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.

项目摘要转移是与恶性黑色素瘤有关的死亡的主要原因。过去十年的研究有揭示了转移过程并非主要由遗传变化驱动。相反，基因的放松管制通过表观遗传，转录或转录后机制以及拷贝数的表达改变可能会促进黑色素瘤转移。我们以前的工作描述了Messenger RNA如何参与蛋白质编码非依赖性的转录后调节，通过隔离的microRNA（miRNA）来自其他转录本，我们称这种天然miRNA海绵竞争性内源性RNA（CERNAS）。放松管制的CERNA表达与癌症的发展有因果关系，因此基因组拷贝 CERNA基因的数量增加可能是黑色素瘤恶性进展的重要驱动力。我们有确定了一组固定在染色体1q的黑色素瘤CERNA基因，该基因经历了拷贝数黑色素瘤25-50％的增益（1QGAIN）。 1qgain在转移中更频繁，表明1QGAIN CERNAS 可能有助于黑色素瘤进展。我们的预测将CEP170确定为有效的1QGAIN CERNA，并且初步实验揭示了其在体外和体内的致癌作用。另外两个1qgain cernas， Nucks1和ZC3H11A表现出致癌潜力，并增强了CEP170介导的效果。因此， 1q的收益可能导致多种CERNA的过表达，这些CERNA促进了通过隔离肿瘤抑制miRNA。我们已经确定了五个与转移相关的miRNA 由CEP170隔离，并促进黑色素瘤细胞迁移和侵袭。在此提案中，我们将系统地检查1QGAIN CERNAS在黑色素瘤转移中的致癌作用。具体而言，在AIM 1中我们将检查CEP170的3'UTR是否促进了miRNA结合特定于miRNA结合的黑色素瘤使用转移和自动模型的方式。在AIM 2中，我们将评估MiRNA是否从内源性CEP170转录本相反，如果这些miRNA具有肿瘤抑制活性在黑色素瘤细胞中。此外，我们将确定并表征介导CEP170-的下游效应子挑衅的表型。最后，在AIM 3中，我们将检查Nucks1和ZC3H11A是否增强了CEP170的影响通过增强miRNA隔离。我们还将测试剩下的1QGAIN CERNAS，总共十个具有致癌活性并与CEP170合作。我们希望我们的研究将揭示生物学 1QGAIN CERNAS与黑色素瘤转移的相关性，并进一步阐明了Cerna-的机制介导的黑色素瘤进展和转移。