Zell Jason A, Ignatenko Natalia A, Yerushalmi Hagit F, Ziogas Argyrios, Besselsen David G, Gerner Eugene W, Anton-Culver Hoda
Genetic Epidemiology Research Institute, University of California Irvine, Irvine, CA 92697-7550, USA.
Int J Cancer. 2007 Feb 1;120(3):459-68. doi: 10.1002/ijc.22311.
Elevated polyamine and nitric oxide levels (both derived from arginine) promote tumorigenesis, whereas non-steroidal anti-inflammatory drugs (NSAIDs) inhibit colorectal cancer (CRC) incidence in experimental and epidemiologic studies. We investigated dietary arginine-induced intestinal tumorigenesis and NSAID-inhibitory effects in Apc(Min/+) mice differentially expressing nitric oxide synthase-2 (Nos2). We also studied effects of estimated arginine exposures through meat consumption on tumor characteristics and survival in human CRC cases. Dietary arginine increased high-grade colon adenoma incidence in Apc(Min/+)Nos2(+/+) mice, but not in Nos2 knockout mice. Additionally, celecoxib suppressed intestinal steady state ornithine decarboxylase RNA levels (p < 0.001), induced steady state spermidine/spermine N(1)-acetyltransferase RNA levels (p = 0.002), decreased putrescine levels (p = 0.04) and decreased tumor number in the small intestines of Apc(Min/+)Nos2(+/+) mice (p = 0.0003). Five hundred and eleven cases from our NCI-supported CRC gene-environment study were analyzed based on self-reported meat (as a surrogate for arginine) consumption. Familial CRC cases (n = 144) in the highest meat consumption quartile (Q4) had no statistically significant differences in tumor grade compared to cases in Q1-Q3 (p = 0.32); however, they were observed to have decreased overall survival (OS) (10-year OS = 42% vs. 65%; p = 0.017), and increased risk of death in an adjusted analysis (hazards ratio [HR] = 2.24; p = 0.007). No differences in tumor grade, OS or adjusted HR were observed for sporadic CRC cases (n = 367) based on meat consumption. Our results suggest important roles for arginine and meat consumption in CRC pathogenesis, and have implications for CRC prevention.
多胺和一氧化氮水平升高（两者均来源于精氨酸）会促进肿瘤发生，而在实验研究和流行病学研究中，非甾体抗炎药（NSAIDs）可抑制结直肠癌（CRC）的发病率。我们研究了饮食中的精氨酸诱导Apc(Min/+)小鼠（该小鼠差异表达一氧化氮合酶2（Nos2））发生肠道肿瘤以及NSAIDs的抑制作用。我们还研究了通过食用肉类估计的精氨酸摄入量对人类CRC病例肿瘤特征和生存的影响。饮食中的精氨酸增加了Apc(Min/+)Nos2(+/+)小鼠高级别结肠腺瘤的发病率，但在Nos2基因敲除小鼠中未出现这种情况。此外，塞来昔布抑制了肠道鸟氨酸脱羧酶的稳态RNA水平（p < 0.001），诱导了精胺/亚精胺N(1)-乙酰转移酶的稳态RNA水平（p = 0.002），降低了腐胺水平（p = 0.04），并减少了Apc(Min/+)Nos2(+/+)小鼠小肠中的肿瘤数量（p = 0.0003）。基于自我报告的肉类（作为精氨酸的替代物）摄入量，对我们由美国国立癌症研究所支持的CRC基因-环境研究中的511例病例进行了分析。肉类摄入量最高四分位数（Q4）中的家族性CRC病例（n = 144）与Q1-Q3中的病例相比，肿瘤分级无统计学显著差异（p = 0.32）；然而，观察到他们的总生存期（OS）降低（10年总生存期 = 42% 对 65%；p = 0.017），并且在调整分析中死亡风险增加（风险比[HR] = 2.24；p = 0.007）。基于肉类摄入量，散发性CRC病例（n = 367）在肿瘤分级、OS或调整后的HR方面未观察到差异。我们的结果表明精氨酸和肉类摄入在CRC发病机制中起重要作用，并对CRC预防具有启示意义。
