Molecular Mediators of Pancreatic Cancer Invasion and Progression

胰腺癌侵袭和进展的分子介质

• 批准号: 9250086
• 负责人: ROBERT S BRESALIER
• 金额: $ 33.2万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/9250086
• 关键词: Adenocarcinoma Cell; Algorithms; Biological Markers; Cell Line; Cells; Computer Simulation; Computers; Data; Detection; Development; Disease; Epigenetic Process; Exhibits; FOXM1 gene; Gene Expression; Gene Targeting; Genetic; Genetic Engineering; Goals; Growth; Human; Knowledge; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediator of activation protein; MicroRNAs; Microarray Analysis; Molecular; Mutation; Names; Nature; Neoplasm Metastasis; Normal tissue morphology; Pancreas; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Property; Protein Isoforms; Proteins; RNA Splicing; Regulation; Reporting; Role; Specimen; Testing; Therapeutic; Tissues; Xenograft Model; base; carcinogenesis; clinically significant; effective therapy; knock-down; novel; outcome forecast; overexpression; pancreatic cancer cells; prognostic value; protein expression; public health relevance; stem; therapeutic target; transcription factor

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命的疾病。尽管大多数关键的遗传和表观遗传学改变已经知道多年了，但迄今为止，这还没有导致有用的治疗剂。我们最重要的目标是确定 PDAC基因表达可用于开发有效的疗法。为此，我们最近一直集中在转录因子FOXM1上，PDAC在PDAC中大大增加了。为了理解这种升高表达的重要性，我们开发了用于过表达FOXM1的PDAC细胞系。这些细胞系均匀地表现出大大升高的生长和转移。在一种以恰当的方式中，我们降低了许多PDAC细胞中FOXM1的表达，并观察到这些细胞的侵略性降低。最近，我们发现人PDAC细胞几乎完全表达了一种称为FOXM1C的FOXM1的剪接形式，在正常组织中未观察到。根据我们的初步研究，我们假设在PDAC癌变期间，miRNA表达失调会导致FOXM1的过度表达，并且其下游靶基因的表达失调是侵袭和转移的关键，从而导致PDAC细胞的恶性增强并导致PDAC的恶性增强。患者。因此，FOXM1是PDAC中的恶性生物标志物和治疗靶标。为了检验我们的假设，我们提出以下三个特定目标。目标＃1。研究胰腺癌中FOXM1表达失调的分子机制。 PDAC中FOXM1的过表达已很好地确定，而潜在的机制尚不清楚。我们最近利用了一种基于计算机的算法来筛选可能的microRNA，该算法靶向FOXM1（在正常胰腺与胰腺癌中miRNA表达的硅分析和微阵列分析），并暂时鉴定了3个与FOXM1相关的MicroRNA。有趣的是，这三者在胰腺癌中均下调。我们预计这些microRNA因果关系会调节FOXM1表达和功能，并表现出预后值。目标＃2。确定FOXM1表达在胰腺癌侵袭和转移中的调节作用。已知人类胰腺癌细胞过表达UPAR，其表达水平与FOXM1直接相关。 UPAR的表达改变会调节胰腺癌的侵袭和转移。因此，我们希望确定UPAR是否是FOXM1的新型重要下游目标和功能介体。我们预计FOXM1同工型调节UPAR在胰腺癌细胞中的表达和功能，而这种新型途径对于胰腺癌的侵袭和转移至关重要。目标＃3。确定人类胰腺癌侵袭和转移中FOXM1同工型的临床意义。 FOXM1由3种同工型组成：FOXM1A，FOXM1B和FOXM1C，最近，另外两个同工型被鉴定出来，并始终命名为FoxM1B1和FoxM1B2。这些同工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，并且这种形式具有独特的特性。我们预计FOXM1C形式与FOXM1的不同同工型的表达尤其改变，包括FOXM1B1和FOXM1B2对FOXM1B，直接影响胰腺癌的生长和转移。

项目成果

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: Journal of the National Cancer Institute
• 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