Altered expression of c-myc, p16 and p27 in rat colon tumors and its reversal by short-term treatment with chemopreventive agents.
Altered expression of c-myc, p16 and p27 in rat colon tumors and its reversal by short-term treatment with chemopreventive agents.
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DOI：
10.1093/carcin/23.9.1447
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发表时间：
2002-09
期刊：
影响因子：
4.7
通讯作者：
L. Tao;P. Kramer;Wei Wang;Siming Yang;R. Lubet;V. Steele;Michael A. Pereira
中科院分区：
文献类型：
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作者：
L. Tao;P. Kramer;Wei Wang;Siming Yang;R. Lubet;V. Steele;Michael A. Pereira
肿瘤中基因表达的调节有可能成为化学预防的替代终点生物标志物。因此，我们确定了化学预防药物对大鼠结肠肿瘤基因蛋白和mRNA表达的调节。雄性F344大鼠每周三次注射15 mg/kg偶氮甲烷。47周后，在饮食中以指示的mg/kg浓度给予阿司匹林(600)、氯化钙(50000)、2-(羧苯基)维甲酰胺(2-CPR，315)、α-二氟甲基鸟氨酸(DFMO，3000)、吡罗昔康(200)、栎素(33600)、9-顺式维甲酸(9-cis RA，30)、芦丁(3000)或舒林酸(280)，连续7天处死。在结肠肿瘤中，相对于粘膜，c-myc的蛋白和mRNA水平升高，而p16和p27的水平降低。氯化钙、DFMO、吡罗昔康和舒林酸治疗7d可降低结肠肿瘤细胞分裂指数，降低c-myc蛋白和mRNA水平。氯化钙、DFMO和吡罗昔康使p16蛋白和mRNA水平升高，与舒林酸一起使p27蛋白水平升高，但不增加其mRNA水平。其他试剂未能同时调节有丝分裂指数和基因的表达。测定了化学预防药物预防结肠癌的能力。雄性F344大鼠每周3次注射15 mg/kg偶氮甲烷，8周后在饲料中加入阿司匹林、2-CPR、DFMO、吡罗昔康、9-顺式维甲酸和芦丁。这些老鼠在开始接受化学预防药物26周后被处死。DFMO和吡罗昔康可降低结肠癌的多样性，芦丁可使其增加，其他药物对其无明显影响。因此，预防结肠癌的药物降低了有丝分裂指数并改变了c-myc、p16和p27的表达，表明这些基因表达的调节是潜在的化学预防活性的生物标志物。
Modulation of gene expression in tumors has the potential of being a surrogate end-point biomarker for chemoprevention. Thus, we determined the modulation by chemopreventive agents of the protein and mRNA expression of genes in rat colon tumors. Male F344 rats were administered three weekly injections of 15 mg/kg azoxymethane. Forty-seven weeks later, they received aspirin (600), calcium chloride (50 000), 2-(carboxyphenyl) retinamide (2-CPR, 315), alpha-difluoromethylornithine (DFMO, 3000), piroxicam (200), quercetin (33 600), 9-cis retinoic acid (9-cis RA, 30), rutin (3000), or sulindac (280) in their diet at the indicated mg/kg concentration for 7 days and were then killed. In colon tumors relative to the mucosa, the protein and mRNA levels of c-myc were increased, while the levels of p16 and p27 were decreased. Calcium chloride, DFMO, piroxicam and sulindac administered for 7 days decreased the mitotic index and reduced the protein and mRNA levels of c-myc in colon tumors. Calcium chloride, DFMO and piroxicam increased the protein and mRNA levels of p16 and along with sulindac increased the protein level of p27, but not its mRNA. The other agents failed to modulate both the mitotic index and the expression of the genes. The ability of the chemopreventive agents to prevent colon tumors was determined. Male F344 rats were administered three weekly injections of 15 mg/kg azoxymethane and 8 weeks later they were administered aspirin, 2-CPR, DFMO, piroxicam, 9-cis RA and rutin in their diet. The rats were killed 26 weeks after they started to receive the chemopreventive agents. The multiplicity of colon tumors was reduced by DFMO and piroxicam, increased by rutin and not affected by the other agents. Hence, agents that prevented colon cancer decreased the mitotic index and altered the expression of c-myc, p16 and p27 suggesting that modulation in the expression of these genes are potential biomarkers for chemopreventive activity.