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: 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
• 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

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.

项目摘要 芳香烃受体（AhR）最初被发现是一种细胞内蛋白， 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 芳香族化合物近年来，已经证明AhR在结构上结合， 功能多样的化合物，包括化学保护性植物化学物质，如黄酮类化合物、多酚类化合物 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，并且可以被分类为选择性AhR调节剂（SAhRM）。本实验室以前的研究 已经利用SAhRM用于治疗疾病的潜在应用，并且6-甲基-1，3，8- 三氯二苯并呋喃（MCDF）最初被鉴定为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中表现出抗雌激素活性， 是一种有效的抗雌激素，通过抑制AhR-雌激素受体（ER）串扰发挥作用。结果 目前的初步研究表明，AhR激动剂如TCDD和MCDF抑制了大量 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， 分类为基底或三阴性细胞。MCDF还抑制无胸腺裸鼠体内肿瘤生长 带有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AhR依赖性的两种抗转移microRNA（miR）的诱导，即miR-335和miR-235。 205.这些研究将进一步探讨其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将侧重于 SAhRM诱导的miR-335和miR-205的调节以及AhR在降低增殖中的作用， 一组ER阴性乳腺癌细胞系的迁移和侵袭。在目标2中，AhR- miR-335和miR-205表达的依赖性调节将在ER阴性乳腺癌细胞中确定 细胞系和调节miR表达的功能性二恶英反应元件（DRES）。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 证实了AhR、miR-335和miR-205在无胸腺小鼠中调节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 这些研究将首次描述AhR-miR相互作用的分子机制， SAhRM在ER阴性乳腺癌治疗中的临床应用。