Fink Stephen P, Yamauchi Mai, Nishihara Reiko, Jung Seungyoun, Kuchiba Aya, Wu Kana, Cho Eunyoung, Giovannucci Edward, Fuchs Charles S, Ogino Shuji, Markowitz Sanford D, Chan Andrew T
Department of Medicine and Case Comprehensive Cancer Center, Case Western Reserve University and University Hospitals Case Medical Center, 10900 Euclid Avenue, Cleveland, OH 44106, USA.
Sci Transl Med. 2014 Apr 23;6(233):233re2. doi: 10.1126/scitranslmed.3008481.
Aspirin use reduces the risk of colorectal neoplasia, at least in part, through inhibition of prostaglandin-endoperoxide synthase 2 (PTGS2, cyclooxygenase 2)-related pathways. Hydroxyprostaglandin dehydrogenase 15-(nicotinamide adenine dinucleotide) (15-PGDH, HPGD) is down-regulated in colorectal cancers and functions as a metabolic antagonist of PTGS2. We hypothesized that the effect of aspirin may be antagonized by low 15-PGDH expression in the normal colon. In the Nurses' Health Study and the Health Professionals Follow-Up Study, we collected data on aspirin use every 2 years and followed up participants for diagnoses of colorectal cancer. Duplication-method Cox proportional, multivariable-adjusted, cause-specific hazards regression for competing risks data was used to compute hazard ratios (HRs) for incident colorectal cancer according to 15-PGDH mRNA expression level measured in normal mucosa from colorectal cancer resections. Among 127,865 participants, we documented 270 colorectal cancer cases from which we could assess 15-PGDH expression. Compared with nonuse, regular aspirin use was associated with lower risk of colorectal cancer that developed within a background of colonic mucosa with high 15-PGDH expression [multivariable HR, 0.49; 95% confidence interval (CI), 0.34 to 0.71], but not with low 15-PGDH expression (multivariable HR, 0.90; 95% CI, 0.63 to 1.27) (P for heterogeneity = 0.018). Regular aspirin use was associated with lower incidence of colorectal cancers arising in association with high 15-PGDH expression, but not with low 15-PGDH expression in normal colon mucosa. This suggests that 15-PGDH expression level in normal colon mucosa may serve as a biomarker that may predict stronger benefit from aspirin chemoprevention.
阿司匹林的使用至少部分地通过抑制前列腺素 - 内过氧化物合酶2（PTGS2，环氧化酶2）相关途径降低结直肠肿瘤的风险。15 - 羟基前列腺素脱氢酶（烟酰胺腺嘌呤二核苷酸）（15 - PGDH，HPGD）在结直肠癌中表达下调，并作为PTGS2的代谢拮抗剂发挥作用。我们推测，正常结肠中15 - PGDH低表达可能会拮抗阿司匹林的作用。在护士健康研究和卫生专业人员随访研究中，我们每两年收集一次阿司匹林使用数据，并对参与者进行结直肠癌诊断随访。采用重复法Cox比例、多变量调整、针对竞争风险数据的病因特异性风险回归，根据在结直肠癌切除术中正常黏膜中测得的15 - PGDH mRNA表达水平计算结直肠癌发病的风险比（HR）。在127,865名参与者中，我们记录了270例结直肠癌病例，并对这些病例进行了15 - PGDH表达评估。与未使用阿司匹林相比，经常使用阿司匹林与在15 - PGDH高表达的结肠黏膜背景下发生的结直肠癌风险较低相关[多变量HR，0.49；95%置信区间（CI），0.34至0.71]，但与15 - PGDH低表达无关（多变量HR，0.90；95%CI，0.63至1.27）（异质性P = 0.018）。经常使用阿司匹林与15 - PGDH高表达相关的结直肠癌发病率较低有关，但与正常结肠黏膜中15 - PGDH低表达无关。这表明正常结肠黏膜中的15 - PGDH表达水平可能作为一种生物标志物，预测阿司匹林化学预防的更强益处。
