Tea Modulation of Colon Carcinogenesis

茶对结肠癌的调节

• 批准号: 8636106
• 负责人: MICHAEL WARGOVICH
• 金额: $ 24.4万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8636106
• 关键词: Age; Area; Asia; Azoxymethane; CDKN2A gene; Cancer Control; Carcinogens; Chemoprevention; Chemopreventive Agent; Clinical Trials; Colon; Colon Carcinoma; Colonic Neoplasms; Colorectal; Colorectal Cancer; Colorectal Neoplasms; DNA Methyltransferase; DNA Modification Methylases; DNA methyltransferase inhibition; Data; Defect; Diet; Disease; Division of Cancer Prevention; Eastern Europe; Enzymes; Epigallocatechin Gallate; Epigenetic Process; Event; Funding; Gene Dosage; Gene Silencing; Gene Targeting; Genes; Goals; Green tea; Growth; Histone Acetylation; Histones; Human; Hypermethylation; Impairment; In Vitro; Incidence; Intervention; Intestines; Laboratories; Lesion; Light; MAP Kinase Gene; MLH1 gene; Malignant Neoplasms; Malignant Squamous Cell Neoplasm; Methylation; Modeling; Mus; National Cancer Institute; Nuclear; Nuclear Receptors; PTGS2 gene; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Phenotype; Phytochemical; Play; Prevention; Prevention strategy; Promoter Regions; RXR; Receptor Gene; Regulation; Regulator Genes; Reporting; Research; Retinoic Acid Receptor; Retinoid X Receptor alpha; Role; Route; Signal Pathway; Signal Transduction; Signaling Molecule; Tea; Vitamin D3 Receptor; Work; beta catenin; cancer chemoprevention; cancer prevention; carcinogenesis; colon cancer cell line; colon carcinogenesis; histone acetyltransferase; in vivo; inhibitor/antagonist; mouse model; novel; polyphenol; promoter; public health relevance; receptor; receptor expression; transcription factor; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Epigenetic re-expression of important genes silenced in the pathway of carcinogenesis represents an exciting new area for cancer chemoprevention. The long-range goal of this project is to identify naturally occurring phytochemicals that reverse the inhibition of master cell signaling pathways. One such master switch is the retinoid X receptor (RXR). That RXR is proposed to also be involved in Apc-independent degradation of beta- catenin pivotally places it at the center of crosstalk of cell signaling molecules, often corrupted in colon tumorigenesis. Polyphenols from green tea have widespread cancer chemopreventive activity. At least one of the green tea catechins, epigallocatechin gallate (EGCG) has been reported to restore activity of silenced growth regulatory genes in squamous cell cancers. Our preliminary data suggest that green tea modulates the hypermethylation of RXR alpha gene promoter, and inhibits intestinal tumorigenesis in the azoxymethane- treated ApcMIN/+ mouse. We hypothesize that RXRa is lost early in colon cancer due to gene and that green tea polyphenols restore this activity by inhibition of DMNTs and HDACs, providing a novel mechanism of chemoprevention for colon cancer. Our aims are: In Specific Aim 1, in colon cancer cell lines and in human colorectal tumors establish that loss of RXRa is an early event in colon cancer. In Specific Aim 2, in colon cancer cell lines, determine if EGCG is responsible for changes in HDACs that associate with the promoter region of RXRa, RAR¿, hMLH1, p14arf, and p16INK4a and compare this activity with other known inhibitors of HDACs. In Specific Aim 3, we will determine if inhibition of DNA methyltransferases (DNMTs) is an important component of epigenetic regulation of RXRa activity and other methylated target genes in colon cancer cell lines. In Specific Aim 4 we will examine the chemopreventive effects of green tea/EGCG intervention on RXRa gene dosage in RXRa+/- mice with the colon carcinogen, AOM. We will also examine the effects of green tea/EGCG intervention in intestinal tumorigenesis in ApcMIN/+ RXR+/- and ApcMIN/+ RXR+/+ bigenic mice. The working hypothesis for this aim is that loss of RXRa will augment colon carcinogenesis in RXRa deficient mice. We also explore the effects of GT and EGCG intervention on the reactivation of silenced RXRa in the AOM- treated ApcMIN/+ RXR+/- bigenic mice.

描述(由申请人提供)：在致癌过程中沉默的重要基因的表观遗传再表达代表了癌症化学预防的一个令人兴奋的新领域。该项目的长期目标是确定自然产生的植物化学物质，这些化学物质可以逆转主细胞信号通路的抑制。维甲酸X受体(RXR)就是这样的主开关。RXR被认为也参与了β-连环素的APC非依赖性降解，这使得它处于细胞信号分子串扰的中心，通常在结肠肿瘤的发生中被破坏。绿茶多酚具有广泛的抗癌化学活性。据报道，至少有一种绿茶儿茶素，表没食子儿茶素没食子酸酯(EGCG)可以恢复鳞状细胞癌中沉默的生长调控基因的活性。我们的初步数据表明，绿茶调节RXRα基因启动子的高甲基化，并抑制偶氮甲烷处理的ApcMIN/+小鼠的肠道肿瘤形成。我们假设RXRA在结肠癌早期由于基因缺失而丢失，绿茶多酚通过抑制DMNTs和HDACs恢复这种活性，为结肠癌的化学预防提供了一种新的机制。我们的目标是：在特定的目标1中，在结肠癌细胞系和人类结直肠肿瘤中确定RXRA的丢失是结肠癌的早期事件。在特定目标2中，在结肠癌细胞系中，确定EGCG是否导致与RXRA、RAR？、hMLH1、p14ARF和p16INK4a启动子区域相关的HDACs的变化，并将这一活性与其他已知的HDACs抑制剂进行比较。在特定的目标3中，我们将确定抑制DNA甲基转移酶(DNMT)是否是结肠癌细胞系中RXRA活性和其他甲基化靶基因的表观遗传调节的重要组成部分。在特定的目的4中，我们将检测绿茶/EGCG干预对RXRA+/-小鼠体内RXRA基因剂量的化学预防作用。我们还将研究绿茶/EGCG干预对ApcMIN/+RXR+/-和ApcMIN/+RXR+/+双基因小鼠肠道肿瘤发生的影响。这一目标的工作假设是，RXRA缺失将增加RXRA缺陷小鼠的结肠癌发生。我们还探讨了GT和EGCG干预对AOM处理的ApcMIN/+RXR+/-双基因小鼠沉默的RXRA重新激活的影响。