Role of circular RNA CDR1as in melanoma

环状RNA CDR1as在黑色素瘤中的作用

• 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
• 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

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袭性的肿瘤类型，发病率不断上升。尽管治疗效果显著 近年来的进展，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 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，环状RNA（circRNA），它是共价连接的RNA环 由顺式反向剪接引起。我们已经观察到在黑色素瘤中circRNA CDR 1as的表达丢失， 细胞系和患者组织。在原发性黑色素瘤患者组织中，CDR 1as的缺失与肿瘤细胞的不良增殖密切相关。 患者的结果，表明其损失可能是黑色素瘤进展的驱动因素。将CDR 1建模为沉默， shRNA介导CDR 1as缺失增强黑色素瘤细胞在异种移植瘤中的侵袭和转移 模型CDR 1as沉默影响肿瘤促肿瘤表型的精确机制 黑色素瘤细胞仍不确定。最初的出版物表明，CDR 1作为内源性 神经元中microRNA miR-7的抑制剂。令人惊讶的是，在黑色素瘤中，我们没有观察到明显的调节， miR-7在CDR 1as耗尽后的表达或功能，表明其具有额外的功能。我们有 初步数据支持新的CDR 1as相互作用蛋白的作用，包括IGF 2BP的成员 家族，已知其在多种癌症背景中是促肿瘤发生的。 我们的目标是：采用候选方法，我们计划剖析贡献 IGF 2BP蛋白与黑色素瘤细胞中CDR 1as沉默的功能性后果之间的关系。另外我们 我计划进行一系列无偏分析，如RNA-seq、RIBO-seq、RNA pull唐斯和蛋白质组学分析。 分析，以全面检查由CDR 1作为沉默调节的可能机制，下游或 与IGF 2BP无关。我们将使用体外、异种移植模型和基因工程小鼠模型 （GEMM）来阐明在CDR 1as期间由CDR 1as控制的生物过程、途径和分子。 黑素瘤进展。我们的研究可能会发现新的治疗靶点或策略， 黑色素瘤患者的治疗