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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.

项目摘要转移是恶性黑色素瘤相关死亡的主要原因。过去十年的研究这表明转移过程主要不是由遗传变化驱动的。相反，基因的失调通过表观遗传、转录或转录后机制以及拷贝数表达改变可促进黑素瘤转移。我们之前的工作描述了信使RNA如何参与蛋白质编码独立的转录后调节通过隔离microRNA（miRNAs）从其他我们将这种天然的miRNA海绵称为竞争性内源性RNA（ceRNA）。去调控的ceRNA表达与癌症发展有因果关系，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。我们有鉴定了位于染色体1 q上的黑色素瘤ceRNA基因簇，在25-50%的黑素瘤中增加（1 qGAIN）。1 qGAIN在转移瘤中更常见，表明1 qGAIN ceRNA 可能导致黑色素瘤进展。我们的预测将CEP 170确定为有效的1 qGAIN ceRNA，初步实验揭示了其在体外和体内的致癌作用。两个额外的1 qGAIN ceRNA， NUCKS 1和ZC 3 H11 A表现出致癌潜力并增强CEP 170介导的作用。因此，在本发明中， 1 q的增加可能导致多种ceRNA的过表达，这些ceRNA通过以下方式促进黑色素瘤转移：隔离肿瘤抑制性miRNAs。我们已经鉴定了五种转移相关的miRNAs，被CEP 170隔离并促进黑素瘤细胞迁移和侵袭。在本提案中，我们将系统地研究了1 qGAIN ceRNA在黑色素瘤转移中的致癌作用。具体而言，目标1 我们将研究CEP 170的3 'UTR是否以miRNA结合位点特异性的方式促进黑色素瘤的播散。方法使用转移和原位模型。在目标2中，我们将评估是否从细胞中释放miRNA 内源性CEP 170转录物对抗转移，如果这些miRNA具有肿瘤抑制活性，在黑色素瘤细胞中。此外，我们将鉴定和表征介导CEP 170的下游效应子。激发型最后，在目标3中，我们将检查NUCKS 1和ZC 3 H11 A是否增强CEP 170的作用。通过增强miRNA的隔离。我们还将测试剩余的1 qGAIN ceRNA中是否有任何一个，总共10个，具有致癌活性并与CEP 170协同作用。我们希望我们的研究能够揭示 1 qGAIN ceRNA与黑色素瘤转移的相关性，并进一步阐明了ceRNA- 介导的黑素瘤进展和转移。