Chromosome 1q ceRNAs in Melanoma Progression and Metastasis

黑色素瘤进展和转移中的染色体 1q ceRNA

基本信息

批准号：
10616492
负责人：
Florian Karreth
金额：
$ 40.86万
依托单位：
H. LEE MOFFITT CANCER CTR & RES INST
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10616492
关键词：
3&apos Untranslated Regions Address Affect Binding Binding Sites Biological Biology Cause of Death Cellular biology Chromosome Mapping Chromosomes Clinical Code Cultured Cells Development Disease Drops Epigenetic Process Excision Exhibits Future Gene Expression Genes Genetic Transcription Genetically Engineered Mouse Genomic Segment Genomics Goals Human In Vitro Incidence Invaded Laboratories Link Malignant - descriptor Malignant Neoplasms Mediating Melanoma Cell Messenger RNA Metastatic Melanoma MicroRNAs Modeling Molecular Molecular Biology Mutation Neoplasm Metastasis Oncogene Deregulation Oncogenic Outcome Persons Phenotype Porifera Positioning Attribute Post-Transcriptional Regulation Process Proteins RNA RNA I Regulation Repression Research Resources Role Series Survival Rate Testing Transcript Untranslated RNA Work cell motility chromosome 1q gain experimental study genetic signature in vivo melanoma melanomagenesis metastatic process migration mouse model mutant non-genetic novel overexpression posttranscriptional programs tool tumor

项目摘要

PROJECT SUMMARY Metastasis is the main cause of deaths related to malignant melanoma. Studies over the last decade have revealed that the metastatic process is not primarily driven by genetic changes. Instead, deregulation of gene expression through epigenetic, transcriptional, or posttranscriptional mechanisms as well as copy number alterations may promote melanoma metastasis. Our previous work described how messenger RNAs engage in protein coding-independent posttranscriptional regulation by sequestering microRNAs (miRNAs) from other transcripts, and we termed such natural miRNA sponges competitive endogenous RNAs (ceRNAs). Deregulated ceRNA expression has been causally linked to cancer development, and thus genomic copy number gains of ceRNA genes may be an important driver of malignant progression of melanoma. We have identified a cluster of melanoma ceRNA genes localized on chromosome 1q, which undergoes copy number gains (1qGAIN) in 25-50% of melanoma. 1qGAIN is more frequent in metastases, suggesting that 1qGAIN ceRNAs may contribute to melanoma progression. Our predictions identified CEP170 as a potent 1qGAIN ceRNA, and preliminary experiments revealed its oncogenic role in vitro and in vivo. Two additional 1qGAIN ceRNAs, NUCKS1 and ZC3H11A, exhibited oncogenic potential and enhanced the CEP170-mediated effects. Thus, gains of 1q may lead to overexpression of multiple ceRNAs that promote melanoma metastasis by sequestering tumor suppressive miRNAs. We have identified five metastasis-associated miRNAs that are sequestered by CEP170 and that promote melanoma cell migration and invasion. In this proposal, we will systematically examine the oncogenic role of 1qGAIN ceRNAs in melanoma metastasis. Specifically, in Aim 1 we will examine if the 3'UTR of CEP170 promotes melanoma dissemination in a miRNA binding site-specific manner using metastasis and autochthonous models. In Aim 2 we will assess if the release of miRNAs from the endogenous CEP170 transcript opposes metastasis, and if these miRNAs have tumor suppressive activity in melanoma cells. Moreover, we will identify and characterize downstream effectors that mediate the CEP170- provoked phenotype. Finally, in Aim 3 we will examine if NUCKS1 and ZC3H11A boost the effect of CEP170 by augmenting miRNA sequestration. We will also test if any of the remaining 1qGAIN ceRNAs, ten in total, possess oncogenic activity and cooperate with CEP170. We expect that our study will reveal the biological relevance of 1qGAIN ceRNAs to melanoma metastasis and further elucidate the mechanisms underlying ceRNA- mediated melanoma progression and metastasis.

项目概要转移是恶性黑色素瘤相关死亡的主要原因。过去十年的研究表明表明转移过程主要不是由基因变化驱动的。相反，放松对基因的管制通过表观遗传、转录或转录后机制以及拷贝数表达改变可能促进黑色素瘤转移。我们之前的工作描述了信使 RNA 如何参与通过将 microRNA (miRNA) 与其他蛋白质隔离来实现独立于蛋白质编码的转录后调控转录本，我们将这种天然 miRNA 海绵称为竞争性内源 RNA (ceRNA)。 ceRNA 表达失调与癌症发展存在因果关系，因此基因组拷贝 ceRNA基因数量的增加可能是黑色素瘤恶性进展的重要驱动因素。我们有鉴定了位于 1q 染色体上的一组黑色素瘤 ceRNA 基因，该基因经历了拷贝数 25-50% 的黑色素瘤获得增益 (1qGAIN)。 1qGAIN 在转移中更为常见，表明 1qGAIN ceRNA 可能有助于黑色素瘤的进展。我们的预测确定 CEP170 是一种有效的 1qGAIN ceRNA，并且初步实验揭示了其体外和体内致癌作用。两个额外的 1qGAIN ceRNA， NUCKS1 和 ZC3H11A 表现出致癌潜力并增强了 CEP170 介导的作用。因此， 1q 的增益可能导致多种 ceRNA 的过度表达，从而促进黑色素瘤转移隔离肿瘤抑制 miRNA。我们已经鉴定出五种与转移相关的 miRNA，它们是被 CEP170 隔离并促进黑色素瘤细胞迁移和侵袭。在本提案中，我们将系统地检查 1qGAIN ceRNA 在黑色素瘤转移中的致癌作用。具体来说，在目标 1 中我们将检查 CEP170 的 3'UTR 是否促进 miRNA 结合位点特异性的黑色素瘤传播使用转移和本地模型的方式。在目标 2 中，我们将评估 miRNA 的释放是否来自内源性 CEP170 转录本可抵抗转移，并且这些 miRNA 是否具有肿瘤抑制活性在黑色素瘤细胞中。此外，我们将识别和表征介导 CEP170- 的下游效应器激发表型。最后，在目标 3 中，我们将检查 NUCKS1 和 ZC3H11A 是否增强 CEP170 的效果通过增强 miRNA 隔离。我们还将测试剩余的 1qGAIN ceRNA 中是否有任何一个（总共 10 个）具有致癌活性并与CEP170协同作用。我们希望我们的研究能够揭示生物学 1qGAIN ceRNA 与黑色素瘤转移的相关性，并进一步阐明 ceRNA 的潜在机制介导黑色素瘤进展和转移。