Tea Modulation of Colon Carcinogenesis

茶对结肠癌的调节

• 批准号: 8686707
• 负责人: MICHAEL WARGOVICH
• 金额: $ 25.18万
• 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 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8686707
• 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（申请人证明）：在癌症中，对癌症的致癌基因的表观遗传重新表达了对癌症的致癌基因，以识别出植物化学物质的自然，这些植物化学物质均涉及MAS质量质量细胞信号途径。涉及的降解β-蛋白素的降解将其放置为细胞信号分子的中心，通常在结肠肿瘤中损坏。基因启动子HAT RXRA在结肠癌的早期因绿色而损失，绿茶多酚通过抑制恢复这种活性。在结肠癌2中，在结肠癌细胞系中的事件确定EGCG是否负责与RXRA启动子区域相关的HDACS THAC的变化HMLH1，P14ARF和P16INK4A与其他已知的HDAC的活性进行了比较4我们将检查绿茶/EGCG干预对RXRA基因剂量的RXRA +/-小鼠的化学方法/ - 和apcmin/+ rxr+/+大元素。 。