Enhancement of development of azoxymethane-induced colonic premalignant lesions in C57BL/KsJ-db/db mice
Enhancement of development of azoxymethane-induced colonic premalignant lesions in C57BL/KsJ-db/db mice
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DOI：
10.1093/carcin/bgh059
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发表时间：
2004-05-01
期刊：
影响因子：
4.7
通讯作者：
Mori, H
中科院分区：
文献类型：
--
作者：
Hirose, Y;Hata, K;Mori, H
流行病学研究表明，肥胖和糖尿病可能是结肠癌的危险因素。然而，这些慢性疾病如何促进结肠癌发生的潜在机制仍不清楚。C57BL/KSJ-db/db小鼠具有肥胖和糖尿病的表型，这是由于瘦素受体的破坏。本研究旨在研究偶氮甲烷(AOM)诱导的结肠发育不良和早期肿瘤(癌前)病变在db/db小鼠中是否受到调节。纯合子db/db小鼠、杂合子db/+小鼠和产仔对照组(+/+)在食物限制下注射AOM(类似于10.8千卡/只/天)，并在致癌物治疗5周后处死。评估他们的结肠是否有AOM所致的癌前病变。我们发现，与db/+或+/+小鼠相比，db/db小鼠的癌前病变总数的多样性显著增加。Db/db小鼠的血清瘦素和胰岛素水平显著高于db/+或+/+小鼠，而体重和血糖水平与db/db、db/+和+/+小鼠相当。此外，瘦素受体和胰岛素样生长因子-I受体的免疫染色显示，这些蛋白水平在皮损中特异性上调。我们的数据表明，在患有高瘦素血症和高胰岛素血症的db/db小鼠中，AOM诱导的癌前病变的发展是加速的。这一结果对进一步探索影响结肠癌和慢性疾病(肥胖和糖尿病)之间正相关的可能潜在事件具有重要意义。
Epidemiological studies have shown that obesity and diabetes mellitus may be risk factors for colon cancer. However, the underlying mechanisms of how these chronic diseases promote colon carcinogenesis remain unknown. C57BL/KsJ-db/db mice have obese and diabetic phenotypes because of disruption of the leptin receptor. The present study was designed to investigate whether development of azoxymethane (AOM)-induced dysplastic and early neoplastic (premalignant) lesions of the colon is modulated in db/db mice. Homozygous db/db mice, heterozygous db/+ mice and littermate controls (+/+) were injected with AOM under food restriction (similar to10.8 kcal/mouse/day) and killed 5 weeks after the carcinogen treatment. Their colons were assessed for premalignant lesions induced by AOM. We found a significant increase in the multiplicity of the total premalignant lesions in db/db mice when compared with db/+ or +/+ mice. Phenotypically, serum leptin and insulin levels in db/db mice were significantly higher than those in db/+ or +/+ mice, whereas the body weights and glucose levels in blood of db/db, db/+ and +/+ mice were comparable. In addition, immunostaining of the leptin receptor and insulin-like growth factor-I receptor showed up-regulation of these protein levels specifically in the lesions. Our data indicate that development of AOM-induced premalignant lesions is enhanced in db/db mice with hyperleptinemia and hyperinsulinemia. The results have important implications for further exploration of the possible underlying events that affect the positive association between colon cancer and chronic diseases (obesity and diabetes).