Role of circular RNA CDR1as in melanoma

环状RNA CDR1as在黑色素瘤中的作用

基本信息

批准号：
10360518
负责人：
Eva Hernando
金额：
$ 55.5万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-02 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10360518
关键词：
Affect Antisense RNA Automobile Driving Back Behavior Binding Sites Biochemical Biogenesis Biological Biological Process Biology Cancer Patient Cause of Death Cell Line Cell physiology Cells Cellular Assay Cerebellar Degeneration Related 1 Antisense Code Cutaneous Melanoma DNA Sequence Alteration Data Disease Family Gene Expression Genetically Engineered Mouse Genome Glioma Goals Histologic Human Immunocompetent In Vitro Incidence Knockout Mice Knowledge Malignant Neoplasms Mass Spectrum Analysis Mediating Mediator of activation protein Melanoma Cell Messenger RNA Metastatic Melanoma Metastatic to MicroRNAs Modeling Molecular Neoplasm Metastasis Neurons Outcome Pathogenesis Pathway interactions Patient-Focused Outcomes Patients Peptides Phenotype Physiology Primary Neoplasm Proteins Proteomics Publications RNA RNA Splicing RNA-Binding Proteins Regulation Regulator Genes Role Therapeutic Tissues Transcript Translations Untranslated RNA Xenograft Model Xenograft procedure cancer type circular RNA clinically relevant in vivo inhibitor mRNA Stability melanoma member migration new therapeutic target novel oncofetal antigen ribosome profiling small hairpin RNA transcriptome sequencing transcriptomics tumor tumor behavior tumor microenvironment tumorigenic

项目摘要

Cutaneous melanoma is a highly aggressive tumor type with rising incidence. Despite remarkable therapeutic advances in recent years, metastatic melanoma remains a lethal disease for thousands of patients each year, thus new treatments are still needed. Overcoming this challenge requires deep knowledge of the underlying biology driving and sustaining melanoma metastasis. We are studying a novel type of RNA species, circular RNA (circRNA), which are covalently ligated RNA loops arising from cis back-splicing. We have observed that expression of the circRNA CDR1as is lost in melanoma cell lines and patient tissues. In primary melanoma patient tissues, loss of CDR1as strongly associates with poor patient outcomes, suggesting its loss may be a driver of melanoma progression. Modeling CDR1as silencing, shRNA-mediated depletion of CDR1as enhanced invasion and metastasis of melanoma cells in xenograft models. The precise mechanism(s) by which CDR1as silencing effects a pro-tumorigenic phenotype of melanoma cells remains undetermined. Initial publications suggested CDR1as functions as an endogenous inhibitor of the microRNA miR-7 in neurons. Surprisingly, in melanoma, we did not observe clear regulation of miR-7 expression or function after depletion of CDR1as, suggesting it has additional functions. We have preliminary data supporting a role for novel CDR1as interacting proteins, including members of the IGF2BP family, which are known to be pro-tumorigenic in a variety of cancer contexts. Our goals with this proposal are the following: Taking a candidate approach, we plan to dissect the contribution(s) of the IGF2BP proteins to the functional consequences of CDR1as silencing in melanoma cells. In addition, we plan to perform a set of unbiased analyses, such as RNA-seq, RIBO-seq, RNA pull downs and proteomic profiling, to comprehensively examine possible mechanism(s) regulated by CDR1as silencing, downstream or independent of IGF2BPs. We will use in vitro, xenograft models and genetically engineered mouse models (GEMMs) to elucidate the biological processes, pathways and molecules controlled by CDR1as during melanoma progression. Our studies might uncover novel therapeutic targets or strategies to exploit for melanoma patient treatment.

皮肤黑色素瘤是一种高度侵略性的肿瘤类型，发病率上升。尽管具有出色的治疗性近年来，转移性黑色素瘤仍然是每年成千上万患者的致命疾病，因此，仍然需要新的治疗方法。克服这一挑战需要深入了解基础生物学驱动和维持黑色素瘤转移。我们正在研究一种新型的RNA种类，即圆形RNA（circrna），它们是共价连接的RNA环路由顺式后拼图产生。我们观察到黑色素瘤中circrna cdr1as的表达丧失细胞系和患者组织。在原发性黑色素瘤患者组织中，CDR1A的损失与较差患者的结局，表明其损失可能是黑色素瘤进展的驱动力。建模CDR1AS沉默， shRNA介导的CDR1AS的耗竭增强了异种移植物中黑色素瘤细胞的侵袭和转移型号。 CDR1AS沉默效应的确切机制一种促肿瘤的表型黑色素瘤细胞仍未确定。首次出版物表明CDR1AS是内源性的神经元中microRNA miR-7的抑制剂。令人惊讶的是，在黑色素瘤中，我们没有观察到明确的调节 CDR1A耗尽后的miR-7表达或功能，表明它具有其他功能。我们有初步数据支持新型CDR1AS相互作用蛋白的作用，包括IGF2BP的成员在多种癌症情况下，众所周知，这些家庭是促肿瘤的。我们提出的建议的目标如下：采用候选方法，我们计划剖析贡献 IGF2BP蛋白会导致黑色素瘤细胞中CDR1AS沉默的功能后果。另外，我们计划执行一组无偏分析，例如RNA-seq，ribo-seq，RNA下降和蛋白质组学分析，全面检查由CDR1AS沉默，下游或独立于IGF2bps。我们将使用体外，异种移植模型和基因工程的小鼠模型（GEMMS）阐明CDR1A控制的生物过程，途径和分子黑色素瘤进展。我们的研究可能会发现新颖的治疗靶标或策略来利用黑色素瘤患者治疗。