Tea Modulation of Colon Carcinogenesis

描述(申请人提供)：绿茶和红茶一起代表了世界上最常消费的饮料，是极少数具有广泛化学预防致癌活性的植物化学物质来源之一。这种活性和无毒性使茶成为一种在降低人类癌症风险方面具有吸引力的潜在用途。饮用绿茶可以降低患肺癌、胃癌和胰腺癌等多种癌症的风险。最近，有研究表明，在美国人口中，习惯喝茶与结肠癌风险降低有关。然而，我们还需要更多的研究，才能充分了解茶的癌症化学预防活性，以及茶在人类癌症预防中的可能应用。这个项目的总体目标是通过阐明茶叶的作用机制和鉴定其中的活性成分来了解茶和癌症的预防。将使用APC Min/小鼠结肠癌及相关细胞系的动物模型。该项目将开发有用的生物标记物、新的药物(活性成分的代谢物或类似物)和有效的剂型来预防人类癌症。具体地说，我们打算测试这一假设，即口服茶叶是一种有效的致癌抑制因子。将以Min小鼠和偶氮甲烷(AOM)处理的Min小鼠为动物模型，对TEA对畸形隐窝病灶和结肠癌形成的影响进行剂量-反应研究。我们将评估绿茶和红茶之间的可能差异，以及咖啡因对结肠癌发生的影响。接下来，我们将确定绿茶和红茶对结肠细胞增殖和凋亡的影响，并将其与肿瘤发生结果相关联。为了研究其分子机制，将测试TEA对Min小鼠结肠中AP-L、ERK、JNK、c-jun、J3-catenin等蛋白的调节能力。为了阐明绿茶和红茶抑制小鼠结肠肿胀发生的机制，我们将用结肠标本对花生四烯酸代谢、环氧合酶(COX)蛋白和mRNA水平以及COX、脂氧合酶和磷脂酶A2的活性进行研究。此外，还将研究茶多酚对COX-2高表达的人结肠腺癌细胞生长的影响。

DESCRIPTION (provided by applicant): Green and black tea together represent the most commonly consumed beverages worldwide and is one of very few sources of phytochemicals with a broad chemopreventive activity against carcinogenesis. This activity and the lack of toxicity make tea an attractive agent for potential use in the reduction of human cancer risk. Consumption of green tea reduces risk for several cancers including lung, stomach, and pancreatic cancer. Recently it has been shown that habitual consumption of tea is associated with a reduced risk for colon cancer in a U.S. population. Nevertheless, much more research is needed before we can fully understand the cancer chemopreventive activities of tea and the possible application of tea in human cancer prevention. The overall goal of this project is to understand tea and cancer prevention by elucidating the mechanisms and identifying the active components involved. The Apc Min/+ mouse animal model for colon cancer and related cell lines will be used. This project will develop useful biomarkers, new agents (metabolites or analogs of the active components), and effective dosage forms for the prevention of human cancer. Specifically, we intend to test the hypothesis that orally administered tea is an effective inhibitor of carcinogenesis. The Min mouse and azoxymethane (AOM)-treated Min mouse will be used as the animal models to conduct dose-response studies for the effect of tea on aberrant crypt foci and colon tumor formation. Possible differences between green tea and black tea and the effect of caffeine on colon tumorigenesis will be assessed. We next will determine the effect of green tea and black tea on the proliferation and apoptosis of cells in the colon and correlate it with the tumorigenesis results. To study the molecular mechanisms, tea will be tested for its ability to modulate AP-l, ERK, JNK, c-Jun, j3-catenin and other proteins in the colons of Min mice. To elucidate the mechanistic basis for the inhibition of colon turnorigenesis by green tea and black tea in the Min and AOMIMin mouse models studies on arachidonic acid metabolism, cyclooxygenase (COX) protein and mRNA levels, and activities of COX, lipoxygenase, and phospholipase A2 will be conducted with colon samples. Furthermore, studies examining the effect of tea polyphenols on the growth of human colon adenocarcinoma cells that have high levels of COX-2 expression will be conducted.