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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.

项目总结