Department of Medicine, Case Western Reserve University and Case Medical Center, 10900 Euclid Ave., Wolstein Research Building, Rm 3-128, Cleveland, OH 44106-7285, USA.
Dig Dis Sci. 2013 Sep;58(9):2615-22. doi: 10.1007/s10620-013-2670-5. Epub 2013 Apr 27.
15-Hydroxprostaglandin dehydrogenase (15-PGDH) mediates a colon neoplasia suppressor pathway, acting through metabolic antagonism of cyclooxygenase-mediated colon carcinogenesis. To determine whether the colon tumor prevention activity of 15-PGDH acts as a constant or variable effect among individuals, we determined whether 15-PGDH levels remain stable over subsite and time in the human colon, determined the extent of differences in 15-PGDH levels between different individuals, and determined whether 15-PGDH modulation mediates any part of the anti-colon tumor effect of aspirin.
Using real-time PCR, we measured 15-PGDH mRNA to determine the correlation of 15-PGDH level in replicate colon biopsies, in biopsies from throughout the length of the colon, in repeat biopsies taken 4 months apart, and in paired biopsies of individuals taken before and after aspirin treatment, and by Western-blot for 15-PGDH protein in mice.
Colonic 15-PGDH levels varied 4.4-fold across the human population. Within individuals, 15-PGDH levels proved highly reproducible (r=0.81 in duplicate biopsies) and stable along the length of the colon, with average 15-PGDH levels deviating by only 17% from rectum to cecum. An individual's 15-PGDH levels are also highly stable over time, with a median coefficient of variation over a 4-month interval of only 12%. Last, colonic 15-PGDH levels proved resistant to alteration by aspirin, with only a 10% difference in 15-PGDH levels measured before and after aspirin treatment.
15-PGDH levels vary across the population in a stable and reproducible manner, and are resistant to alteration by aspirin. 15-PGDH represents an independent target for modulation by candidate colon tumor chemopreventive agents.
15-羟前列腺素脱氢酶（15-PGDH）介导结肠肿瘤抑制途径，通过代谢拮抗环氧合酶介导的结肠癌发生。为了确定 15-PGDH 对结肠肿瘤的预防作用在个体中是恒定的还是可变的，我们确定 15-PGDH 水平在人类结肠的亚部位和时间上是否保持稳定，确定不同个体之间 15-PGDH 水平的差异程度，以及确定 15-PGDH 调节是否介导阿司匹林对结肠癌的任何部分抗肿瘤作用。
使用实时 PCR，我们测量了 15-PGDH mRNA，以确定重复结肠活检中 15-PGDH 水平的相关性，在整个结肠长度的活检中，在相隔 4 个月的重复活检中，以及在阿司匹林治疗前后的个体配对活检中，以及在小鼠中使用 Western-blot 进行 15-PGDH 蛋白。
人群中结肠 15-PGDH 水平差异 4.4 倍。在个体内，15-PGDH 水平证明具有高度重现性（重复活检中 r=0.81），并且在结肠长度上稳定，平均 15-PGDH 水平从直肠到盲肠仅偏离 17%。个体的 15-PGDH 水平也非常稳定，在 4 个月的时间间隔内，中位数变异系数仅为 12%。最后，结肠 15-PGDH 水平对阿司匹林的改变具有抗性，仅在阿司匹林治疗前后测量的 15-PGDH 水平有 10%的差异。
15-PGDH 水平在人群中以稳定和可重复的方式变化，并且对阿司匹林的改变具有抗性。15-PGDH 代表候选结肠肿瘤化学预防剂调节的独立靶标。
