MicroRNAs in frequently deleted loci regulate prostate cancer EMT and metastasis

频繁缺失位点中的 MicroRNA 调节前列腺癌 EMT 和转移

• 批准号: 8698027
• 负责人: Sharanjot Saini
• 金额: $ 38.33万
• 依托单位: NORTHERN CALIFORNIA INSTITUTE/RES/EDU
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8698027
• 关键词: 8p21; Affect; Animal Model; BMI1 gene; Biological Assay; Biological Markers; Cell Line; Cells; Chromosomes; Clinical; Complex; DNA Methylation; Data; Data Set; Development; Diagnostic; Disease Outcome; Down-Regulation; E-Cadherin; Epigenetic Process; Epithelial; Epithelial Cells; Event; Family; Genes; Genetic; Genomics; Goals; Homeodomain Proteins; In Vitro; Lead; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Mesenchymal; Metastatic Prostate Cancer; MicroRNAs; Modeling; Molecular; Molecular Profiling; NKX3-1 gene; Neoplasm Metastasis; New Agents; Outcome; PC3 cell line; Pathway interactions; Pattern; Phenotype; Play; Prostate; Regulation; Relative (related person); Reporting; Repression; Role; Specimen; Staging; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Transcription Repressor/Corepressor; Tumor Suppressor Genes; Tumor Suppressor Proteins; base; chromosome loss; clinically significant; cohort; design; histone modification; in vivo; in vivo Model; member; neoplastic cell; novel; outcome forecast; prevent; prognostic; programs; prostate cancer cell; prostate carcinogenesis; public health relevance; transcription factor; tumor; tumor progression

DESCRIPTION (provided by applicant): We propose that a novel cluster of microRNAs (miRNAs) in the most frequently deleted genomic region associated with prostate cancer (PCa) repress epithelial-mesenchymal transition (EMT) and PCa progression and metastasis. EMT, a complex cellular program whereby epithelial tumor cells lose their epithelial polarity and gain mesenchymal phenotypes, is considered a critical step in invasion and metastases. The role of miRNAs in prostate cancer EMT and metastasis is largely unknown. We first identified that miR-203 represses EMT and PCa metastasis by directly targeting ZEB2 and other EMT regulators. Our recent data suggests that a cluster of miRNA genes on chromosome 8p21 (miR-3622a, 3622b, 4287, 4288) act as critical negative regulators of EMT in PCa. Loss of chromosome 8p21 is a frequent alteration in the prostate oncogenome, particularly in advanced PCa suggesting its role in PCa progression. It has been postulated that this region harbors alternative tumor suppressor genes, the identity of which have largely remained elusive. We have identified a cluster of novel miRNA genes (miR-3622a, 3622b, 4287, 4288) that are located in this region that have never been explored. Our analysis suggests that these miRNAs regulate EMT and PCa progression and metastasis by directly targeting key EMT regulators including the SNAIL and ZEB family of transcription factors. In view of this, we propose that a cluster of miRNA genes at the frequently deleted chromosome 8p21 region function coordinately to repress the EMT program by directly targeting EMT inducing factors, thereby preventing prostate cancer progression and metastasis. We hypothesize that these miRNAs inhibit EMT by maintaining the epithelial phenotype through a direct inhibition of transcriptional repressors of E-cadherin including members of the SNAIL and ZEB family and thereby inhibit PCa progression and metastasis. We will test this hypothesis, under the following specific aims - Specific Aim I: Investigate the role of proposed miRNAs in frequently deleted genomic region in regulation of EMT and PCa progression and metastasis using both in vitro and in vivo models. Specific Aim II: Determine whether expression profiling of proposed EMT-regulating miRNAs in chromosome 8p21 region have associated prognostic and diagnostic potential in prostate cancer. Specific Aim III: Investigate the molecular basis of repression of EMT regulating miRNAs in prostate cancer. This project is highly novel and significant as it will potentially integrate the impact of common genomic deletions observed in prostate cancer with the EMT and metastatic program, an aspect that has never been explored. In particular, characterization of miRNA genes at chromosome 8p21 region will be a highly significant step forward in the field of prostate cancer Accomplishment of this project will uncover novel miRNA-mediated molecular pathways that drive PCa progression and metastasis with potential clinical implications in design of better prognostic and therapeutic strategies for advanced prostate cancer.

描述（由申请人提供）：我们提出，与前列腺癌（PCA）相关的最常删除的基因组区域中的新型microRNA（miRNA）抑制上皮 - 间质转变（EMT）和PCA进展和转移。 EMT是一种复杂的细胞程序，上皮肿瘤细胞失去其上皮极性并获得间质表型，被认为是入侵和转移酶的关键步骤。 miRNA在前列腺癌EMT和转移中的作用在很大程度上是未知的。我们首先确定miR-203通过直接靶向Zeb2和其他EMT调节剂来抑制EMT和PCA转移。我们最近的数据表明，在8p21染色体（miR-3622a，3622b，4287，4288）上的miRNA基因簇起到PCA中EMT的关键负调节剂。 8p21染色体的丧失是前列腺致癌组的常见改变，尤其是在晚期PCA中表明其在PCA进展中的作用。据推测，该地区具有替代性肿瘤抑制基因，其身份在很大程度上仍然难以捉摸。我们已经确定了一个新的miRNA基因（miR-3622a，3622b，4287，4288），这些基因位于该地区从未探索过的群集。我们的分析表明，这些miRNA通过直接靶向包括蜗牛和Zeb转录因子家族（包括转录因子家族）来调节EMT和PCA的进展和转移。鉴于这一点，我们建议在经常被删除的8p21区域的一个miRNA基因协同起作用，以通过直接靶向EMT诱导因子来抑制EMT程序，从而防止前列腺癌的进展和转移。我们假设这些miRNA通过直接抑制E-钙粘着蛋白的转录阻遏物来抑制EMT，包括蜗牛和Zeb家族的成员，从而抑制PCA进展和转移。我们将根据以下特定目的检验这一假设 - 具体目的I：研究拟议的miRNA在经常删除的基因组区域中使用体外和体内模型在EMT和PCA进展和转移调节中的作用。具体目标II：确定在8p21染色体区域中提出的EMT调节miRNA的表达分析是否具有前列腺癌中的预后和诊断潜力。特定的目标III：研究抑制EMT调节miRNA在前列腺癌中的分子基础。该项目非常新颖且重要，因为它将有可能将前列腺癌中常见基因组缺失的影响与EMT和转移性程序相结合，EMT和转移性程序从未被探索过。特别是，在8p21染色体区域的miRNA基因的表征将是该项目的前列腺癌实现领域的高度显着的一步，它将发现新颖的miRNA介导的分子途径，这些分子途径在促进PCA进展和转移具有潜在的临床意义，并在更好的预后和治疗疗法策略中具有潜在的临床意义。