Regulation and Role of miR-183-96-182 in Melanocyte Differentiation and Melanoma
miR-183-96-182 在黑色素细胞分化和黑色素瘤中的调节和作用
基本信息
- 批准号:8761356
- 负责人:
- 金额:$ 16.26万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-11-29 至 2014-12-31
- 项目状态:已结题
- 来源:
- 关键词:7q31Aggressive behaviorBehaviorBindingBioinformaticsBiological AssayCancer EtiologyCell LineCellsChIP-seqDataDevelopmentDevelopmental GeneDiseaseEpigenetic ProcessEvolutionGenomicsHistone AcetylationHistonesHomeostasisIn VitroIncidenceInjection of therapeutic agentLaboratoriesLinkMalignant - descriptorMalignant NeoplasmsMelanoma CellMetastatic MelanomaMicroRNAsMolecularMusNatureNeoplasm MetastasisNeural CrestOperative Surgical ProceduresPhenotypePhysiologicalPlatelet Factor 4PopulationPrimary NeoplasmProcessPromoter RegionsPropertyRegulationRepressionRoleSkin CancerStagingStem cellsSurvival RateTailTestingTherapeutic InterventionTimeTissue DifferentiationTissuesTranscriptional RegulationTransferaseUncertaintyVeinsWorkbasecalincancer cellcancer stem cellcancer typeembryonic stem cellgenome-widehuman embryonic stem cellin vivointerestmelanocytemelanomamigrationmortalitymouse modeloverexpressionpluripotencyprogramsself-renewalstemstem cell differentiationtranscription factortranscriptome sequencingtumor
项目摘要
DESCRIPTION (provided by applicant): The incidence and mortality of melanoma, the most aggressive form of skin cancer, are rapidly increasing worldwide. The abysmal survival rates stem from the highly metastatic and chemoresistant behavior of these tumors, but the molecular basis of this aggressive phenotype remains unclear. We and others have shown that melanoma cells display stem-cell-like properties: they often express developmental genes, have multi-differentiation potential, and seem to evoke the migratory nature of neural crest stem cells from which melanocytes arise. These observations suggest that alterations in developmental programs within the melanocytic lineage might underlie the malignant evolution of these cells into metastatic melanoma. In fact, metastasis can be conceived as a normal migration program gone awry, and our laboratory has found that a particular cluster of miRNAs (which in general regulate development, differentiation, and tissue homeostasis) is frequently overexpressed in melanoma cell lines and tissues. We have shown that this miR-183-96-182 cluster promotes migration in vitro and metastasis in vivo in part by controlling the expression of MITF, a master regulator of melanocyte differentiation. Intriguingly, we have also found that miR-183-96-182 is highly expressed in embryonic stem cells (ES), and is silenced during in vitro melanocyte differentiation, inversely correlating with MITF levels. Furthermore, our preliminary studies indicate that histone acetylation and Krupple-like factor-4 (KLF4), a canonical pluripotency transcription factor, govern miR-183-96-182 expression in both hESCs and melanoma cells. We hypothesize that miR-183-96-182 repression is required for melanocyte differentiation, and that alterations in this cluster promote melanoma metastasis, perhaps by conferring stem cell properties to melanoma cells. To test these hypotheses, we will first determine the transcriptional and epigenetic regulation of the miR-183-96-182 cluster in physiological and pathological contexts, from human embryonic stem cell stage through melanocyte differentiation and in melanoma cells (Aim 1). In Aim 2 we will test whether miR-183-96-182 and/or KLF4 confer stem-cell-like properties (e.g., self-renewal, multi-differentiation capacity) on melanoma cells through several cell-based assays. In Aim 3, we will determine how modulation of this miRNA cluster and/or KLF4 influence the propensity of melanoma cells for metastasis in mice. Understanding the mechanisms that modulate miR-183-96-182 overexpression, which is clearly involved in metastasis, could provide a foothold for altering the aggressiveness of this very aggressive cancer, and perhaps provide a framework for similar studies in other recalcitrant cancer types.
描述(由申请人提供):黑色素瘤是最具侵袭性的皮肤癌,其发病率和死亡率在全世界范围内迅速增加。糟糕的生存率源于这些肿瘤的高度转移和化疗耐药行为,但这种侵袭性表型的分子基础仍不清楚。我们和其他人已经证明,黑色素瘤细胞表现出干细胞样特性:它们经常表达发育基因,具有多分化潜力,并且似乎唤起了产生黑色素细胞的神经嵴干细胞的迁移性质。这些观察结果表明,黑素细胞谱系内发育程序的改变可能是这些细胞恶性进化为转移性黑素瘤的基础。事实上,转移可以被认为是正常的迁移程序出了差错,我们的实验室发现,特定的 miRNA 簇(通常调节发育、分化和组织稳态)在黑色素瘤细胞系和组织中经常过度表达。我们已经证明,该 miR-183-96-182 簇部分通过控制黑素细胞分化的主要调节因子 MITF 的表达来促进体外迁移和体内转移。有趣的是,我们还发现 miR-183-96-182 在胚胎干细胞(ES)中高表达,并在体外黑素细胞分化过程中被沉默,与 MITF 水平呈负相关。此外,我们的初步研究表明,组蛋白乙酰化和 Krupple 样因子 4 (KLF4)(一种典型的多能性转录因子)在 hESC 和黑色素瘤细胞中控制 miR-183-96-182 的表达。我们假设 miR-183-96-182 抑制是黑素细胞分化所必需的,并且该簇的改变可能通过赋予黑素瘤细胞干细胞特性而促进黑素瘤转移。为了检验这些假设,我们将首先确定 miR-183-96-182 簇在生理和病理背景下的转录和表观遗传调控,从人类胚胎干细胞阶段到黑素细胞分化以及黑素瘤细胞(目标 1)。在目标 2 中,我们将通过几种基于细胞的测定来测试 miR-183-96-182 和/或 KLF4 是否赋予黑色素瘤细胞干细胞样特性(例如自我更新、多分化能力)。在目标 3 中,我们将确定该 miRNA 簇和/或 KLF4 的调节如何影响小鼠黑色素瘤细胞的转移倾向。了解调节 miR-183-96-182 过度表达的机制(显然与转移有关)可以为改变这种极具侵袭性的癌症的侵袭性提供立足点,并可能为其他顽固性癌症类型的类似研究提供框架。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Eva Hernando其他文献
Eva Hernando的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Eva Hernando', 18)}}的其他基金
Developing new therapeutic strategies for brain metastasis
开发脑转移的新治疗策略
- 批准号:
10578405 - 财政年份:2023
- 资助金额:
$ 16.26万 - 项目类别:
NYULH Metastasis Research Network Center - Admin Supplement
NYULH 转移研究网络中心 - 管理补充
- 批准号:
10867093 - 财政年份:2022
- 资助金额:
$ 16.26万 - 项目类别:
Project 1: Tumor Cell Intrinsic Determinants of Early Dissemination in Melanoma
项目1:黑色素瘤早期播散的肿瘤细胞内在决定因素
- 批准号:
10705072 - 财政年份:2022
- 资助金额:
$ 16.26万 - 项目类别:
NYULH Metastasis Research Network Center (NYULH MetNet Center)
NYULH 转移研究网络中心(NYULH MetNet 中心)
- 批准号:
10414442 - 财政年份:2022
- 资助金额:
$ 16.26万 - 项目类别:
Project 1: Tumor Cell Intrinsic Determinants of Early Dissemination in Melanoma
项目1:黑色素瘤早期播散的肿瘤细胞内在决定因素
- 批准号:
10414444 - 财政年份:2022
- 资助金额:
$ 16.26万 - 项目类别:
Defining epigenetic regulators of tumor heterogeneity and metastasis in melanoma
定义黑色素瘤肿瘤异质性和转移的表观遗传调节因子
- 批准号:
10659255 - 财政年份:2022
- 资助金额:
$ 16.26万 - 项目类别:
Defining epigenetic regulators of tumor heterogeneity and metastasis in melanoma
定义黑色素瘤肿瘤异质性和转移的表观遗传调节因子
- 批准号:
10512423 - 财政年份:2022
- 资助金额:
$ 16.26万 - 项目类别:
相似海外基金
Relationship between two types of narcissism, anger, aggressive behavior and adaptation
两种自恋、愤怒、攻击行为和适应之间的关系
- 批准号:
23K18995 - 财政年份:2023
- 资助金额:
$ 16.26万 - 项目类别:
Grant-in-Aid for Research Activity Start-up
Molecular biomarkers of future aggressive behavior in pituitary tumors
垂体瘤未来攻击行为的分子生物标志物
- 批准号:
10650948 - 财政年份:2023
- 资助金额:
$ 16.26万 - 项目类别:
Neuronal mechanisms of visually-driven aggressive behavior
视觉驱动攻击行为的神经机制
- 批准号:
9978478 - 财政年份:2020
- 资助金额:
$ 16.26万 - 项目类别:
Development of a Nursing Intervention Model to Prevent Aggressive Behavior in Hospitalized Elderly Patients with Dementia
预防住院老年痴呆症患者攻击行为的护理干预模型的建立
- 批准号:
20K23236 - 财政年份:2020
- 资助金额:
$ 16.26万 - 项目类别:
Grant-in-Aid for Research Activity Start-up
Development of a Management Sheet on Aggressive Behavior for Working with Patients in a Psychiatric Ward
为精神科病房的患者制定攻击行为管理表
- 批准号:
18K10309 - 财政年份:2018
- 资助金额:
$ 16.26万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Social determinants of corticolimbic development and aggressive behavior
皮质边缘发育和攻击行为的社会决定因素
- 批准号:
9765038 - 财政年份:2018
- 资助金额:
$ 16.26万 - 项目类别:
Examination of factors that promote and suppress aggressive behavior on the Internet
检查促进和抑制互联网上攻击行为的因素
- 批准号:
17K04438 - 财政年份:2017
- 资助金额:
$ 16.26万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Identifying patterns and mechanistic pathways from violence exposure trajectories to aggressive behavior and psychological disorders
识别从暴力暴露轨迹到攻击行为和心理障碍的模式和机制路径
- 批准号:
9372567 - 财政年份:2017
- 资助金额:
$ 16.26万 - 项目类别:
EAPSI: The Role of Monoamine Oxidase - A Gene Polymorphism in Aggressive Behavior in Macaques
EAPSI:单胺氧化酶的作用 - 基因多态性在猕猴攻击行为中的作用
- 批准号:
1713932 - 财政年份:2017
- 资助金额:
$ 16.26万 - 项目类别:
Fellowship Award
analysis on genetic abnormality related to aggressive behavior of uterine leiomyosarcoma
子宫平滑肌肉瘤侵袭行为相关基因异常分析
- 批准号:
16K11124 - 财政年份:2016
- 资助金额:
$ 16.26万 - 项目类别:
Grant-in-Aid for Scientific Research (C)