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: 8470085
• 负责人: Stephen H. Safe
• 金额: $ 24.36万
• 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/8470085
• 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; 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 最初发现芳基碳氢化合物受体（AHR）是一种结合与 环境毒物2,3,7,8-四氯迪本佐-P-二恶英（TCDD）和与结构相关的氯化 芳香化合物。近年来，已证明AHR与结构上的结合， 功能多样的化合物，包括化学保护性植物化学物质，例如类黄酮，多形苯酚 和Indole-3-Carbinol。毫不奇怪，这些化合物表现出组织特异性的AHR激动剂和拮抗剂 活动可以归类为选择性AHR调节器（SAHRMS）。该实验室的先前研究 已经利用了SAHRM在治疗疾病的潜在应用和6-甲基-1,3,8-- Trichlorodibenzofuran（MCDF）最初被描述为AHR拮抗剂，但像TCDD一样，MCDF 在雌激素反应性乳腺癌细胞和乳腺肿瘤和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）串扰起作用。结果 现在的初步研究表明，诸如TCDD和MCDF之类的AHR激动剂抑制了大量的生长 ER阴性乳腺癌细胞，包括高度侵入性MDA-MB-231和MDA-MB-468细胞 分类为基础或三重阴性细胞。 MCDF还抑制腹膜裸鼠体内肿瘤的生长 将ER阴性细胞作为异种移植。此外，MCDF和TCDD的抗肿瘤活性为 伴随AHR依赖性诱导了两种抗转移的microRNA（miRS），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和与结构相关的SAHRM用于治疗ER阴性乳腺癌。 AIM 1将重点关注 SAHRM诱导的miR-335和miR-205的调节以及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入侵。在AIM 2中，AHR的机制 MiR-335和miR-205表达的依赖调节将确定ER阴性乳腺癌细胞 将确定线条和调节miR表达的功能性二恶英响应元件（DRES）。在 另外，还将研究由AHR-MIR-335和AHR-MIR-205相互作用调节的基因。目标3意志 确认AHR，miR-335和miR-205在调节无胸腺肿瘤中的原位乳腺肿瘤生长中的作用 使用细胞系进行AHR，miR-335和miR-205的表达的细胞系。提议 研究将是第一个表征AHR-MIR相互作用和发展的分子机制的研究和 用于治疗ER阴性乳腺癌的临床应用的SAHRM。