Z;Fülöp, P;Baffy, G
氧化应激对癌症发展有复杂的影响。为了进一步研究这一过程，我们用氧化偶氮甲烷（AOM）在缺乏解偶联蛋白-2（UCP 2）的小鼠中诱导结肠肿瘤。UCP 2最近已成为线粒体氧化剂产生的负调节剂。当过表达时，UCP 2保护细胞免受氧化应激，而其缺失可能导致活性氧物质的丰富、促炎细胞因子的释放和核因子κ B（NF-κ B B）的持续活化，NF-κ B是一种在癌症中具有越来越多的公认作用的多效性转录因子。在这里，我们表明，在完成AOM治疗（每周腹腔注射10 mg/kg，共6周，n = 8-12）24周后检查时，Ucp 2（-/-）小鼠比Ucp 2（+/+）同窝小鼠出现更多异常隐窝病灶和结肠肿瘤。这种效应主要见于Ucp 2（-/-）小鼠的近端结肠（P < 0.05），与指示氧化应激增加的变化相关（丙二醛和诱导型一氧化氮合酶染色增加），增强NF-κ B活化（磷酸化I κ B水平增加和p65核存在增加）和肠上皮细胞增殖之间的平衡被破坏（更高的5-溴-2 '-脱氧尿苷掺入率和增加的ERK 1/2和AKT磷酸化）和凋亡（减少的末端脱氧核苷酸转移酶介导的缺口末端标记（TUNEL）阳性细胞的数量和增加的Bcl-2表达）。总之，我们的研究结果提供了UCP 2和肿瘤发生之间联系的第一个体内证据，并表明需要进行更多的研究来评估线粒体解偶联在癌症发展中的作用。
Oxidative stress has a complex effect on cancer development. To further study this process, we induced colon tumors with azoxymethane (AOM) in mice deficient for uncoupling protein-2 (UCP2). UCP2 has recently emerged as a negative regulator of mitochondrial oxidant production. When overexpressed, UCP2 protects cells from oxidative stress, while its absence may cause abundance of reactive oxygen species, release of pro-inflammatory cytokines and persistent activation of nuclear factor kappaB (NF-kappa B), a pleiotropic transcription factor with an increasingly recognized role in cancer. Here we show that Ucp2(-/-) mice develop more aberrant crypt foci and colon tumors than Ucp2(+/+) littermates when examined 24 weeks after the completion of treatment with AOM (10 mg/kg i.p. weekly for a total of 6 weeks, n = 8-12). This effect is primarily seen in the proximal colon of Ucp2(-/-) mice (P < 0.05), in association with changes indicative of increased oxidative stress (increased staining for malondialdehyde and inducible nitric oxide synthase), enhanced NF-kappa B activation (increased levels of phosphorylated I kappa B and increased nuclear presence of p65) and a disrupted balance between intestinal epithelial cell proliferation (greater 5-bromo-2'-deoxy-uridine incorporation rates and increased phosphorylation of ERK1/2 and AKT) and apoptosis (decreased number of terminal deoxynucleotidyltransferase-mediated nick-end-labeling (TUNEL)-positive cells and increased expression of Bcl-2). In conclusion, our findings provide the first in vivo evidence for a link between UCP2 and tumorigenesis and indicate the need for additional studies to assess the role of mitochondrial uncoupling in cancer development.