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Promotive effects of hyperlipidemia on pancreatic ductal carcinogenesis and the mechanisms

高脂血症对胰腺导管癌的促进作用及其机制

基本信息

批准号：
18590390
负责人：
TAKAHASHI Mami
金额：
$ 2.57万
依托单位：
National Cancer Center Research Institute and Research Center for Innovative Oncology, National Cancer Center Hospital East
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590390/
关键词：
Pancreatic cancer Hyperlipidemia Hamster PPARγ Lipoprotein lipase BOP OLETF rat Diabetes

项目摘要

To examine the role of hyperlipidemia in pancreatic carcinogenesis, the effects of anti-hyperlipidemic agents on BOP-induced pancreatic carcinogenesis were investigated in hamsters.1. Markedly high levels of serum triglycerides and total cholesterol were found in Syrian golden hamsters, but not in C57BL/6 mice, ICR mice, F344 rats and Wistar rats, even at 6 weeks of age Consistent with this finding, LPL activities in the liver were lower in hamsters compared to mice and rats.2. The effects of pioglitazone, a peroxisome proliferator-activated receptor γ (PPARγ) ligand, on LPL expression, serum lipid levels and pancreatic cancer development were examined in hamsters treated with BOP. Pioglitazone treatment elevated LPL mRNA expression in the liver and significantly improved hyperlipidemia. Concurrently, the incidence and multiplicity of pancreatic ductal adenocarcinomas were significantly decreased by pioglitazone in comparison with the controls. These results suggested that suppression … More of pancreatic adenocarcinoma development by pioglitazone is associated with enhanced LPL expression and improvement in the serum lipid profile.3. The effects of other types of anti-hyperlipidemic agents on BOP-induced hamster pancreatic carcinogenesis were examined by analyzing the ductular proliferation in the pancreas as a surrogate marker for carcinogenesis Bazafibrate, a PPAR ligand, and metformine which improves insulin resistance, were effective in the reduction of BOP-induced ductular proliferation in the pancreas.4. The sensitivity of pancreatic ductal epithelium to BOP treatment in the model animals for hyperlipidemia was examined. BOP treatment did not affect proliferation of pancreatic ductal epithelium cells in Mongolian gerbils, but slightly increased the proliferation in OLETF rats.These results indicate that hyperlipidemia could be an enhancing factor for the development of pancreatic cancer in hamsters. However, animals in the hyperlipidemic state were not always sensitive to BOP-induced pancreatic carcinogenesis. Less

为了探讨高脂血症在胰腺癌发生中的作用，我们研究了抗高脂血症药物对bop诱导的仓鼠胰腺癌发生的影响。在叙利亚金仓鼠中发现血清甘油三酯和总胆固醇水平明显升高，但在C57BL/6小鼠、ICR小鼠、F344大鼠和Wistar大鼠中则没有，即使在6周龄时，与这一发现一致，仓鼠肝脏中的LPL活性比小鼠和大鼠低。研究了吡格列酮（一种过氧化物酶体增殖物激活受体γ (PPARγ)配体）对BOP治疗仓鼠LPL表达、血脂水平和胰腺癌发展的影响。吡格列酮可提高肝脏LPL mRNA表达，显著改善高脂血症。同时，与对照组相比，吡格列酮显著降低了胰腺导管腺癌的发生率和多样性。这些结果表明，吡格列酮抑制胰腺腺癌的发展与提高LPL表达和改善血清脂质谱有关。通过分析胰脏导管增生情况，考察其他类型的抗高脂血症药物对bop诱导的胰脏导管增生的影响。bazafibate、PPAR配体和改善胰岛素抵抗的二甲双胍均能有效减少bop诱导的胰脏导管增生。观察高脂血症模型动物胰管上皮对BOP治疗的敏感性。BOP处理对蒙古沙鼠胰腺导管上皮细胞的增殖没有影响，但对OLETF大鼠的增殖有轻微的促进作用。这些结果表明，高脂血症可能是仓鼠胰腺癌发展的一个增强因素。然而，处于高脂血症状态的动物并不总是对bop诱导的胰腺癌发生敏感。少