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）：最初发现芳基烃受体（AHR）是一种与环境毒物结合的细胞内蛋白，该蛋白与2,3,7,8-甲基氯迪本佐-P-二恶英（TCDD）和结构相关的氯化芳族化合物结合。近年来，已经证明AHR与结构和功能上不同的化合物结合，包括化学保护植物化学物质，例如类黄酮，多苯酚和吲哚-3-核糖。毫不奇怪，这些化合物表现出组织特异性的AHR激动剂和拮抗剂活性，可以分类为选择性AHR调节剂（SAHRMS）。该实验室中的先前研究利用了SAHRM在治疗疾病治疗中的潜在应用，而6-甲基-1,3,8-氯二苯并芬曲兰（MCDF）最初以AHR拮抗剂为特征，但是，像TCDD一样抑制性AHR雌激素受体（ER）串扰。现在的初步研究的结果表明，TCDD和MCDF等AHR激动剂抑制了大量ER阴性乳腺癌细胞的生长，包括高度侵入性的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还抑制了带有ER阴性细胞作为异种移植物的无胸腺裸鼠体内肿瘤生长。此外，MCDF和TCDD的抗肿瘤活性伴随着AHR依赖性诱导了两种抗移动微microRNA（miRS），即miR-335和miR-205。拟议的研究将进一步研究MCDF和结构性癌症治疗的分子机制和潜在的SAHRMS癌症的分子机制以及潜在的临床应用。 AIM 1将集中于SAHRM诱导的miR-335和miR-205的调节，以及AHR在减少一系列ER阴性乳腺癌细胞系的增殖，迁移和侵袭中的作用。在AIM 2中，将确定ER阴性乳腺癌细胞系的miR-335和miR-205表达的AHR依赖性调节机制，并确定调节miR表达的功能性二恶英响应元件（DRES）。此外，还将研究由AHR-MIR-335和AHR-MIR-205相互作用调节的基因。 AIM 3将使用AHR，miR-335和miR-205的表达调节AHR，miR-335和miR-205在调节无胸腺裸鼠的原始乳腺肿瘤生长中的作用。拟议的研究将是第一个表征AHR-MIR相互作用的分子机制和SAHRM的分子机制，用于治疗ER阴性乳腺癌时的临床应用。 公共卫生相关性：选择性芳基烃受体（AHR）调节剂（SAHRMS）结合并激活AHR，在雌激素受体阴性乳腺癌细胞中，这些化合物抑制了小鼠异种移植物中的细胞增殖和肿瘤的生长。拟议的研究将研究抗转移性microRNA-335和microRNA-205的AHR依赖性诱导，并描述它们在SAHRMS的抗癌活性中的作用。