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疾病。虽然大多数关键的遗传和表观遗传改变多年来已为人所知，但迄今为止尚未产生有用的治疗方法。我们最重要的目标是识别变化 PDAC 基因表达可用于开发有效的疗法。为此，我们最近一直关注转录因子 FoxM1，它在 PDAC 中急剧增加。为了了解这种升高表达的重要性，我们开发了经过基因工程改造的 PDAC 细胞系，以过度表达 FoxM1。这些细胞系均表现出显着升高的生长和转移。在一种互补的方法中，我们减少了许多 PDAC 细胞中 FoxM1 的表达，并观察到这些细胞的攻击性减少。最近，我们发现人类 PDAC 细胞几乎只表达 FoxM1 的一种剪接形式，称为 FoxM1C，而在正常组织中未观察到这种剪接形式。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过度表达及其下游侵袭和转移关键靶基因的表达失调，导致PDAC细胞恶性潜能增强，导致PDAC预后不良患者。因此，FoxM1 是 PDAC 的恶性生物标志物和治疗靶点。为了检验我们的假设，我们提出以下三个具体目标。目标#1。研究胰腺癌中 FoxM1 表达失调的分子机制。 FoxM1 在 PDAC 中的过度表达已得到充分证实，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可能靶向 FoxM1 的 microRNA（包括正常胰腺与胰腺癌中 miRNA 表达的计算机分析和微阵列分析），并初步鉴定出 3 个与 FoxM1 相关的 microRNA。有趣的是，这三种蛋白在胰腺癌中均下调。我们期望这些 microRNA 因果性地调节 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。已知人类胰腺癌细胞过度表达 uPAR，其表达水平与 FoxM1 的表达水平直接相关。 uPAR 表达的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。我们预计 FoxM1 亚型调节胰腺癌细胞中 uPAR 的表达和功能，这一新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 个亚型组成：FoxM1A、FoxM1B 和 FoxM1C，最近又鉴定出另外两个亚型，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，并且这种形式具有独特的特性。我们预计 FoxM1C 形式与特别侵袭性的疾病相关，并且 FoxM1 不同亚型（包括 FoxM1B1 和 FoxM1B2 至 FoxM1B）的表达改变，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。

• 发表时间: 2018
• 作者: Yang, Yibing;Gao, Xinya;Zhang, Maolei;Yan, Sheng;Sun, Chengjun;Xiao, Feizhe;Huang, Nunu;Yang, Xuesong;Zhao, Kun;Zhou, Huangkai;Huang, Suyun;Xie, Bo;Zhang, Nu
• 通讯作者: Zhang, Nu