Velázquez O C, Zhou D, Seto R W, Jabbar A, Choi J, Lederer H M, Rombeau J L
Harrison Department of Surgical Research, University of Pennsylvania Medical Center, Philadelphia, USA.
JPEN J Parenter Enteral Nutr. 1996 Jul-Aug;20(4):243-50. doi: 10.1177/0148607196020004243.
Studies on colon carcinogenesis suggest that the short-chain fatty acid butyrate may be protective, whereas the secondary bile acid deoxycholate may promote tumor development. Crypt surface hyperproliferation is regarded as a biomarker of colon cancer risk and can be modulated in vitro by the differentiation inducer butyrate and the tumor promoter deoxycholate. We hypothesized that butyrate decreases and deoxycholate increases crypt surface proliferation in vivo and that these effects are mediated by changes in the expression of the protooncogenes c-Fos and c-Jun, which are known to regulate proliferation and differentiation.
Twenty-five adult Sprague-Dawley rats underwent colonic isolation and 24-hour intraluminal instillation of 10 mmol/L sodium chloride, 10 mmol/ L sodium butyrate, or 10 mmol/L sodium deoxycholate. Proliferation of the whole crypt and five crypt compartments from base to surface was assessed by proliferating cell nuclear antigen immunohistochemistry. The øh value, an index of "premalignant" hyperproliferation, was calculated as the ratio of labeled cells in the two surface compartments divided by the labeled cells in the entire crypt. Expression of c-Fos and c-Jun was evaluated by Western blot.
Crypt surface proliferation and the øh value were significantly decreased by butyrate and increased by deoxycholate. Butyrate increased colonic expression of c-Jun, whereas deoxycholate significantly induced c-Fos.
The in vivo effects on surface proliferation are consistent with a potential protective [corrected] role for butyrate and a promotive role for deoxycholate in colon carcinogenesis. The concurrently observed effects on colonic c-Jun and c-Fos expression represent a novel finding and suggest that direct or indirect modulation of protooncogene expression may be the mechanism by which these dietary byproducts regulate proliferation in vivo.
关于结肠癌发生机制的研究表明，短链脂肪酸丁酸可能具有保护作用，而次级胆汁酸脱氧胆酸可能促进肿瘤发展。隐窝表面过度增殖被视为结肠癌风险的生物标志物，并且在体外可被分化诱导剂丁酸和肿瘤启动子脱氧胆酸调节。我们假设丁酸在体内可降低隐窝表面增殖，而脱氧胆酸则会增加，并且这些作用是由原癌基因c-Fos和c-Jun表达的变化介导的，已知这两个基因可调节增殖和分化。
25只成年Sprague-Dawley大鼠接受结肠分离，并在肠腔内滴注24小时10 mmol/L氯化钠、10 mmol/L丁酸钠或10 mmol/L脱氧胆酸钠。通过增殖细胞核抗原免疫组织化学评估整个隐窝以及从底部到表面的五个隐窝区室的增殖情况。“癌前”过度增殖指数øh值计算为两个表面区室中标记细胞的比例除以整个隐窝中标记细胞的比例。通过蛋白质印迹法评估c-Fos和c-Jun的表达。
丁酸显著降低了隐窝表面增殖和øh值，而脱氧胆酸则使其增加。丁酸增加了结肠中c-Jun的表达，而脱氧胆酸显著诱导了c-Fos的表达。
对表面增殖的体内作用与丁酸在结肠癌发生中潜在的保护作用以及脱氧胆酸的促进作用一致。同时观察到的对结肠c-Jun和c-Fos表达的影响代表了一项新发现，并表明原癌基因表达的直接或间接调节可能是这些饮食副产品在体内调节增殖的机制。
