Molecular Mechanisms and Application of Ah Receptor-MicroRNA Interactions

Ah受体-MicroRNA相互作用的分子机制及应用

基本信息

批准号：
8269955
负责人：
Stephen H. Safe
金额：
$ 25.92万
依托单位：
TEXAS A&M UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8269955
关键词：
7-ketocholesterol Adverse effects Affinity Agonist Aromatic Amines Aromatic Compounds Aromatic Polycyclic Hydrocarbons Aryl Hydrocarbon Receptor Benzo(a)pyrene Bilirubin Binding Biochemical Breast Cancer Cell CYP1A1 gene Cancer cell line Cell Line Cell Proliferation Cells Chemopreventive Agent Chemoprotective Agent Cleft Palate Cytotoxic agent Development Dioxins Disease Disease-Free Survival Elements Endometrial Carcinoma Estrogen Antagonists Estrogen Receptor Modulators Estrogen Receptors Estrogen receptor negative Estrogens Exhibits Family Flavonoids Food Genes Growth Indole-3-Carbinol Ink Laboratories Ligands Malignant neoplasm of prostate Mammary Neoplasms Mediating Metabolism MicroRNAs Molecular Mus Nuclear Receptors Nude Mice Patients Pharmaceutical Preparations Pharmacologic Substance Phytochemical Porphyrias Protein Binding Regulation Research Role Staging Tetrachlorodibenzodioxin Tissues Toxic Environmental Substances Xenograft procedure chemotherapy clinical application immunotoxicity in vivo malignant breast neoplasm member migration outcome forecast pancreatic cancer cells receptor receptor binding response transcription factor tumor growth

项目摘要

PROJECT SUMMARY The aryl hydrocarbon receptor (AhR) was initially discovered as an intracellular protein that binds to the environmental toxicant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and structurally related chlorinated aromatic compounds. In recent years, it has been demonstrated that the AhR binds with structurally and functionally diverse compounds including chemoprotective phytochemicals such as flavonoids, polyphenolics and indole-3-carbinol. Not surprisingly, these compounds exhibit tissue-specific AhR agonist and antagonist activities and can be classified as selective AhR modulators (SAhRMs). Previous studies in this laboratory have taken advantage of the potential applications of SAhRMs for treatment of diseases, and 6-methyl-1,3,8- trichlorodibenzofuran (MCDF) was initially characterized as an AhR antagonist but, like TCDD, MCDF exhibited antiestrogenic activity in estrogen-responsive breast cancer cells and mammary tumors, and MCDF is a potent antiestrogen that acts through inhibitory AhR-estrogen receptor (ER) crosstalk. Results of preliminary studies now show that AhR agonists such as TCDD and MCDF inhibit growth of a large number of ER-negative breast cancer cells including highly invasive MDA-MB-231 and MDA-MB-468 cells that are classified as basal or triple negative cells. MCDF also inhibits tumor growth in vivo in athymic nude mice bearing ER-negative cells as xenografts. Moreover, the antitumorigenic activity of MCDF and TCDD is accompanied by AhR-dependent induction of two antimetastatic microRNAs (miRs), namely miR-335 and miR- 205. The proposed studies will further investigate the molecular mechanisms and potential clinical applications of MCDF and structurally-related SAhRMs for treatment of ER-negative breast cancer. Aim 1 will focus on SAhRM-induced modulation of miR-335 and miR-205 and the role of the AhR in decreasing the proliferation, migration and invasion of a panel of ER-negative breast cancer cell lines. In Aim 2, the mechanism of AhR- dependent regulation of miR-335 and miR-205 expression will be determined ER-negative breast cancer cell lines and the functional dioxin responsive elements (DREs) regulating miR expression will be identified. In addition, genes regulated by AhR-miR-335 and AhR-miR-205 interactions will also be investigated. Aim 3 will confirm the role of the AhR, miR-335 and miR-205 in regulating orthotopic mammary tumor growth in athymic nude mice using cell lines in which expression of the AhR, miR-335 and miR-205 is regulated. The proposed studies will be the first to characterize the molecular mechanisms of AhR-miR interactions and development of SAhRMs for clinical applications in the treatment of ER-negative breast cancer.

项目概要芳烃受体 (AhR) 最初被发现是一种细胞内蛋白，可与环境毒物 2,3,7,8-四氯二苯并-对二恶英 (TCDD) 和结构相关的氯化物芳香族化合物。近年来，已经证明AhR在结构上和功能多样的化合物，包括化学保护性植物化学物质，如黄酮类、多酚类和吲哚-3-甲醇。毫不奇怪，这些化合物表现出组织特异性 AhR 激动剂和拮抗剂活性，可归类为选择性 AhR 调节剂 (SAhRM)。该实验室之前的研究已利用 SAhRM 治疗疾病的潜在应用，以及 6-甲基-1,3,8- 三氯二苯并呋喃 (MCDF) 最初被定性为 AhR 拮抗剂，但与 TCDD 一样，MCDF 在雌激素反应性乳腺癌细胞和乳腺肿瘤以及 MCDF 中表现出抗雌激素活性是一种有效的抗雌激素，通过抑制性 AhR 雌激素受体 (ER) 串扰发挥作用。结果目前初步研究表明，TCDD和MCDF等AhR激动剂可抑制大量细胞的生长。 ER 阴性乳腺癌细胞，包括高度侵袭性的 MDA-MB-231 和 MDA-MB-468 细胞，分类为基底细胞或三阴性细胞。 MCDF 还可抑制无胸腺裸鼠体内的肿瘤生长携带 ER 阴性细胞作为异种移植物。此外，MCDF和TCDD的抗肿瘤活性是伴随着两种抗转移 microRNA (miR) 的 AhR 依赖性诱导，即 miR-335 和 miR- 205. 拟议的研究将进一步研究分子机制和潜在的临床应用 MCDF 和结构相关的 SAhRM 用于治疗 ER 阴性乳腺癌。目标 1 将重点关注 SAhRM 诱导的 miR-335 和 miR-205 调节以及 AhR 在减少增殖中的作用，一组 ER 阴性乳腺癌细胞系的迁移和侵袭。在目标 2 中，AhR 的机制- miR-335和miR-205表达的依赖性调节将由ER阴性乳腺癌细胞确定细胞系和调节 miR 表达的功能性二恶英反应元件 (DRE) 将被鉴定。在此外，还将研究 AhR-miR-335 和 AhR-miR-205 相互作用调控的基因。目标3将证实 AhR、miR-335 和 miR-205 在调节无胸腺原位乳腺肿瘤生长中的作用使用AhR、miR-335和miR-205的表达受到调节的细胞系的裸鼠。拟议的研究将是第一个描述 AhR-miR 相互作用的分子机制和发展的研究 SAhRM 用于治疗 ER 阴性乳腺癌的临床应用。