GENE EXPRESSION IN DIET INDUCED PROSTATE CANCER

流行病学研究表明，一代人以上的高脂肪饮食与前列腺癌风险增加有关。更全面地了解饮食脂肪在前列腺癌发生、促进和发展中的分子基础，对于设计合理的前列腺癌防治方案是至关重要的。我们用高牛肉脂肪饲料(体重22.52%)喂养ACI大鼠两代(母亲和雄性幼鼠)，观察到第二代雄性大鼠比对照组(5%脂肪饲料)发生前列腺癌的几率更高，并且更早。值得注意的是，高牛肉脂肪饮食的大鼠在前列腺背叶发生了肿瘤，因为大鼠的前列腺背叶与前列腺癌最常见的人类前列腺的外围区同源。所有的动物研究和组织学分析已经完成，我们已经从6月、12月和18月龄的第二代大鼠的背部前列腺中提取了RNA。我们现在建议分析高脂饮食大鼠与对照饮食大鼠前列腺背部的分子差异，以跟踪饮食诱导的前列腺癌的进展分子阶段的基因表达。我们建议使用Affymetrix微阵列(大约7000个基因)来识别高牛肉脂肪饮食和对照饮食大鼠前列腺背部mRNA表达谱的差异。此外，我们建议使用Northern杂交和免疫组织化学来确认使用微阵列获得的数据，并识别差异表达相关基因的细胞类型。这些实验的成功完成将有助于我们了解饮食相关前列腺癌的分子基础。此外，它还可能识别受饮食调节并与人类前列腺癌相关的中间生物标记物。

Epidemiological studies suggest that a high fat diet for more than one generation is associated with an increased risk of prostate cancer. A more complete understanding of the molecular basis for prostate cancer initiation, promotion and progression by dietary fat is essential for the design of rational programs for prostate cancer prevention and treatment. We have maintained ACI rats on a high beef fat diet (22.52% by weight) for two generations (mothers and male pups) and observed that 2nd-generation male rats develop prostatic neoplasia at a higher incidence, and earlier in life, than rats on a control, 5% fat diet. It is significant that rats on the high beef fat diet developed neoplasia in the dorsal lobes of the prostate, as the dorsal lobe of the rat prostate is homologous to the peripheral zone of the human prostate, where prostate cancer is most prevalent. All animal studies and histological analyses have been completed and we have prepared RNA from dorsal prostates of 6, 12 and 18-month-old 2nd-generation rats. We now propose to analyze the molecular differences in the dorsal prostates of rats maintained on a high fat diet, compared to rats on a control diet to follow gene expression through the progressive molecular stages of diet-induced prostatic neoplasia. We propose to use Affymetrix microarrays (approximately 7000 genes) to identify differences in mRNA expression profiles in the dorsal prostates of rats on high beef fat and control diets. Further we propose to use northern blots and immunohistochemistry to confirm data obtained using microarrays and to identify the cell types differentially expressing the genes in question. The successful completion of these experiments will contribute to our understanding of the molecular basis of diet-associated prostate cancer. Further, it can potentially identify intermediate biomarkers that are modulated by diet and are relevant to human prostate cancer.