Targeted genetic disruption of peroxisome proliferator-activated receptor-delta and colonic tumorigenesis.
Targeted genetic disruption of peroxisome proliferator-activated receptor-delta and colonic tumorigenesis.
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DOI：
10.1093/jnci/djp078
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发表时间：
2009-05
期刊：
影响因子：
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通讯作者：
Xiangsheng Zuo;Zhanglong Peng;M. Moussalli;Jeffrey S. Morris;R. Broaddus;S. Fischer;I. Shureiqi
中科院分区：
文献类型：
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作者：
Xiangsheng Zuo;Zhanglong Peng;M. Moussalli;Jeffrey S. Morris;R. Broaddus;S. Fischer;I. Shureiqi
过氧化物酶体增殖物激活受体-δ（PPAR-delta）在人类结肠癌中过表达，但其对结肠肿瘤发生的作用存在争议。我们建立了一种小鼠模型，其中通过外显子4的靶向缺失，在结肠上皮细胞中对PPAR-delta进行遗传破坏。通过实时逆转录-聚合酶链反应（实时RT-PCR）、免疫印迹和活性测定证实了结肠特异性PPAR-delta表达的消除。测试具有和不具有靶向PPAR-delta遗传破坏的小鼠（每组10-11只小鼠）的氧化偶氮甲烷诱导的结肠肿瘤的发生率。通过实时定量RT-PCR测定靶向PPAR-delta缺失对血管内皮生长因子表达的影响。靶向PPAR-delta基因破坏抑制结肠癌发生：具有PPAR-delta（-/-）结肠的小鼠比野生型小鼠少98.5%的肿瘤（PPAR-delta（（-/-））vs野生型，平均值= 0.1个肿瘤/小鼠vs 6.6个肿瘤/小鼠，差异= 6.5个肿瘤/小鼠，95%置信区间= 4.9至8.0个肿瘤/小鼠，P <0.001，双侧检验）。与正常结肠相比，结肠肿瘤中血管内皮生长因子表达的增加被PPAR-delta表达的丧失抑制。这些发现表明PPAR-delta在促进结肠肿瘤发生中具有关键作用。
Peroxisome proliferator-activated receptor-delta (PPAR-delta) is overexpressed in human colon cancer, but its contribution to colonic tumorigenesis is controversial. We generated a mouse model in which PPAR-delta was genetically disrupted in colonic epithelial cells by targeted deletion of exon 4. Elimination of colon-specific PPAR-delta expression was confirmed by real-time reverse transcription-polymerase chain reaction (real-time RT-PCR), immunoblotting, and activity assays. Mice with and without targeted PPAR-delta genetic disruption (10-11 mice per group) were tested for incidence of azoxymethane-induced colon tumors. The effects of targeted PPAR-delta deletion on vascular endothelial growth factor expression were determined by real-time RT-PCR. Targeted PPAR-delta genetic disruption inhibited colonic carcinogenesis: Mice with PPAR-delta((-/-)) colons developed 98.5% fewer tumors than wild-type mice (PPAR-delta((-/-)) vs wild-type, mean = 0.1 tumors per mouse vs 6.6 tumors per mouse, difference = 6.5 tumors per mouse, 95% confidence interval = 4.9 to 8.0 tumors per mouse, P < .001, two-sided test). Increased expression of vascular endothelial growth factor in colon tumors vs normal colon was suppressed by loss of PPAR-delta expression. These findings indicate that PPAR-delta has a crucial role in promoting colonic tumorigenesis.