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

• 批准号: 7984095
• 负责人: Stephen H. Safe
• 金额: $ 26.72万
• 依托单位: TEXAS A&M UNIVERSITY
• 依托单位国家: 美国
• 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/7984095
• 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; 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 pancreas; Mammary Neoplasms; Mediating; Metabolism; MicroRNAs; Molecular; Mus; Nuclear Receptors; Nude Mice; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phytochemical; Porphyrias; Prostate; Protein Binding; Regulation; Research; Role; Staging; Tetrachlorodibenzodioxin; Tissues; Toxic Environmental Substances; Xenograft procedure; cancer cell; chemotherapy; clinical application; immunotoxicity; in vivo; malignant breast neoplasm; member; migration; outcome forecast; public health relevance; receptor; receptor binding; response; transcription factor; tumor growth

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Selective aryl hydrocarbon receptor (AhR) modulators (SAhRMs) bind and activate the AhR and, in estrogen receptor-negative breast cancer cells, these compounds inhibit cell proliferation and tumor growth in mouse xenografts. The proposed research will investigate the AhR-dependent induction of the antimetastatic microRNA-335 and microRNA-205 and delineate their role in the anticarcinogenic activity of SAhRMs.

描述（由申请人提供）：芳烃受体（AhR）最初被发现是一种细胞内蛋白质，可与环境毒物2,3,7,8-四氯二苯并-对二恶英（TCDD）和结构相关的氯化芳香族化合物结合。近年来，已经证明 AhR 与结构和功能多样的化合物结合，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利用了 SAhRM 在疾病治疗方面的潜在应用，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 表现出抗雌激素活性在雌激素反应性乳腺癌细胞和乳腺肿瘤中，MCDF 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。初步研究结果表明，TCDD 和 MCDF 等 AhR 激动剂可抑制大量 ER 阴性乳腺癌细胞的生长，包括高度侵袭性的 MDA-MB-231 和 MDA-MB-468 细胞，这些细胞被分类为基础或三阴性细胞。 MCDF 还可以抑制携带 ER 阴性细胞作为异种移植物的无胸腺裸鼠的体内肿瘤生长。此外，MCDF和TCDD的抗肿瘤活性伴随着两种抗转移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MCDF的分子机制和潜在的临床应用，并在结构上相关的 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 在减少一组 ER 阴性乳腺癌细胞系的增殖、迁移和侵袭中的作用。在目标 2 中，将确定 ER 阴性乳腺癌细胞系的 AhR 依赖性调节 miR-335 和 miR-205 表达的机制，并鉴定调节 miR 表达的功能性二恶英反应元件 (DRE)。此外，还将研究 AhR-miR-335 和 AhR-miR-205 相互作用调节的基因。目标 3 将使用 AhR、miR-335 和 miR-205 表达受到调节的细胞系证实 AhR、miR-335 和 miR-205 在调节无胸腺裸鼠原位乳腺肿瘤生长中的作用。拟议的研究将首次描述 AhR-miR 相互作用的分子机制以及 SAhRM 的开发，用于治疗 ER 阴性乳腺癌的临床应用。 公共健康相关性：选择性芳烃受体 (AhR) 调节剂 (SAhRM) 结合并激活 AhR，在雌激素受体阴性乳腺癌细胞中，这些化合物可抑制小鼠异种移植物中的细胞增殖和肿瘤生长。拟议的研究将调查抗转移 microRNA-335 和 microRNA-205 的 AhR 依赖性诱导，并阐明它们在 SAhRM 抗癌活性中的作用。