Molecular Mediators of Pancreatic Cancer Invasion and Progression
胰腺癌侵袭和进展的分子介质
基本信息
- 批准号:9250086
- 负责人:
- 金额:$ 33.2万
- 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:2013-04-01 至 2020-03-31
- 项目状态:已结题
- 来源:
- 关键词:Adenocarcinoma CellAlgorithmsBiological MarkersCell LineCellsComputer SimulationComputersDataDetectionDevelopmentDiseaseEpigenetic ProcessExhibitsFOXM1 geneGene ExpressionGene TargetingGeneticGenetic EngineeringGoalsGrowthHumanKnowledgeMalignant - descriptorMalignant NeoplasmsMalignant neoplasm of pancreasMediator of activation proteinMicroRNAsMicroarray AnalysisMolecularMutationNamesNatureNeoplasm MetastasisNormal tissue morphologyPancreasPancreatic Ductal AdenocarcinomaPathway interactionsPatientsPropertyProtein IsoformsProteinsRNA SplicingRegulationReportingRoleSpecimenTestingTherapeuticTissuesXenograft Modelbasecarcinogenesisclinically significanteffective therapyknock-downnoveloutcome forecastoverexpressionpancreatic cancer cellsprognostic valueprotein expressionpublic health relevancestemtherapeutic targettranscription factor
项目摘要
DESCRIPTION (provided by applicant): Metastatic pancreatic cancer is a lethal disease. While most of the critical genetic and epigenetic alterations have been known for years, to date this has not resulted in useful therapeutics. Our most important goal is to identify alterations in
PDAC gene expression that can be utilized to develop effective therapies. To this end we have recently been focusing on the transcription factor FoxM1, which is drastically increased in PDAC. To understand the importance of this elevated expression we have developed PDAC cell lines genetically engineered to over-express FoxM1. These cell lines uniformly exhibit greatly elevated growth and metastasis. In a complimentarily approach, we have reduced FoxM1 expression in numerous PDAC cells and observed a reduction in the aggressive nature of these cells. Recently, we discovered that human PDAC cells almost exclusively express a splice form of FoxM1 called FoxM1C, which is not observed in normal tissues. Based on our preliminary studies, we postulate that during PDAC carcinogenesis, dysregulated miRNA expression leads to overexpression of FoxM1 and dysregulated expression of its downstream target genes key to invasion and metastasis, resulting in an enhanced malignant potential of PDAC cells and cause poor prognosis of PDAC patients. Thus, FoxM1 is a malignant biomarker and therapeutic target in PDAC. To test our hypothesis, we propose the following three specific aims. Aim #1. Investigate the molecular mechanisms underlying the dysregulated FoxM1 expression in pancreatic cancer. The overexpression of FoxM1 in PDAC is well established, while the underlying mechanisms are unknown. We have recently utilized a computer based algorithm to screen for possible microRNAs that target FoxM1 (both in silico analysis and microarray analysis of miRNA expression in normal pancreas vs. pancreatic cancer) and have tentatively identified 3 FoxM1-related microRNAs. Interestingly, all three are down-regulated in pancreatic cancer. We expect that those microRNAs causally regulate FoxM1 expression and function and exhibit prognostic values. Aim #2. Determine the regulatory role of FoxM1 expression in pancreatic cancer invasion and metastasis. Human pancreatic cancer cells are known to overexpress uPAR and its expression levels directly correlate with those of FoxM1. Altered expression of uPAR regulates invasion and metastasis of pancreatic cancer. Therefore, we wish to determine whether uPAR is a novel important downstream target and functional mediator of FoxM1. We expect that FoxM1 isoforms regulate the expression and function of uPAR in pancreatic cancer cells and this novel pathway is essential to pancreatic cancer invasion and metastasis. Aim #3. Determine the clinical significance of FoxM1 isoforms in human pancreatic cancer invasion and metastasis. FoxM1 consists of 3 isoforms: FoxM1A, FoxM1B, and FoxM1C, and most recently, two additional isoforms are identified and provisionally named as FoxM1B1 and FoxM1B2. The expression and functions of those isoforms in pancreatic cancer are not completely known. Our preliminary studies have indicated that pancreatic cancer cells predominantly express FoxM1C and that this form has unique properties. We expect that the FoxM1C form is associated with particularly aggressive disease and altered expression of different isoforms of FoxM1, including FoxM1B1 and FoxM1B2 to FoxM1B, directly impact on pancreatic cancer growth and metastasis.
描述(由申请人提供):转移性胰腺癌是一种致死性疾病。虽然大多数关键的遗传和表观遗传改变已经知道多年,但迄今为止,这还没有导致有用的治疗方法。我们最重要的目标是识别
PDAC基因表达,可用于开发有效的疗法。为此,我们最近一直专注于转录因子FoxM1,它在PDAC中急剧增加。为了理解这种表达升高的重要性,我们开发了基因工程化的PDAC细胞系,以过表达FoxM1。这些细胞系一致地表现出大大提高的生长和转移。在一种互补的方法中,我们已经减少了许多PDAC细胞中FoxM1的表达,并观察到这些细胞的侵袭性降低。最近,我们发现人类PDAC细胞几乎只表达一种称为FoxM1C的FoxM1剪接形式,这在正常组织中是没有观察到的。基于我们的初步研究,我们推测在PDAC癌变过程中,miRNA表达失调导致FoxM1过表达及其下游靶基因表达失调,这些靶基因是PDAC细胞侵袭和转移的关键,导致PDAC细胞恶性潜能增强,导致PDAC患者预后不良。因此,FoxM1是PDAC中的恶性生物标志物和治疗靶点。为了验证我们的假设,我们提出了以下三个具体目标。目标1。研究胰腺癌中FoxM1表达失调的分子机制。FoxM1在PDAC中的过表达已得到证实,但其潜在机制尚不清楚。我们最近利用基于计算机的算法来筛选靶向FoxM1的可能的microRNA(正常胰腺与胰腺癌中miRNA表达的计算机分析和微阵列分析),并初步鉴定了3种FoxM1相关的microRNA。有趣的是,这三种基因在胰腺癌中均下调。我们期望这些microRNA因果调节FoxM1的表达和功能,并表现出预后价值。目标2。确定FoxM1表达在胰腺癌侵袭和转移中的调节作用。已知人胰腺癌细胞过表达uPAR,其表达水平与FoxM1的表达水平直接相关。uPAR表达改变调节胰腺癌的侵袭和转移因此,我们希望确定uPAR是否是FoxM1的一个新的重要下游靶点和功能介质。我们预期FoxM1亚型调节胰腺癌细胞中uPAR的表达和功能,并且这一新的途径对于胰腺癌的侵袭和转移至关重要。目标3。确定FoxM1亚型在人胰腺癌侵袭和转移中的临床意义。FoxM1由3种亚型组成:FoxM1A、FoxM1B和FoxM1C,最近,另外两种亚型被鉴定并暂时命名为FoxM1B1和FoxM1B2。这些亚型在胰腺癌中的表达和功能尚不完全清楚。我们的初步研究表明,胰腺癌细胞主要表达FoxM1C,这种形式具有独特的性质。我们预计FoxM1C形式与特别侵袭性的疾病相关,并且FoxM1的不同亚型(包括FoxM1B1和FoxM1B2到FoxM1B)的表达改变直接影响胰腺癌的生长和转移。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Novel Role of FBXW7 Circular RNA in Repressing Glioma Tumorigenesis.
FBXW7 环状 RNA 在抑制神经胶质瘤肿瘤发生中的新作用。
- DOI:10.1093/jnci/djx166
- 发表时间:2018-03-01
- 期刊:
- 影响因子:0
- 作者:Yang Y;Gao X;Zhang M;Yan S;Sun C;Xiao F;Huang N;Yang X;Zhao K;Zhou H;Huang S;Xie B;Zhang N
- 通讯作者:Zhang N
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ROBERT S BRESALIER其他文献
ROBERT S BRESALIER的其他文献
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{{ truncateString('ROBERT S BRESALIER', 18)}}的其他基金
Multi-cancer early detection using cell-free DNA methylome analysis
使用游离 DNA 甲基化分析进行多癌症早期检测
- 批准号:
10763305 - 财政年份:2023
- 资助金额:
$ 33.2万 - 项目类别:
Colorectal cancer risk factors, risk prediction and blood-based biomarker by tumor consensus molecular subtype
按肿瘤共有分子亚型分类的结直肠癌危险因素、风险预测和血液生物标志物
- 批准号:
10591999 - 财政年份:2019
- 资助金额:
$ 33.2万 - 项目类别:
Colorectal cancer risk factors, risk prediction and blood-based biomarker by tumor consensus molecular subtype
按肿瘤共有分子亚型分类的结直肠癌危险因素、风险预测和血液生物标志物
- 批准号:
10021547 - 财政年份:2019
- 资助金额:
$ 33.2万 - 项目类别:
Integrated Signaling in Pancreatic Cancer Progression
胰腺癌进展中的整合信号转导
- 批准号:
9493432 - 财政年份:2016
- 资助金额:
$ 33.2万 - 项目类别:
Integrated Signaling in Pancreatic Cancer Progression
胰腺癌进展中的整合信号转导
- 批准号:
10018467 - 财政年份:2016
- 资助金额:
$ 33.2万 - 项目类别:
Integrated Signaling in Pancreatic Cancer Progression
胰腺癌进展中的整合信号转导
- 批准号:
10247023 - 财政年份:2016
- 资助金额:
$ 33.2万 - 项目类别:
Integrated Signaling in Pancreatic Cancer Progression
胰腺癌进展中的整合信号传导
- 批准号:
9266771 - 财政年份:2016
- 资助金额:
$ 33.2万 - 项目类别:
Great Lakes New England Clinical Validation Center
新英格兰五大湖临床验证中心
- 批准号:
10484455 - 财政年份:2000
- 资助金额:
$ 33.2万 - 项目类别:
Great Lakes New England Clinical Validation Center
新英格兰五大湖临床验证中心
- 批准号:
10698103 - 财政年份:2000
- 资助金额:
$ 33.2万 - 项目类别:
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