Insulin-independent promotion of chemically induced hepatocellular tumor development in genetically diabetic mice
Insulin-independent promotion of chemically induced hepatocellular tumor development in genetically diabetic mice
复制标题
DOI：
10.1111/j.1349-7006.2009.01345.x
复制
发表时间：
2010-01-01
期刊：
影响因子：
5.7
通讯作者：
Lee, Gang-Hong
中科院分区：
文献类型：
--
作者：
Yamasaki, Kohtaro;Hayashi, Yoshihiro;Lee, Gang-Hong
糖尿病已被认为是人类肝癌发生的流行病学危险因素。一种合理的可能性是，这归因于高胰岛素血症，以补偿肥胖相关的胰岛素抵抗。然而，糖尿病是一种复杂的疾病，本质上是由高血糖引起的多种异常情况。因此，目前尚不清楚高胰岛素血症是否是癌症风险增加的先决条件。为了获得回答这个问题的线索，我们对胰岛素遗传缺陷的糖尿病模型小鼠的化学诱导肝癌发生进行了表征。起源于C57BL/6品系的秋田近交系小鼠携带胰岛素II基因的杂合子胚系突变，并以常染色体显性方式患有遗传性胰岛素缺乏和糖尿病。将它们与对肝癌发生高度敏感的正常C3H/HeJ小鼠交配，所产生的F-1胎无论是正常的还是胰岛素缺乏的，都暴露于二乙基亚硝胺中，并对诱发的肝细胞肿瘤的数量、大小、增殖活性和细胞凋亡进行评估。出乎意料的是，胰岛素缺乏动物的肝细胞肿瘤的平均体积和总体积都是正常对照组的两倍多，而肿瘤数量没有显著差异。胰岛素缺乏小鼠的肿瘤细胞凋亡率显著降低，但细胞增殖无明显变化。综上所述，我们的结果表明，糖尿病小鼠发生了胰岛素非依赖性促进肝肿瘤的作用。显然，人类病例的胰岛素非依赖性机制也值得考虑。(癌症科学2009)。
Diabetes mellitus has been proposed as an epidemiological risk factor for human liver cancer development. One reasonable possibility is that this is attributable to hyperinsulinemia compensatory for obesity-related insulin resistance. However, diabetes mellitus is a complex disease with multiple abnormal conditions essentially caused by hyperglycemia. Therefore, it is not evident whether hyperinsulinemia is prerequisite for the elevated cancer risk. To gain a clue to answer this question, we characterized chemically induced hepatocarcinogenesis in diabetic model mice genetically deficient for insulin. Akita inbred mice originating from the C57BL/6 strain carry a heterozygous germline mutation of the insulin II gene and suffer from inherited insulin deficiency and diabetes in an autosomal dominant manner. They were mated with normal C3H/HeJ mice with high sensitivity to liver carcinogenesis and the resultant F-1 littermates, which were either normal or insulin deficient, were exposed to diethylnitrosamine and induced hepatocellular tumors were evaluated for number, size, proliferative activity, and apoptosis. Unexpectedly, both mean and total volumes of hepatocellular tumors in the insulin-deficient animals were more than twofold larger than those in the normal controls, with no significant difference in tumor number. The tumors in insulin-deficient mice showed a significantly lower frequency of apoptosis but no alteration in cell proliferation. In conclusion, our results indicate that insulin-independent liver tumor promotion occurred in diabetic mice. Clearly, insulin-independent mechanisms for the human case also deserve consideration. (Cancer Sci 2009).