Tea Modulation of Colon Carcinogenesis

茶对结肠癌的调节

• 批准号: 7905557
• 负责人: MICHAEL WARGOVICH
• 金额: $ 26.41万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 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/7905557
• 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; Genus Cola; 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; Progress Reports; Promoter Regions; RXR; 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; 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. PUBLIC HEALTH RELEVANCE: Silencing of critical regulatory genes by epigenetic mechanisms may play a critical role in colon cancer. We hypothesize that green tea polyphenols suppress DNA methyltransferases and histone acetylase activity. This, in turn, may allow re-expression of growth regulatory genes and provide a means of cancer control for this disease. Because RXRa loss involves impairment of regulatory gene networks, the impact of green tea reversal of this transcription factor's loss is significant.

描述（由申请人提供）：在致癌途径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天然存在的植物化学物质，逆转主细胞信号通路的抑制。一个这样的主开关是类维生素A X受体（RXR）。提出RXR也参与β-连环蛋白的APC-非依赖性降解，这将其枢轴地置于细胞信号传导分子的串扰的中心，通常在结肠肿瘤发生中被破坏。绿色茶中的多酚具有广泛的癌症化学预防活性。据报道，至少一种绿色茶儿茶素，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节基因的活性。我们的初步数据表明，绿色茶调节RXR α基因启动子的超甲基化，并抑制氧化偶氮甲烷处理的ApcMIN/+小鼠的肠道肿瘤发生。我们假设RXR α在结肠癌早期由于基因而丢失，而绿色茶多酚通过抑制DMNT和HDAC来恢复这种活性，为结肠癌的化学预防提供了一种新的机制。我们的目标是：在具体目标1中，在结肠癌细胞系和人结肠直肠肿瘤中确定RXR α的丢失是结肠癌的早期事件。在具体目标2中，在结肠癌细胞系中，确定EGCG是否负责与RXRa，RAR？，hMLH 1，p14 arf和p16 INK 4a的启动子区域相关的HDAC的变化，并将此活性与其他已知的HDAC抑制剂进行比较。在具体目标3中，我们将确定DNA甲基转移酶（DNMT）的抑制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控的重要组成部分。在具体目标4中，我们将检查绿色茶/EGCG干预对具有结肠致癌物AOM的RXRa+/-小鼠中的RXRa基因剂量的化学预防作用。我们还将研究绿色茶/EGCG干预对ApcMIN/+ RXR+/-和ApcMIN/+ RXR+/+双基因小鼠肠肿瘤发生的影响。该目标的工作假设是RXR α缺失将增加RXR α缺陷小鼠的结肠癌发生。我们还探讨了GT和表没食子酸酯没食子酸酯（EGCG）干预对AOM处理的ApcMIN/+ RXR+/-双基因小鼠中沉默的RXRa重新激活的影响。 公共卫生相关性：通过表观遗传机制沉默关键调控基因可能在结肠癌中起关键作用。我们推测，绿色茶多酚抑制DNA甲基转移酶和组蛋白乙酰化酶的活性。反过来，这可能允许生长调节基因的重新表达，并为这种疾病提供癌症控制的手段。由于RXR α的损失涉及调节基因网络的损伤，因此绿色茶逆转这种转录因子损失的影响是显著的。