Mechanisms of tumor suppressor gene reactivation in colon cancer by berries

浆果重新激活结肠癌抑癌基因的机制

• 批准号: 8606827
• 负责人: Li-Shu Wang
• 金额: $ 28.8万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-08 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8606827
• 关键词: Adenomatous Polyposis Coli; Animal Model; Animals; Anthocyanins; Apoptosis; Azoxymethane; Berry; Birds; Cancer Etiology; Cancer Patient; Carcinogenesis Inhibition; Carcinogens; Cell Culture System; Cell Proliferation; Cells; Cessation of life; Chemoprevention; Chemopreventive Agent; Clinical; Colon; Colon Carcinoma; Colonic Adenoma; Colonic Neoplasms; Color; Colorectal Cancer; Colorectal Neoplasms; Consumption; DNA Methyltransferase; DNA Modification Methylases; DNA Nucleotidylexotransferase; Development; Diagnosis; Diet; Disease; Distant Metastasis; Drug Kinetics; E-Cadherin; ENG gene; Epidemiologic Studies; Esophageal; Fractionation; Freeze Drying; Gene Expression; Gene Silencing; Genes; Goals; Grant; Human; Human Development; Hypermethylation; In Situ Nick-End Labeling; Intervention; Intervention Trial; Intestines; Knock-out; Label; Laboratories; Malignant Neoplasms; Mediating; Methylation; Modeling; Mus; Oral; Pathway interactions; Patients; Persons; Polyps; Powder dose form; Prevention; Prevention strategy; Raspberries; Rattus; Rectal Polyp; Rectal Suppositories; Role; Serum; Small Intestines; Specimen; Staining method; Stains; Testing; Tissues; Tumor Suppressor Genes; Tumor Tissue; United States; Water; Woman; adenoma; angiogenesis; base; c-myc Genes; cancer cell; cancer prevention; carcinogenesis; colorectal cancer prevention; demethylation; fruits and vegetables; men; mortality; neoplastic cell; novel; protective effect; protein expression; public health relevance; trend; tumor; tumorigenesis; uptake; urinary

DESCRIPTION (provided by applicant): Although mortality rates from colorectal cancer have declined in both men and women over the past two decades, the 5-year survival from this disease is 64% and continues to decline to 57% at 10 years after diagnosis. For persons with distant metastases at diagnosis, the 5-year survival is only 10%. Therefore, the prevention of colon cancer remains an important goal and chemoprevention is a viable approach to achieve this goal. Our laboratory has been evaluating the use of freeze-dried berries, mainly black raspberries (BRBs), for the prevention of colon cancer in animals and in humans. The addition of BRB powder to the diet inhibited the development of colonic adenomas and carcinomas in azoxymethane (AOM)-treated rats, and of spontaneous adenomas in the intestine of ApcMin/+ mice. Two pilot intervention trials have been conducted in humans: one in patients with sporadic colorectal cancer and the other in patients with familial adenomatous polyposis (FAP). Our results suggest that short-term treatment of sporadic colorectal cancer patients with oral BRB powder (20g/3x/day) significantly reduced cell proliferation rates and produced a positive trend for changes in apoptosis, angiogenesis, and in genes associated with the Wnt pathway in colorectal tumors. Our FAP trial indicated that nine month treatment of FAP patients with BRB powder administered both orally (20g/3x/day) and in the form of rectal suppositories caused a 53% regression rate of rectal polyps. These results suggest that berries have potential for prevention of colorectal cancer in humans. Using bio-directed fractionation, we and our collaborators found that the anthocyanins in BRBs are important for their chemopreventive effects. Recent preliminary studies suggest that the colorectal cancer inhibitory effect of BRBs may be due, at least in part, to their ability to inhibit DNA methyltransferase 1 (DNMT1) protein expression and total DNMT activity in human colon tumor cells, which led to demethylation and reactivation of hypermethylation-silenced tumor suppressor genes such as p16. Short-term BRB intervention in colorectal cancer patients resulted in the demethylation of p16 and re-expression of the gene in aberrant crypts of colonic tumor tissues. We propose therefore to determine if demethylation and reactivation of hypermethylation- silenced genes by BRB anthocyanins in human colon cancer cells and in ApcMin/+ mice is associated with inhibition of tumorigenesis (Specific Aim 1) and the role of DNMT1 in BRB anthocyanin-induced demethylation of tumor suppressor genes (Specific Aim 2). We will also determine if BRBs influence the methylation state of hypermethylation-silenced tumor suppressor genes in specimens obtained from the two human BRB intervention trials, and its association with reduced cell proliferation and polyp regression (Specific Aim 3). Finally, we will conduct a pharmacokinetic study to determine the uptake of anthocyanins into human colon cells, and intestinal tissue and serum, as well as urinary levels of anthocyanins and their metabolites when administered at different concentrations in the diet to ApcMin/+ mice (Specific Aim 4). Ultimately, we plan to evaluate anthocyanins for prevention of colorectal cancer in humans.

描述（由申请人提供）：尽管在过去的二十年中，男性和女性的结直肠癌死亡率都有所下降，但这种疾病的5年生存率为64%，并在诊断后10年继续下降至57%。对于诊断时有远处转移的人，5年生存率仅为10%。因此，结肠癌的预防仍然是一个重要的目标，化学预防是实现这一目标的可行方法。我们的实验室一直在评估使用冻干浆果，主要是黑树莓（BRB），用于预防动物和人类的结肠癌。在饮食中添加BRB粉末可抑制氧化偶氮甲烷（AOM）处理的大鼠结肠腺瘤和癌的发生，以及ApcMin/+小鼠肠中自发性腺瘤的发生。两项初步干预试验已在人类中进行：一项在散发性结直肠癌患者中进行，另一项在家族性腺瘤性息肉病（FAP）患者中进行。我们的研究结果表明，短期治疗散发性结直肠癌患者口服BRB粉末（20 g/3x/天）显着降低细胞增殖率，并产生积极的趋势，细胞凋亡，血管生成，并在结直肠肿瘤中与Wnt通路相关的基因的变化。我们的FAP试验表明，口服（20 g/3x/天）和直肠栓剂形式的BRB粉末治疗FAP患者9个月，导致直肠息肉消退率为53%。这些结果表明，浆果具有预防人类结直肠癌的潜力。使用生物定向分馏，我们和我们的合作者发现BRB中的花青素对其化学预防作用很重要。最近的初步研究表明，BRB的结直肠癌抑制作用可能是由于，至少部分是由于它们能够抑制DNA甲基转移酶1（DNMT 1）蛋白表达和总DNMT活性在人类结肠肿瘤细胞，这导致去甲基化和重新激活的超甲基化沉默的肿瘤抑制基因，如p16。结直肠癌患者短期BRB干预导致结肠肿瘤组织异常隐窝中p16基因的去甲基化和重新表达。因此，我们建议确定在人结肠癌细胞和ApcMin/+小鼠中BRB花青素引起的超甲基化沉默基因的去甲基化和再激活是否与肿瘤发生的抑制（特异性目的1）以及DNMT 1在BRB花青素诱导的肿瘤抑制基因的去甲基化中的作用（特异性目的2）相关。我们还将确定BRB是否影响从两项人类BRB干预试验中获得的标本中高甲基化沉默肿瘤抑制基因的甲基化状态，以及其与细胞增殖减少和息肉消退的相关性（具体目标3）。最后，我们将进行药代动力学研究，以确定在ApcMin/+小鼠的饮食中以不同浓度给药时，人结肠细胞、肠组织和血清对花青素的摄取，以及花青素及其代谢物的尿液水平（具体目标4）。最终，我们计划评估花青素对人类结直肠癌的预防作用。

项目成果

An overview of epigenetics and chemoprevention.

• DOI: 10.1016/j.febslet.2010.11.002
• 发表时间: 2011-07-07
• 期刊: FEBS letters
• 影响因子: 3.5
• 作者: Huang YW;Kuo CT;Stoner K;Huang TH;Wang LS
• 通讯作者: Wang LS

Urolithin A suppresses the proliferation of endometrial cancer cells by mediating estrogen receptor-α-dependent gene expression.

• DOI: 10.1002/mnfr.201600048
• 发表时间: 2016-11
• 期刊: MOLECULAR NUTRITION & FOOD RESEARCH
• 影响因子: 5.2
• 作者: Zhang, Wei;Chen, Jo-Hsin;Aguilera-Barrantes, Irene;Shiau, Chung-Wai;Sheng, Xiugui;Wang, Li-Shu;Stoner, Gary D.;Huang, Yi-Wen
• 通讯作者: Huang, Yi-Wen

Black raspberry-derived anthocyanins demethylate tumor suppressor genes through the inhibition of DNMT1 and DNMT3B in colon cancer cells.

• DOI: 10.1080/01635581.2013.741759
• 发表时间: 2013
• 期刊: Nutrition and cancer
• 作者: Wang LS;Kuo CT;Cho SJ;Seguin C;Siddiqui J;Stoner K;Weng YI;Huang TH;Tichelaar J;Yearsley M;Stoner GD;Huang YW
• 通讯作者: Huang YW

Can Natural Products Suppress Resistant Helicobacter pylori to Fight Against Gastric Diseases in Humans?

• DOI: 10.2991/efood.k.200211.001
• 发表时间: 2020-02
• 期刊: eFood
• 作者: Wang LS;Echeveste CE;Yu J;Huang YW;Lechner J;Mei L;Sanvanson P;Yearsley M;Wang CK;Stoner G
• 通讯作者: Stoner G

Beneficial Regulation of Metabolic Profiles by Black Raspberries in Human Colorectal Cancer Patients.

• DOI: 10.1158/1940-6207.capr-15-0065
• 发表时间: 2015-08
• 期刊: Cancer prevention research (Philadelphia, Pa.)
• 作者: Pan P;Skaer CW;Stirdivant SM;Young MR;Stoner GD;Lechner JF;Huang YW;Wang LS
• 通讯作者: Wang LS